Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-11-30
2003-06-24
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S276000
Reexamination Certificate
active
06583298
ABSTRACT:
The invention relates to a new process for the synthesis of 17&bgr;-hydroxy-17&agr;-methyl-2-oxa-5&agr;-androstane-3-one of the formula (I)
called further as oxandrolone—from 17&bgr;-hydroxy-17&agr;-methyl-1,3-seco-2-nor-5&agr;-androstane-1,3-diacide of formula (III)
called further as secodicarboxylic acid.
The invention relates furthermore to the new 17&bgr;-hydroxy-17&agr;-methyl-1,3-seco-2-nor-5&agr;-androstane-1,3-diacid anhydride, too.
The oxandrolone is an anabolic, which is used in pediatrics and for mitigation of loss of weight developed as a consequence of infections, traumas and surgical intervention and recently for improvement of the condition of AIDS patients.
The synthesis of oxandrolone is described in several patents, i.e. the U.S. Pat. Nos. 3,101,349, 3,128,283 and 3,155,684, the German patent No. 1,171,425 and the French patent No. M1697. These patents describe the oxidation of 17&bgr;-hydroxy-17&agr;-methyl-5&agr;-androst-1-ene-3-one by lead tetraacetate in the presence of osmium tetroxide, when 17&bgr;-hydroxy-17&agr;-methyl-1-oxo-1,3-seco-2-nor-5&agr;-androstane-3-acid is obtained. In the next step of the reaction sequence the aldehyde group is reduced by sodium borohydride to furnish the hydroxymethyl group and the desired compound is synthesised from the obtained A-nor-hydroxy carboxylic acid by ring closure reaction. The descriptions do not give yields. The use of lead tetraacetate and especially the osmium tetroxide is extremely dangerous for health and not environmental friendly. We note, that the synthesis of the starting material, the 17&bgr;-hydroxy-17&agr;-methyl-5&agr;-androst-1-ene-3-one, can be carried out only in low yield by bromnination of 17&bgr;-hydroxy-17&agr;-methyl-5&agr;-androstane-3-one and subsequent hydrogen bromide elimination. This procedure is described i.e. in the U.S. Pat. No. 3,128,283.
According to the U.S. Pat. No. 3,109,016 the oxidation of the above mentioned starting material is carried out by ozone in carbon tetrachloride to yield the mixed anhydride of 17&bgr;-hydroxy-17&agr;-methyl-1-oxo-1,3-seco-2-nor-5&agr;-androstane-3-acid formed with formic acid, which is closed to a ring after reduction of the aldehyde group with sodium borohydride as described above. The oxidation was also carried out in dichloromethane in the presence of methanol to yield the methyl ester of the seco compound. The patent description does not give yields. As the use of carbon tetrachioride is restricted because of its harmful effect to health, the synthesis can not be used on industrial scale.
In the procedure described in the U.S. Pat. No. 3.282,962 the seco compound and the ring-closed oxandrolone are obtained as by-products and the latter is separated by crystallisation.
According to the Japanese patent No. 7,005,773 the desired compound is obtained by oxidation with perbenzoic acid from 17&agr;-methyl-A-nor-5&agr;-androstane-17&bgr;-ol-2-one. The above starting material can be synthesised from the 2,3-seco-diacid anhydride: by pyrolysis. The procedure is not economical and difficult to carry out even for the synthesis of lab scale quantities.
The paper, Tetrahedron Letters 9, 365-371 (1962), describes the oxidation by lead tetraacetate/osmium tetroxide and the subsequent reduction.
In the J. Med. Chem 14(10), 958-61 (1971) the cyclization coupled with acetylation of 17-hydroxy-seco-steroid diacids is shown.
J. Chem. Soc. Perkin Trans 1 no. 5., 1239-1245 (1990) shows the reduction of oxo group of D-homo-aza-steroids.
It can be seen from the above mentioned facts, that although there is need for oxandrolone in therapeutic use, its synthesis is not an industrially applicable, environmental friendly, harmless procedure.
Surprisingly it was found that our following process does not have the disadvantages of the known procedures, can be used industrially, is easily realisable, environmental friendly and the very pure final product, which fulfil the high standard of the present requirement of purity, can be obtained in good yield.
According to our process the secodicarboxylic acid of formula (III) is transformed into the ring-closed dicarboxylic anhydride (secodicarboxylic anhydride) of formula (II)
in an inert solvent with a C
2
-C
3
alkane acid anhydride or a substituted carbodiimide of formula R
1
—N═C═N—R
2
— wherein R
1
and R
2
independently are C
1
-C
6
alkyl group, C
1
-C
6
allyl group substituted by tertiary or quaternary amino group or 1-3 phenyl group, C
5
-C
6
cycloalkyl group, aryl group substituted by 1-3 nmethoxy, tertiary amino, nitro, C
1
-C
4
alkyl group or 1-3 halogen atom
and the obtained secodicarboxylic anhydride of formula (II) is reduced regioselectively by a complex alkali metal hydride in an inert solvent.
When the secodicarboxylic anhydride is obtained in the reaction with C
2
-C
3
alkane acid anhydride in an inert solvent, the reduction can be carried out without isolation of the obtained secodicarboxylic anhydride by reacting it with a solution of a complex alkali metal hydride dissolved in an inert solvent
The first step of the process according to our invention is preferably carried out by dissolving the secodicarboxylic acid in tetrahydrofuran and after addition of acetic anhydride, refluxing the reaction mixture until the completion of the reaction, evaporating the tetrahydrofuran and crystallisation of the obtained secodicarboxylic anhydride from diisopropyl ether. Instead of acetic anhydride propionic anhydride or dicyclohexyl carbodiimide can also be used in this reaction. In case of the use of the latter reactant the dicyclohexyl urea, formed during the reaction, can be separated by filtration from the reaction mixture before work-up.
The second step is preferably carried out by dissolving the crystalline secodicarboxylic anhydride in tetrahydrofuran, cooling to −5° C. and adding a solution of sodium borohydride in dry dimethyl formamide over a period of 2 h, at 0-(−5)° C. The reaction mixture is stirred at 0-(−5)° C. until the completion of the reaction, which is checked by thin layer chromatography, then 10% sulfuric acid solution is added to the mixture over a period of 30 min keeping the temperature below 10° C. Then the reaction mixture is diluted with water and the precipitation of the desired compound is made complete by addition of further sulfuric acid solution. The precipitate is filtered, washed till it is neutral and dried. Instead of sodium borohydride lithium aluminum hydride, lithium tri-tertiary-butoxyaluminohydride or lithium triethylborohydride can be used as complex alkali metal hydride reducing agent.
The process according to our invention can be carried out in the following way, too: the secodicarboxylic acid is dissolved in tetrahydrofuran and after addition of acetic anhydride the reaction mixture is refluxed until the completion of the reaction, then cooled to −5° C. and a solution of sodium borohydride in dry dimethyl formamide is added over a period of 2 h at 0-(−5)° C. The mixture is stirred until the completion of the reaction, which is checked by thin layer chromatography. Then 10% sulfuric acid solution is added over a period of 30 min keeping the temperature below 10° C. After this the reaction mixture is diluted with water and the precipitation of the desired compound is made complete by addition of further sulfuric acid solution. The precipitate is filtered, washed till it is neutral and dried.
Purification of the crude material is carried out by dissolving it in an alkane, alcohol, ketone, ester, nitril or ether type solvent, treating with charcoal, filtering and filtering off the product obtained after concentration of the filtrate. An other possibility is that the crude material is dissolved in a solvent mentioned above, treated with charcoal, filtered, mixed with water and the purified product is obtained with or without evaporation. This way the yield of the oxandrolone is about 80%.
REFERENCES:
patent: 3101349 (1963-08-01), Pappo
patent: 3109016 (1963-10-01), Nysted
patent: 3128283 (1964-04-01), Pappo et al.
patent: 31556
Ferenczi Katalin
Horvath Peter
Lancos Krisztina
Maho Sandor
Mester Tamas
Covington Raymond
Herbert Dubno Jonathan Myers
Richter Gedeon Vegyeszeti Gyar Rt.
Rotman Alan L.
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