BE677227A - - Google Patents

Description

  

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 EMI1.1
 



  "Antiandrogenic compositions"
 EMI1.2
 r10r1té of three patent applications filed in the United States of America on March 2, g65 under No. 4,6671 in the name of James
 EMI1.3
 ? -rancio KERWIN;
 EMI1.4
 May 3, 965 Mud the N 452-878. in the names of Louis Riehsrd IARE, Kennath Gearge HO? aT7EN st Joseph Ronald VAIENTA; on August 6, 96 under the N 477.949 to the Kenneth number
 EMI1.5
 George HOLDEN,
 EMI1.6
 is :: \: / useful that Four requests of 1 ... 19 were filed with the State8-TJnis of America on March 10, 1964 under es N 35o.6i2, 350.642p 350.671 and 350-641, all four to the notices of Louis Richard 1A.EE, Kenneth George HOThN E3t Joseph Ronr d VALENT !.

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 EMI2.1
 



  This intention relates to
 EMI2.2
 derivative of Bnortestoet6rone possessing
 EMI2.3
 depressive on the central nervous system as well as
 EMI2.4
 anti-azidrogenic activity. In particular, the present invention relates to cyclopentenyl ethers and tetrahydropyranyl ethers of B-nortestosterone #
 EMI2.5
 optionally substituted with a 4-halo group; Has
 EMI2.6
 B-nortestolo; 1onee and 19-nor-B "nortestololaotone; 11-hydroxy-B-nortestosteronest to 2-alkyl-B-nortestosterones and to 6-halo and 6-hydroxy-B-nortestos- téxones ; thus WHO to analogues 49 (il) and to 14 of these.
 EMI2.7
 



  The compounds according to the present invention are represented by the following structural formulas:
 EMI2.8
 
 EMI2.9
 where X is H, 01 or'Br; and R is a 1-cyclopentenyl, 1-cyclohexenyl or 2-tetrahydropyranyl radical;

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 EMI3.1
 
 EMI3.2
 where R is H or OH3; and the A1 analog of the compound wherein R is OH3;
 EMI3.3
 
 EMI3.4
 wherein R2 is H, CH3 or a2H5; is Kt the acyl radical of a carboxylic acid or when R 2 is H, Rx can be 1-oyolopentenyl # 1-cyolohex4nyl or 2-tetrahydropyranYl R4 is H, 01, Br or OH; L 5 H or
 EMI3.5
 R is / a lower alkyl group containing
 EMI3.6
 up to 4 carbon atoms;
 EMI3.7
 .

   R6 is H or OH
 EMI3.8
 and analogs A9 (1 ') and A14 of this compound, where B4t R5 and R are H; with the condition that one of lubutituanta B4, R and Ha must be '' other than H, except in an analogous to 9 (il) or A14.

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 EMI4.1
 



  Also part of the present invention is 17-methyl-Al-B-nortestosterone. Lees composed of formula I wherein R is 1-cyolopentenyl or 1-cyclohexenyl are prepared.
 EMI4.2
 res by heating the appropriate 17P-hydroxy-B-norsteroid with a diethyl or dimethyl ketal of cyclopentanone or cyolohexanone at a temperature of about 13p.-180 $ C for a period ranging from 30 minutes to 3 hours.



  The matter is slowly distilled; volatile, so as to cause the reaction to end. You can also use
 EMI4.3
 an oddly high boiling solvent, such as benzene, along with an acid catalyst. Alternatively, the 1 hour oxy-naretexode can be heated with reflux with the ketal in a low boiling solvent, such as chloroform, in the presence of a catalyst.
 EMI4.4
 acidic sor such as p-tolueneaultonic acid. The 1? - ('1-a7 koxycycloallocyj intermediate thus obtained is then melted at 190-200 C in the presence of a small amount of an organic base, such as quinoline or pyridine, so as to form the cycloalkenyloxy derivative. of formula I.



   The compounds of formula I in which R is a 2-tetrahydropyranyl group are prepared by treating the alcohol at position 17 with dihydropyran in the presence
 EMI4.5
 an acid catalyst, such as p-toluenesulfonic acid.



  The starting Bnarteetoeterone is described in
 EMI4.6
 the work "Chemistry and Industry, 1 t" 8, 1665 ".



   The compounds of formula II are prepared by miorobiological or chemical methods or by a combination of these two methods. B-nortestololaotone (II, R1 = CH,) is prepared by a microbiological process.

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  ¯1-B-nortestololactone is prepared from B-nortes-tololaotone by chemical or microbiological means.



  19-nor-B-nortestololactone (II, R = -H) is prepared by a chemical process.



   B-norteetololactone is obtained by subjecting B-norprogesterone to the action of enzymes from Penicillium oitrinum ATCC 16040. After fermentation, filtration and extraction, the residual solid which is a mixture of B -nortestololactone and open chain intermediate B-norteatolic (IV) acid, is refluxed in a base in order to obtain the complete transformation into B-nortestolic acid of the formula:

   
 EMI5.1
 Treatment of the intermediate with a strong acid such as perchloric acid gives rise to ring closure so as to obtain B-norteetololaotone. The introduction of the double bond is effected by subjecting B-nortestololactone to the action of enzymes from Arthrobaoter simplex ATCC 6946 or Protaminobacter ruber ATCC 8457.



   Compound ¯1 is also prepared by treating B-nortestololactone with 2,3-dichloro-5,6-dioyanobenzoquinone.



   19-nor-B-nortestololactone is prepared by the chemical process illustrated and described below:

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 EMI6.1
 
 EMI6.2
 3p <15-diacetoxy-5P'-hydroxy-17-oxo-B-norandroBtane-6-caarboxylic acid 5,6-lactone (V) is oxidized to dilactone VI using peraoetic acid . The dilao-
 EMI6.3
 ton is heated to a temperature above its melting point, so as to achieve its decarboxylation An

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 compound VII. Basic hydrolysis with, for example, sodium hydroxide makes it possible to obtain trihydroxy secocarboxylic acid VIII.



   Acidification with a strong acid, such as perchloric acid, reforms lactone IX. The 3-hydroxy group is oxidized to a ketone group by the process
 EMI7.1
 of Oppenauer, using oyclohexanone and aluminum iaopropoxy- de, the carbon atom in position 19 bearing a hydroxy group is oxidized to a carboxyl-acid group.
 EMI7.2
 than with Jona's reagent (chromium trioxide and sulfuric acid in acetone} and this carboxyl group is removed by heating the acid to reflux with Girard's reagent T in acetic acid and methanol.
 EMI7.3
 product thus obtained is 19-nor-B-nprteetololactone (XII).



  The starting B-norprogent6rone for the preparation of B. naxteatola3.actones is described in US Pat. No. 3,072,681. 3p, 19-Diaoetoxy.-5-hydroxy-1 acid 5,6 Lactone? The starting axoH-norandroetane-6p-carboxylic acid for the preparation of 19-nor-B-norteatololactone is prepared in the same manner. boasts: from 3 °, 19-acetoxyandrost - en-.1'î.-on L-J. Kalvoda et al., Helv. Chim. Acta, 46, 1361 t193) p7 and epoxidized with m-chloroperbenzoic acid. Chromic acid converts this compound into 35,19-diacetoxy.a-hydxoxyandrotane-6,17 - dione.

   The nucleus B is then opened by treatment with m-chloroperbenzoic acid so as to obtain 3,19-a: étcxy-5,17-dioxa, 6-secoardroa tan-6¯oTque, Ce compound is then dissolved in pyridine and treated with benzoyl chloride so as to obtain 5,6-laotone of 30919-diaodtoxy-50- acid

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 hydroxy-17-oxo-B-norandres ane-6ss-carboxylique.



   When using miccobiological methods, microorganisms first feel that they are cultivated in or on an environment favorable to their development.



   It is preferred to use liquid media for submerged fermentations. For P. citrinum mold, media such as malt extract broth, corn maceration liquor, soy flour broth, peanut flour broth or Czapek-Dox broth have all governed themselves to give complete satisfaction. For the aforementioned bacterial species, a simple nutrient broth, the trypticase-type broth
Soy (Baltimore Biolo? Ical Laboratories) or yeast extract broth gives the most satisfaction. The media should contain available mineral, nitrogen and carbon sources.



     Arbohydrates, such as starches, dextrins and sweat, including hexoaes and pentoses, can be used to supply the energy and carbon requirements of microorganisms. However, other carbon sources can also be used, for example, citric acid and its salts, sodium acetate or the sodium or potassium salts of other low molecular weight fatty acids or alcohols.



   As sources of nitrogen in assimilable form, there may be mentioned soluble or insoluble vegetable or animal proteins or protein derivatives, such as maize maceration liquor, soybean flour, peanut flour, casein. , meat extracts, peptones and yeast extract.

   Amino acids, ammonium salts or <nitrate $, can also be used for this purpose.

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The minerals naturally present in the aforementioned complex carbon and nitrogen scures are usually sufficient to meet the mineral requirements of microorganisms. If mineral deficient media are used, any of the following can be used. physiological mineral solutions commonly used to successfully overcome chemical deficiencies in the environment.



   A sterile air supply must be maintained during fermentation. This can be done by exposing a large area of the culture medium 4 to the atmosphere with constant agitation or by the use of submerged aeration devices. Aeration at a rate of about 0.5 to 2.0 volumes of air per volume of culture medium per minute gives satisfactory results.



   During fermentation, the temperature should be maintained between about 23 C to 32 C, preferably between about 25 C to 30 C.



   Optimal growth of microorganisms and transformation of steroid substrates are obtained when the pH of the fermentation is maintained at a value ranging from * 6.0 to 6.8. This can be achieved by the intermittent addition of mineral acids or bases in order to adjust the pH or by incorporating buffering agents into the fermentation medium. Buffering agents, such as calcium carbonate or potassium bi-acid phosphate, can be used.



   The steroid substrate to be transformed is added to the culture of the microorganism in the form of a finely divided solid or it is added in solution in a suitable solvent, such as ethanol, methanol or acetone.

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  Addition of the substrate steroid to the microbial culture should be done under aseptic conditions. Incubation and aeration of the culture continues in order to effect transformation of the substrate steroid. The steroid substrate can also be added to the fermentation medium when the medium is first inoculated with the culture of the microorganism.



   Fermentation or biotranformation continues until the maximum amount of product has accumulated. This usually takes place in about 24-48 hours and is most easily determined by periodic analysis of the fermentation system. This analysis can best be performed chromatographically and this product gives a rapid and reliable representation of the types and relative concentrations of the steroid compounds present. The Applicant has used both paper and thin layer chromatography techniques in order to perform the aforementioned analysis. The processes used as cited in the examples below are well known to those skilled in the art.



   When the transformation of the steroid has progressed to its optimum stage, the fermentation is complete and the steroid compounds, i.e. the untranted substrate and the products obtained by the transformation, are recovered. This is most commonly accomplished by extracting the aqueous fermentation broth with non-organic solvents which are not miscible with water. Chloroform, methylene chloride or methyl isobutyl ketone are most successfully used for this purpose.

   The entire fermentation broth, including microbial cells and aqueous supernatant liquid, can be extracted

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 However, the cell mass of the microorganism can first be separated from the aqueous supernatant liquid by entrification or filtration. In the latter case, the extraction of the steroid compounds from the microbial cell mass is carried out in the best way by a mixture of solvents, one of these being miscible with water and the other not being miscible. at the water. The Applicant has discovered that a mixture 1; 1 of methylene chloride and ethanol gives the most satisfaction.

   By extracting the cells and the aqueous supernatant broth separately, the formation of troublesome emulsions is often avoided,
The solvent extracts are combined and traces of residual water are removed by the use of suitable drying agents, such as anhydrous sodium sulfate. The dried solvent extract is then concentrated in vacuo to. To dryness at temperatures generally not exceeding 60 ° C. There is thus obtained a brownish residue which contains the steroid compounds of interest as well as many various solvent-extractable compounds produced by microbial metabolism.

   It is necessary to remove these contaminating materials in order to obtain the steroid compounds in the purified state,
In some cases where the desired steroid product is present in high concentration, the purification can be accomplished by direct crystallization with solvents.



   Mixtures of acetone and hexane are often used for this purpose.



   However, if a mixture of steroid products is obtained by the fermentation process or if a large amount of unconverted substrate steroid remains, more elaborate purification procedures must be used. The Applicant has used in the most satisfactory manner, column chromatography to carry out these purifications. The methods used are known to

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 specialists and find, generated by the gradual elution of steroids from a column of adsorbent material (such as silica or alumina) by mixtures of organic solvents.

   The presence of the separated steroid compounds in the solvent fractions obtained after the chromatography of these columns is most easily determined by ohromatographic analysis on paper or in thin layer samples of these fractions. The appropriate fractions containing the purified steroids are combined, concentrated in vacuo and the purified steroids are crystallized from suitable solvent mixtures.



   Formal III compounds in which R5 is a lower alkyl group are prepared by stirring the corresponding unsubstituted B-norsteroid in position 2a with ethyl oxalate at room temperature in the presence of a strongly basic catalyst, such as than sodium hydride in an inert solvent such as benzene, toluene, chloroform or ether. The resulting enolic 2-ethoxalyl compound is then dissolved in a solvent such as acetone or ethanol and heated for a period of about 6 to 50 hours with an alkyl halide in the presence of a weak base. such as potassium carbonate or sodium carbonate. The 2-alkyl-2-ethoxalyl ester thus produced is left to stand in an alcoholic solution of an alcoholate.

   Reverse oxalate condensation gives 2O-alkyl-B-norsterolde.



   The term "lower alkyl" as used to define the substituent at position 2 is intended to include alkyl groups having up to about 4 carbon atoms. Among the alkyl halides

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 which can therefore be used for the preparation of the compounds according to the present invention, there may be mentioned methyl iodide, ethyl iodide, propyl iodide and butyl bromide.



   Among the starting 2-unsubstituted steroids that can be used for the ethyl oxalate condensation and subsequent alkylation process are B-nortestosterone, 17Ó-methyl-B-nortestosterone, and 17Ó-ethyl. -B-nortestosterone. The preparation of this starting β-norsteroid is either described herein, or described in US Pat. No. 3,072,681, or further described in Coll. Czech. Cem. Comm. 25, 1086-90 (1960),
The term acyl radical of an arboxylic acid "is intended primarily to include acyl groups having up to about 6 carbon atoms, in particular, acetyl, propionyl, butyryl and valeryl.



   Compounds of formula III in which R is an acyl group are prepared by treating the corresponding 17ss-hydroxy compound with the appropriate aQyl anhydride or halide in the presence of a base such as pyridine. Compounds in which R3 is a 1-cyolopentenyl group,
1-oyclohexenyl or 2-tetrahydropyranyl are prepared by treating 17p-ol with cyclopentanone or cyclohexanone diethyl ketal or with dihydropyran in the presence of an acid catalyst such as P-toluenesulfonic acid.



   The Iberian configuration of the 2-alkyl group in the prepared compounds described herein is a rather than p believed. The compounds are, therefore, referred to as "2O-alkyl compounds". It is, however, obvious that the invention relates to compounds currently

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      obtained by the methods described herein, whatever configuration the substituent in position 2 may have.



   Compounds of formula III where R6 is a group
 EMI14.1
 OH are prepared by subjecting the 11-substituted D-n.orsteroid to the microbiological action of cells of a mold of the genus Trichoteoium (see US Pat.
 EMI14.2
 United States of America I 2,925-366 for examples of # pces) of the order Mhcoralee (see United States patent ± America 2,671,096 for species), or the sword Aepeil1l ocra- ceūs- ( see U.S. Patent No. 2,802,775).



  The preferred molds are Trichothec1uE ro-3f-ui, and Rhizopus arrhizus. The fermentations are carried out by the techniques described above.



  Ha-hydroxy-B-norsteroids are oxidized by chromic acid in a suitable solvent such as a mixture of acetone and chloroform at a temperature between about 0 and about 10 C to produce compounds 11- oxo. Reducing the 11-keto group of
 EMI14.3
 11.-Aeto-E - Norteatostexanes by lithium aluminum hydride gives a 3t 11, 1? -Trihydroxy-B. narar3rast = 4.aet which is oxidized in position 3 by 2i; -dichloro-5.6-d1-oyanobenzoquinone to 11.hydroxy-E-narteetostéxane.



   Compounds of formula III where R4 is chlorine, bromine or a hydroxy group, are prepared by methods
 EMI14.4
 mierobiologiquee and / or chemicals. 17āmethyl or ethy3.-E.mortestosterane (see US Pat. No. 3,072,681) is biotranaformed using organisms Trlchotnecium roseum, or preferably Rhizopus arrhizus, to compound 6a-hydroxy, to compound 6ss-hydroxy or both of these compounds to the liver.

   Each of the iso
 EMI14.5
 6-hydroxy mothers is treated with p-toluenewul- chloride

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 toluene
 EMI15.1
 fonyl or p-7ôlfonyl bromide in pyridine at room temperature to give the 6-halo derivative of opposite configuration,
The compounds of formula III having a double
 EMI15.2
 A9 bond (11) are prepared by forming the toeylate of an 11o {-hydroxy-B-norsteroid by treatment with p-toluenesulfonyl chloride in pyridine and then decomposing the tosylate in the presence of a base such as a mixture of lithium chloride and lithium carbonate in a solvent such as dimethyltormamide.

   The compound ¯9 (11) is thus obtained,
Compounds of formula III possessing a ë14 double bond are prepared by first subjecting an unsubstituted β-norateroid in position 15 to the action of whole cells of the oxygenating mold Aspergillus ochraceus to form a 15α-hydroxy derivative.



   The tosyl derivative is prepared by making
 EMI15.3
 Gir the 15α-hydroxy-B-norsteroid with p-toluene sulfonyl chloride (toeyl chloride) in excess pyridine at room temperature, usually until the next day. Sudden cooling separates the
 EMI15.4
 toaylate ester- 15α-Toeyloxy-.noratdroide is decomposed to form daired A'4 B-noret6roide by reaction with a base, such as a combination of lithium chloride and lithium carbonate, in a solvent such as
 EMI15.5
 dimethyltormamide or dimethylacetamide at reflux for several hours.



  17a-methyl¯A 1-B-nortestoctone is prepared by dehydrogenation with dee mioroorganiem # of the genus Septomyxa, such as Septomyxa aesculio Septomyxa oorni and in particular, Septomyxa affina.

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 EMI16.1
 



  Some of the B-noret6roide derivatives according to the present invention are best prepared using as starting materials 179-acYloxy-B-noretdrolde or 17α-lower alkyl17-hydroxy-B-norBtero! This% acylda derivatives are prepared by the common technique which consists in treating the alcohol with an anhydride 'or a
 EMI16.2
 Decyl halide in base - The acylation product can be hydrolyzed in a base, if delirious, using standard techniques *
When the materials *:

  ! Non-alkylated or unesterified 170-hydrojcy starting materials are used, some of the subsequent reactions may affect the 17ss-hydroxy groups in an undesirable manner. If this happens,
 EMI16.3
 we use rëaot. ' 'na habitual to regenerate this group.



   The compounds of the present invention are! use
 EMI16.4
 lized to decrease or eliminate Z - \.) ';' eponla androgen or the effects of androgens as well as to subdue the sys-
 EMI16.5
 The preferred compounds of the present invention are as follows 2 #, 17 # -dmethyl-B..norte8tost6rone, 'ther i-cyclopentenyl of 13-norteotoeterona, 17a-methyl-69 (11) - Br, ortesto4 'idrone, 11-hydroxy-'7a-methyl-B-nortstosterone, i7o-aiethyl-A B-nortestosterone 6a-chloro-17a-methyl-B-nortesto3terey, 6a-bromo'7 "-methylB-nortestoeterone and 6" Jhydroxy ... 1'1a ... methyl-D ... norta2 to.terone.

   These compounds provide potent antlaridrogenic activity in AT. oii the poucc1n to which they Mont administered orally, ouboutanuo and topically, in doses of 20 * 100 mg / kg. Mont island preferably, in the form of solutions or suspem: d.o.h13 dana oil of aésaae, but they can also be formulated in various dosage forms well

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 known to the pharmaceutical world.
 EMI17.1
 



  The following compounds: 17āmethyl¯A 11) -B .... nortestosteronep 11-hydroxy-17 # -methYl-B-norteBtoeteronet.



  '7-Methyl-A -B-nortestosterone, e-nortestololactone and iB-norteatololactone are also preferred compounds, distinguished by their activity as a central nervous system depressant. They are active in mice orally in doses of 100-200 mg / kg. They can be formulated: in the usual way,
The following examples illustrate the preparation of the compounds of the present invention without, however, limiting the latter,
EXAMPLE 1
 EMI17.2
 Ether 1-e c1o en 1i ue of B-nortestoaterone.



   A mixture of 5 g of B-norteatoaterone and 10 ml of cyclopentanone diethyl cetl is heated at 140-145 C for 45 minutes. The temperature is then brought to 160-170 C and the volatile material is slowly distilled over a period of about 2 hours. About 6 ml of distillate are collected. The reaction mixture is cooled, diluted with aqueous methanol containing several drops of pyridine and cooling continued. The solid is collected and recrystallized from methanol containing a small amount of pyridine to obtain the product indicated in the title, having a melting point of 114-116 C.



   EXAMPLE 2 B-nortestololactone
The inoculum is prepared as follows 50 ml of 0.5 glucose in maceration liquor

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 2% corn are sterilized in a 250 ml flask by autoclaving it for 15 minutes at a pressure of about 1.05 kg / cm2 and at a temperature of 121 C. Then introduced into this flask a vegetative culture (0.5 ml) of Penicillium oitrinum ATCC 16040 and system one is then incubated for 24 hours at 30 ° C. on a rotating shaker at 200 rpm.



   The fermentation medium is prepared as follows:
65 liters of 2.56 male maceration liquor with 0.5% dextrose are autoclaved at 125 C, under a pressure of about 1.40 kg / cm2 for about 30 nutea in a fermentation apparatus of the type "New
Brunswick Batch 130 liters.



     'The percentage of the inoculum is then introduced into the fermentation medium, the stirring speed is set at 200 rpm, the aeration speed is set at 0.5 VVM and the temperature is set. maintained at 30 C.



   Ucon oil is used as an anti-foaming agent.



   The fermentation medium is then Incubated for 6 to
24 hours.



   The fermentation medium is added to a solution of 65 g of B-norprogesterone in 500 ml of ethanol and the fermentation proceeds for about 16 hours after addition of the B-norprogesterone.



   The fermentation broth is then filtered through Supercel, the broth is then extracted with methylene chloride) and the filtered cells are extracted with a mixture of methylene chloride and ethanol. The solvents are evaporated off to give a solid residue.

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   The residue is dissolved in 800 ml of ethanol, treated with 100 ml of a 40% aqueous solution of sodium hydroxide and then refluxed under a nitrogen atmosphere for 3 hours. cooled solution is diluted with 3 liters of cold water and extracted with methylene chloride. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with ethylene chloride. Evaporation of this extract with dried methylene chloride gives B-nortestolic acid.



   This acid is dissolved in 300 ml of tetrahydro-
 EMI19.1
 furan containing 1 ml of 70 perchloric acid and then allowed to stand for 1 hour at room temperature. After dilution to 3 liters with cold water, the reaction mixture is extracted with methylene chloride and the methylene chloride extracts are washed with a 2% aqueous solution of sodium hydroxide.



  The dried methylene chloride extracts are filtered through 125 g of Woelm type alumina of activity III and the filtrate is evaporated so as to give B-nortes-tololactone which after crystallization from a mixture of acetone and d. 'hexane and then in a mixture of methanol-
 EMI19.2
 water melts at 150-15200, UV: i Xmax 240 mp 15.00).



  EXAMPLE 3 1-B-nortestololaatone B-nortestololaotone (4t35 g) is dissolved in 100 ml of dioxane and treated with 3t7 g of 2,3-diohloro- * 5,6.dicyanobenzoquinone. After heating under reflux at room temperature for 16 hours, the reaction mixture is filtered and the filtrate is evaporated so as to

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 EMI20.1
 crude¯ give B-norteetololactone /. brutlne further purification give A -B-norteatoJ.olactonw. Further purification is carried out by chromatography on alumina, followed by recrystallization from a mixture of acetone and hexane.



   EXAMPLE 4
 EMI20.2
 A 1 -Bnorteatololactone
1 ml of an Arthrobacter simplex ATCC 6946 culture broth is inoculated into 50 ml of sterile besillon of
 EMI20.3
 type 2rypticaaB Soy (Baltimore Biological laboratories, contained in a 250 ml flask and incubated for 24 hours at 25 C on a gyrorotating shaker device describing a circle of about 5 em at 200 rpm. The above culture is in turn used to inoculate 500 ml of the same medium in a 2 liter capacity way which was shaken for 24 hours at 25 ° C. This culture is used for the transformation process.
 EMI20.4
 



  1 g of 3.nortesta.olac .'r .: is dissolved in 10 ml of ethanol and added to the 24 hour culture. above under sterile conditions. Incubation of the culture containing the steroid is continued for a further 24 hours.



   The reaction is checked by taking samples.
 EMI20.5
 lons of 1 ml during the bifltrans'arnation and by extracting: these samples with 0.2 ml of methyl isobutyl ketone
 EMI20.6
 (MIBK). 5 microliters of the MIBK extract are spotted on silica gel G thin layer chromatography plates, which are then developed in ethyl acetate. The dried plates were thoroughly sprayed with sulfuric acid 40 in ethanol to detect the presence and relative concentrations of the steroid compounds.

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  The transformation is completed 24 hours later
 EMI21.1
 addition of etérolde to the culture and the bacterial cells are separated from the supernatant broth by centrifugation. The centrifugate is acidified to pH.
 EMI21.2
 about bzz with phosphoric acid and extracted twice with equal volumes of methylene chloride. The separated bacterial cells are extracted with 100 ml of a mixture of equal volumes of ethanol and methylene chloride. These extracts are combined, dried with anhydrous sodium sulfate and evaporated to dryness.



   The dried residue is dissolved in benzene and applied to an alumina column (Woelm grade III). To separate the product from the unconverted substrate steroid, the following set of eluting solvents is used; benzene, benzene / methylene chloride, methylene chloride and finally 1% methanol in methylene chloride.



  Fractions of 15 ml are collected during the process.
 EMI21.3
 From elution, 5 to 10 microliters: c "-a of each fraction are plotted in the form of spots on thin-layer chromatography plates of silica gel G for analysis.



   The fractions containing the product, namely the
 EMI21.4
 A1-B-nortestololaotonet are combined and evaporated so as to be brought to dryness under vacuum. The purified product is crystallized from a mixture of acetone and hexane and pos-
 EMI21.5
 of a melting point of T6-hBC G.



  EXAMPLE 5 19-norB-nortestolole.etone To a solution of 43 <6 g of 30,19-diacdtoxyandrost-5-on-17-one "see J. Kalvoda et al., Helv. Chim.

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  Acta., 46, 1361 (1963) 7 in 300 ml of chloroform are added 25.8 g of m-chloroperbenzoic acid in 150 ml of chloroform. The addition is carried out while stirring so that the temperature of the reaction mixture is maintained at 25-30 ° C. As soon as the addition is complete, the reaction mixture is left to stand for 3 hours and is then washed with an aqueous solution of sodium sulfite and then with an aqueous solution of sodium carbonate. Drying and evaporation of the chloroform phase gives a residue which is crystallized from a mixture of acetone and hexane to give 3ss, 19-diacetoxy-5,6-epoxyandrostan-17-one, PF 128. -129 C.



   To a stirred solution of 3ss-19-diacetoxy-5,6-epoxyandrostan017-one (42 g) in 1200 ml of methyl ethyl ketone is added aqueous chromic acid (50 g of chromium trioxide in 100 ml of water ) at a rate such that the temperature of the reaction mixture does not exceed 40 C.



  As soon as the addition is complete, the reaction mixture is maintained at 40 ° C. for 1 hour and it is then poured into 2500 ml of water. Extraction with methylene chloride followed by drying and evaporation of the organic extracts gives crude 38,19-diacetoxy-5Ó-hydroxy-androstan -6,17-dione which can be used in the next step without purification.



   To a solution of 42 g of the crude dione in 200 ml of chloroform is added 50 g of m-chloroperbenzoic acid in 350 ml of chloroform. The addition is carried out slowly and while stirring so that the reaction temperature does not exceed 30 C. After stirring at room temperature for 24 hours, the reaction mixture is washed with a 10% aqueous solution of sodium sulfite (500 ml) and then with a 5% aqueous solution of

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 sodium bicarbonate (700 ml).

   The sodium bicarbonate phase is acidified with phosphoric acid and extracted with chloroform to give, after drying and evaporation of the chloroform, a mixture of m-chlo- acid.
 EMI23.1
 robenzotque and 3Pt19-diaodtoxy-5,17-dioxo-5,6-seco-androetan-6-oic acid.



   The above mixture is dissolved in 150 ml of pyridine and treated with 50 ml of benzoyl chloride while cooling it. After standing for 24 hours at room temperature, the reaction mixture is poured into 1500 ml of water and extracted with methylene chloride.



  After washing with phosphoric acid in cold aqueous solution and sodium carbonate solutions, the methylene chloride extracts are combined, dried and evaporated. The residue is crystallized from ether
 EMI23.2
 to give 3S, 19-.diaeetoxy .. 5-hydroxy-17-oxo-B-norandrostane-6-carboxylic acid 5,6-lactone having a melting point of 170 0.



   Has a solution of 5.0 g of 5,6-lactone acid
 EMI23.3
   6-Q-carbnxyllque 3P, 19-diacetoxy¯5p¯hydroxy-i7-oxōB - norandrostan / in 5 ml of glacial acetic acid containing 0.5 g of p-toluenesulphonic acid, 5, 0 ml of peracetic acid in 20 ml of glacial acetic acid. The solution is kept at room temperature in the dark for 24 hours and is then poured into 300 ml of ice water. The precipitate is collected by filtration and is purified by recrystallization from a mixture of acetone and hexane to give the
 EMI23.4
 5,6-.13,1'diaotane of the acid, 1g-.diaadtoxy.-5r laadihy. droxy..nor h3, 1? eeooandrostane 65, 1? .sâi.car.boxyl.que.



   The dilaotone (23.2 g) is heated to a temperature above its melting point under atmosphere.

 <Desc / Clms Page number 24>

 nitrogen for 15 minutes, cooled and recrystallized from a mixture of acetone and hexane to give 13,17-
 EMI24.1
 3Pt19 * -diacetoxy-13'x-'hydroxy-B-nor-'13t17- '6ecoandrost-5-en-17-oic acid lactone.



   A solution of 18.5 g of the lactone in 250 ml of ethanol is heated under reflux with 20 ml of a 40% aqueous solution of sodium hydroxide for 3 hours under a nitrogen atmosphere. The cooled reaction mixture is diluted with 1.51 water, adjusted to pH 3 with phosphoric acid and extracted with methylene chloride. The
 EMI24.2
 methylfeu chloride extracts combined and dried are evaporated under reduced pressure to give 3, 13a, 1-trihydroxy acid. Bnor- 3, * 7 '<V coandroat-5-en-17-oIque.



   A solution of 14.3 g of the acid in 100 ml of tetrahydrofuran containing 0.5 ml of perchloric acid la
 EMI24.3
 at 70% is kept at room temperature for 1 hour.



  The solution is diluted with 500 µl! of cold water and the precipitate of 3,17-lactone of 3,13a, 19-trihydroxy-B-nor-13,17-seooardr.ostw5e. *. z-17oque acid is collected by filtration and purified by recriatallization in a mixture of acetone and hexane.



   A mixture of 12.1 g of the lactone, 60 ml of cyclohexanone and 200 ml of toluene is slowly distilled until about 10 ml of the distillate is collected.



  Then 3.0 g of aluminum isopropoxide is added and the distillation is continued until 140 ml of distillate is collected. The cooled reaction mixture is poured into 300 ml of cold dilute hydrochloric acid and extracted with benzene. Benzene extracts
 EMI24.4
 rI ;, A..J.8 are distilled by steam until the distillate is clear. The cooled non-volatile fraction is extracted with methylene chloride. After drying and

 <Desc / Clms Page number 25>

 evaporation of the extracts with methylene chloride, the re-
 EMI25.1
 sidu of, 19¯kydroxy¯B-nort isololactone is purified by crystallization from a mixture of acetone and hexane.



   To a solution of 8.7 g of the lactone in 160 ml of acetone, 24 ml of Jones reagent (chromium trioxide and sulfuric acid in acetone) is added for 20 minutes at 5 C. After an additional 15 minutes at 5 ° C. C. the reaction mixture is poured into 1 liter of ice-water and is extracted with methylene chloride. The methylene chloride extracts are extracted with a 5% sodium carbonate solution (5 x 100 ml). The combined sodium carbonate solutions are adjusted to pH 3 with phosphoric acid and are extracted with methylene chloride. Evaporation of the chloride extracts
 EMI25.2
 methylene gives B-norteetolactone19-oIic acid.



   A solution of 7.1 g of the acid and 13.5 g of Girard's T reagent in 160 ml of acetic acid and 300 ml of methanol is heated at reflux for 2 hours.



  The cooled solution is treated with 17.8 g of sodium carbonate in 2.5 liters of water and the solution is then extracted with methylene chloride. The aqueous layer is acidified to pH 1 with hydrochloric acid and left to stand at room temperature for 2 hours. Extraction with methylene chloride gives, after drying and evaporation of the extracts, 19-nor-B-nortestololactone which is crystallized from a mixture of acetone and hexane.



   EXAMPLE 6
 EMI25.3
 2a, 17a-dimethyl .-. B-nortestoaterone A mixture of 12.0 g (0.042 mole) of 17a-methyl-B-nortestosterone and 6.8 g of sodium hydride (suspension

 <Desc / Clms Page number 26>

 53% in mineral oil), and 12 ml of ethyl oxalate in 300 ml of anhydrous thiophene-free benzene is stirred for 4 hours. The mixture is filtered, the filter cake being washed vigorously with benzene and hexane. The filter cake is dried in vacuo and then added in portions to an ice-cold solution of 40 ml of 35% hydrochloric acid in 500 ml of water.

   The mixture is extracted with methylene chloride and the combined organic extracts are washed, dried and evaporated in vacuo, so as to give the enol of 2-ethoxalyl-17a-methyl-B-nortestosterone, m.p. 151-
152 C.



   The above 2-ethoxalyl compound is dissolved in 400 ml of eletone and the solution is treated with 37.5 ml of methyl iodide and 12.5 g of anhydrous potassium carbonate. The mixture is heated at moderate reflux for 12 hours, after which a further 20 ml of methyl iodide is added and heating at reflux is continued for
36 more hours. The reaction mixture is filtered and the filtrate is concentrated in vacuo almost to dryness *
Dilution with water gives an oil which is extracted with methylene chloride.

   The organic extracts are washed with 1% sodium hydroxide and with water, dried and evaporated in vacuo to give 2-methyl-2- 'ethoxyalyl-17Ó-methyl-B-nortestosterone as d. 'an oil.



   The oil is treated with a solution of 1 g of metallic sodium in 100 ml of absolute alcohol and it is then left to stand at room temperature for more than 48 hours This solution is then diluted with
10 volumes of water and the precipitate thus obtained is extracted with methylene chloride. Organic extracts

 <Desc / Clms Page number 27>

 are washed, dried and evaporated. The residue is chromatographed on 200 g of alumina (aotivity III), the elution being carried out with 500 ml of benzene filters.



  The material obtained by the evaporation of the first three fractions is rechromatographed, the elution taking place with a mixture of benzene and petroleum ether (1 1).



  Fractions N 4 to 7 from the rechromatography are combined in aqueous and recrystallized from methanol so as to
 EMI27.1
 give 2a, 1? a-dimethyl-B-nortestosterone.



  EXAMPLE 76a and 6-hydroxy-17a-methyl-B-norte8toBterone and a-hydroxy-17a-meth, yl-B-nortestosterone.



   The fermentation medium consists of 10 liters of 2% corn maceration liquor adjusted to pH 6.5 with sodium hydroxide, which has been autoclaved under a pressure of approximately 1.05 kg. / om 2 at 121 C. Fermentation is carried out in stirring vessels with a water bath temperature of 28-30 C at an aeration speed of 3 liters of air per minute per 10 liters of medium. The speed of the agitator is 200 rpm.

   The inoculum is prepared using Rhizopus arrhizus ATCC 11145 by standard methods. 5 g of
 EMI27.2
 1?-MéthyZ-.B-nortestosterare in 50 ml of ethanol at 95 are added to the medium below its surface after a growth of 48 hours: 1 g after 48 hours, 2 g after
55 hours, 1 g after 72 hours and 1 g after 78 hours.



  The fermentation is completed 24 hours after the addition of the last substrate.

 <Desc / Clms Page number 28>

 



   The solids are removed by centrifugation.



  The effluent broth is further clarified by! filtration.



  The collected material is washed with one liter of ethanol which is added to the aqueous phase.



   The aqueous broth is extracted exhaustively with methylene chloride. The dried organic extract is evaporated under vacuum at 50 ° C. The residue is taken up in benzene and is passed through a column of neutral alumina (Woelm, III). Elution with increasing amounts of methylene chloride to pure methylene chloride to methanol in methylene chloride
 EMI28.1
 gives the following products: 6hydroxy-.17a-methyl.-B-nortestosterone, P.I. 196-199OCe 6a-hydroxy¯17, a-methyl-B-nortestoeterone, P, '. 204-201 C, and 11α-hydroxy-i7cc-methyl-B-nortestosterone, P.P, 202-205 * 0.



  EXAMPLE @ 8
 EMI28.2
 ####! # wiirwiwuii #i> liwf <c *> 11a-hydroxy and 1 a - h drox -1? a-meth 1-H-nortestoeterone
A fermentation medium is prepared using 20 g of enzymatic digest of edamine, lactalbumin (Sheffield Co.), 50 g of commercial dextrose (cerelose), 5 g of corn maceration liquor.
 EMI28.3
 and water to Ioxmer 1 liter, 10 liters of this medium are adjusted to pH 6.3-6.5 with sodium hydroxide and then autoclaved for 1 hour and a half
 EMI28.4
 at 12190 exert a pressure of about 1,

  05 kg / cm * The fermentation is carried out as described above with an aeration speed of 5 liters of air per minute per 10 liters and at a stirrer speed of 200 rpm.
 EMI28.5
 The medium is inoculated with triohotheoium roseum ATCC 12543, prepared and is fermented for 48 hours. The

 <Desc / Clms Page number 29>

 cells of 10 liters of medium are collected by centrifugation, washed with distilled water and suspended in 10 liters of 0.1 M trishydroxhmethylamino methane buffer (pH 9.0), then reintroduced in a stirred container. A sterile concentrated glucose solution is added until a concentration of 0.5% is obtained.



   The aeration speed for the bioconversion is 4 liters of air per minute per 10 liters of buffered suspension at 250 rpm. A solution of 17a-methyl-B-nortestosterone in 95 ethanol (1 g / 10 ml) is added as follows: 2.5 g at once, 2.5 / 10 liters after 18 hours, 2.5 g after 42 hours to a total of 52 g of substrate. Sterile glucose is added to maintain the concentration at 0.5%. Fermentation ends 65 hours after the last addition of substrate.



   After fermentation, the cells are separated.



  Separate extraction of cells and broth is carried out with methylene chloride as described in Example 7 to give a crude residue after evaporation. This product is treated with acetone at the boiling point.



   The insoluble material is separated and recrystallized from a mixture of chloroform and methanol to give 15 15-hydroxy-17 17-methyl-b-nortestosterone (21).



   The acetone-soluble fraction is evaporated and the residue is chromatographed on neutral alumina (Woelm, III), Elution with a mixture of benzene and methylene chloride gives 6Ó-hydroxy-17Ó-methyl - B-norteetosterone (4%). Elution with methylene chloride and a mixture of methylene chloride and methanol

 <Desc / Clms Page number 30>

 
 EMI30.1
 gives a solid which is purified by recrystallization from a mixture of acetone and hexane to give Ilot-hydroxy-17a-methyl-B-nortestosterone, mp 202-205 * 0.



  EXAMPLE 9 ¯-hydroxy-17a-methyl-B-norteatoeterone A a solution of 4.0 g of 11 ¯hydroxy-17a-methyl-B-nortestosterone in a mixture of acetone (75 ml) and chloroform (25 ml) ) 6.8 ml of normal chromic acid (26.72 g of chromium trioxide, 23 ml of aci-
 EMI30.2
 sulphide) and water up to 100 ml). The addition is made over a minute, while the reaction mixture is stirred and maintained at 0 ° C.
 EMI30.3
 tion is pulivized for two more minutes after the addition. The reaction mixture is then poured into cold water and is extracted three times with methylene chloride.

   Evaporation of the combined and dried extracts gives a crude product which is purified by crystallization from. a mixture of acetone and hexane.
 EMI30.4
 



  The pure product melts at 16 ° --165 C after sublimation and is 11-xo-17e-methyl-.D-nortestoeterone.
To the mixture, stirred with 1.25 g of lithium aluminum hydride and 50 ml of ether, one. add a solution of
 EMI30.5
 2.5 g of 11-oxa-1amethyl-B.-nortestoaterone in 20 ml of tetrahydrofuran.



   The addition is carried out dropwise at 0 under a nitrogen atmosphere. The reaction mixture is allowed to warm to room temperature and is then heated under reflux for 2 hours. After cooling to 0 ° C., the reaction mixture is treated carefully with 5 ml of water with rapid stirring. The

 <Desc / Clms Page number 31>

 The white precipitate formed is separated by filtration and the filtrate is vaporized to dryness. the residue cris-
 EMI31.1
 tallin which is a, 11, 1 '. v, Rihydroxy. 1 Crude Tamethy..P rorandoet4e4; 1 is used in the following reaction without further purification.



     The.;, 65 g of crude triol are dissolved in 25 ml of dioxane and treated with a solution of 2.27 g
 EMI31.2
 of 2,3.-diahlao-5,6-dicyanobenzaquinone in 25 ml of dioxanpc After standing for 18 hours at 250, the reaction mixture is evaporated to softness. The residue is dissolved in ohloroform-metlanol (9 1) and poured into a column of 60 g of Woelm type alumina with aotivity III. The filtrate is evaporated to dryness and recrystallized from a mixture of acetone and methanpl to give
 EMI31.3
 11S-hydroxy - 17a - mdthyl.B-nortestoateronc, P.F. 253-258 C.



  EXAMPLE 10 17α-Meth-A -B-nortestoeterone To a solution of 0.70 g of 11α-hydroxy-17a methyl-B-nortestosterone in 10 ml of pyridine is added 0.70 g of p-toluenesulfonyl chloride in 5 ml. of pyridine. After standing for 18 hours at 25 ° C., the reaction mixture is poured into water and extracted three times with methylene chloride, the organic extracts washed with cold dilute phosphoric acid.



  Evaporation of the combined and dried extracts gives a crude
 EMI31.4
 etosylate7qûi is purified by crystallization from a mixture of acetone and hexane. The purified product is 11o-tusyloxy. 17a-.methyl $ .noxtestaatdxons, P.1. 185-
186 C.



   A mixture of 0.30 g of tosylate, 0.3 g of anhydrous lithium chloride and 0.3 g of sodium carbonate

 <Desc / Clms Page number 32>

 
 EMI32.1
 lithium in OueqPe2-LIQU in 5 ml of dimeth; Ylformam: 1.de is heated to reflux. under a nitrogen atmosphere while stirring for 2 hours. The cooled reaction mixture is poured into dilute sodium carbonate solution and is extracted with benzene. Drying and evaporation
 EMI32.2
 benépqu'r6uniB extracts give a crude product which after crystallization from a mixture of acetone and hexane and sublimation melts at 18? -. 18 C and is A911- 17a-methyl-B-.nortestosté.-one ..



  EXAMPLE 11
 EMI32.3
 ..., ....... 6 - chlôro-.1? A-méthl-B- nortestoe +, drone A solution of., 5 I, 6a-hydroxy-.17e-methyl'- B- nortestosterone and ', 1.12 g of p-toluenesulfonyl chloride in 10 ml of pyridine is left to stand at room temperature for 72 hours * The reaction mixture is poured into water and is extracted with chloride of methylene, The organic extracts are combined, washed with dilute phosphoric acid, dried and evaporated, so as to give a residue which is purified by ohromatography on 60 g of alumina (Woelm, III) with benzene serving as solvent * , development in a
 EMI32.4
 to obtain 6p¯chloro-i7āmethyl B¯norte8tosterone, P. '. 2? -. 129.



  The 6a isomer. ehloro is prepared analogously using a 6p-hydroxy isomer as a starting material. Other 6-halo analogs can be prepared by using the corresponding tosyl halide such as toayl bromide or by adding an excess of the particular sodium or potassium halide to the reaction mixture.

 <Desc / Clms Page number 33>

 



  EXAMPLE 12
 EMI33.1
 17oc-methyl'-A -B-nortestosterone '#
A fermentation medium consisting of 10 liters of corn maceration liquor, adjusted to pH 6.3-6.5 with sodium hydroxide solution, is autoclaved for 2 hours at a pressure of 1.05 kg. / cm2 at a temperature of 121 C. The medium is inoculated with a normal preparation of Septomyxa affinis NRRL 2746. The fomentation is allowed to continue for 48 hours with aeration of 3 liters of air per minute per 10 liters and a speed of 'agitator of 200 rpm.
 EMI33.2
 



  5 g of 11a-methyl-B-norteatoaterone are dissolved! in 50 ml of 95% ethanol and are added below the surface of the medium: 1 g after 48 hours, 2 g after 55 hours, 1 g after 72 hours and 1 g after 78 hours.



   As soon as the transformation is complete, the melan. Ge is centrifuged. The solids are recovered and extracted with ethanol and then with a mixture of ethanol and methylene chloride. The extracts are filtered and added to the clarified broth which is exhaustively extracted with methylene chloride. After drying, the extracts are evaporated under vacuum at 50 ° C.



   The residue is taken up in a mixture of ether and petroleum and benzene / chromatographed on alumina (Woelm, III), The fractions eluded with benzene-petroleum ether (1: 1) through benzene- methylene chloride (1: 1) are combined and evaporated.

   The solid residue is recrystallized from acetone-hexane to give
 EMI33.3
 of 1..17a-methyl-B - norteatosterone (48 ad), P.P. 140-141 C after sublimation.

 <Desc / Clms Page number 34>

 
 EMI34.1
 EXAMPLE EXAMPLE 1 15a.h drox -.17a.méth 1-B-no estosterone The fermentation medium consists of 20 g
 EMI34.2
 a commercial lactalbumin digestion product, enzymatic (examine, hfiela.Co, 50 g of commercial dextrose (cerelose, Corn Products), 5 g of corn maceration liquor and water to make 1 liter * 10 liters of this medium are prepared, adjusted to pH 6.3-6.5
 EMI34.3
 with sodium hydride solution and autoclaved for 1.5 hours at 4112 C at a pressure of 1.05 kg / cm 2.



     -The fermentation reaction is carried out in stirring vessels of one liter of sets of fermenta-
 EMI34.4
 tion of type N: ", ¯Erunawick with a water bath temperature of 28-30 C with an aeration speed of one liter of air per minute per liter stirred at a stirrer speed of 200 rpm , a usual defoamer being added.



   The inoculum is prepared using 100 ml of the medium in 500 ml Erlenmeyer flasks on a rotary shaker at 200 rpm, at room temperature, using Aspergillus ochraceus ATCC 12337. 200 ml of inoculum is used to '10 liters of fermentation.
 EMI34.5
 A substrate solution of 17α-methyl-B-nortes-tosterone in 95% ethanol, at a rate of 1 g per 16 ml, is prepared. After 48 hours growth, the substrate solution containing 1 g of substrate is pumped below the surface of the liquid medium at 4 hour intervals until 10 g of substrate is used.

   Product formation is periodically monitored using thin layer chromatography with. an ethyl acetate solvent system. The fermentation is completed 6 hours after the addition of the last substrate.

 <Desc / Clms Page number 35>

 



   The cells are separated by filtration through musline and are then extracted with a 1: 1 mixture of 95% ethanol and methylene chloride. After filtration, the extracts are combined with the clarified broth which is then extracted with methylene chloride. The dried organic extracts are evaporated to dryness under vacuum at 50 ° C.



   Crystallization of the residue from a mixture of methylene chloride and methanol gives 57% 15a-
 EMI35.1
 hydroxy-17a-methyl-B-nortestosterone, P.F. 243-249 C.



  Recrystallization from acetone of the residue of the mother liquors gives a minor amount of na-hydroxy-17a-methyl-B-nortestosterone.



   EXAMPLE 14
 EMI35.2
 1ia-methyl.- 14-B-nortestosterone A solution of 8.22 g of 15a.-hydroxy 1? A-methyl-B-nortestosterone in 70 ml of pyridine is mixed with 6.76 g of p-toluenesulfonyl chloride. After standing for 18 hours at room temperature, the mixture is poured into 500 ml of ice water. The precipitate which forms is collected by filtration to give, after reoristallization in a mixture of acetone and hexane, 15α-tosyl-.
 EMI35.3
 oxy-17K-methyl-B-nortestosterone, P. '. 90-9300. A mixture of 5 g of 15α-tooyloxy 17o-methyl-B-nortestosterone, 1.5 g of anhydrous lithium chloride, 1.5 g of lithium carbonate and 50 ml of N, N-dimethylformamide is heated to reflux under a nitrogen atmosphere for 3 hours. The mixture is poured into water.



   Extraction with benzene gives, after recrystallization
 EMI35.4
 in a mixture of acetone and hexane of A 14- 17a-methylH.-nortestasterone, PP ', 160-16800,

 

Claims (1)

CLAIMS 1.- Compound corresponding to one of the following structural formulas t EMI36.1 wherein X is H, 01 or Br and R is a 1-oyolopentenyl, 1-cyclohexenyl or 2-tetrahydropyranyl radical; EMI36.2 in which R 'is H or OH, and the analogue ¯1 of the compound in which R1 is CH3 EMI36.3 where R2 is H, OH, or C2H5 R3 is H, the acyl radical of an arboxylic acid or when R2 is H, R3 may be 1-oyolopentenyl, 1-oyolohexenyl <Desc / Clms Page number 37> EMI37.1 or 2-tetrahydiopyranyl j R4 eet. H, Cl, Br- or OH; R5 is a lower alkyl group ocontaining up to 4 carbon atoms; or H. R6 is H or OH; ' EMI37.2 and analogues 9 (.1 ') and A14 of these compounds., where R4 ,. R5 and R6 are H; with the proviso that one of the substituents R4, R5 and R6 must be other than H, except in an analogue ¯9 (11) or ¯14. 2.- Compound of formula EMI37.3 where X is H, C1 or Br; and R is a radical EMI37.4 1-CYCloPentenyl or 2-tetrahydropyranyl. 3.- Compound of formula EMI37.5 wherein R1 is H or CH3 1 or the analogue A 1 of the compound where R1 is OH- <Desc / Clms Page number 38> 4. Compound of formula EMI38.1 EMI38.2 where Ruz is H, OR 3 or a 2 E 5 R3 is H, the acyl radical of carboxylic acid or, when R2 is H, a 1-cyclopentenyl, 1-cyclohexenyl or 2-tetrahydropyranyl radical; is H, Cl, Br or OH; R5 is H or a lower alkyl radical having up to 4 carbon atoms; R6 is H or OH; or a 4 9 (il) or ¯14 analogue of these compounds, EMI38.3 where R4, R5, and Ru are H, with the proviso that one of the substituents R4, R5 and R6 must be other than hydrogen, except in o (11) 14 EMI38.4 an analogue A9 11 or 41 '. of 5 * "1-Cyolopentenyl ether-8e'noxeteatoAaterone * 6.- B-norte8tololaotone. 7t "A 1 -B-nor.testololaotone. 6.- 2a, 17a-dimethyl-B-nortestoaterone. 9.- i7a-methyl-A '' '-B-norteataaterone 10.- 11-hydroxy-1? A-methyl-8-norteataaterone. 11, - 17a-methyl-t11 '.- B-norteatoaterane. 12.- 6a-ohloro-i7a-methyl-B-nortestoterone, <Desc / Clms Page number 39> EMI39.1 1.- 6a-bromg "I? A.mdthyl .nrtestostxonc" 14, <- 6-hydroxy-'7 -methyl-B-norteatoaterone. 15 * "1? C-méthy .-- A -.- narteststxana, $ 1 ,. New B-noreteroldest substance, as described above and in particular in the examples. 17.- Pharmaceutical compositions containing EMI39.2 any .norstéxpd described above in addition to a pharmaceutical carrier. 18.- Pharmaceutical compositions containing EMI39.3 any of the B-norateros according to any of claims 1 to 15, in addition to a pharmaceutical carrier.