DE1147225B - Process for the preparation of 17ª ‡ -Methyl-17ª ‰ -hydroxyandrostan-11-one - Google Patents
Process for the preparation of 17ª ‡ -Methyl-17ª ‰ -hydroxyandrostan-11-oneInfo
- Publication number
- DE1147225B DE1147225B DEU6747A DEU0006747A DE1147225B DE 1147225 B DE1147225 B DE 1147225B DE U6747 A DEU6747 A DE U6747A DE U0006747 A DEU0006747 A DE U0006747A DE 1147225 B DE1147225 B DE 1147225B
- Authority
- DE
- Germany
- Prior art keywords
- methyl
- hydroxyandrostan
- preparation
- activity
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title description 2
- 238000004519 manufacturing process Methods 0.000 claims description 3
- -1 methylmagnesium halide Chemical class 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- 230000001195 anabolic effect Effects 0.000 description 2
- 230000001548 androgenic effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000001441 androstanes Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- XCOBTUNSZUJCDH-UHFFFAOYSA-B lithium magnesium sodium silicate Chemical compound [Li+].[Li+].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Na+].[Na+].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3 XCOBTUNSZUJCDH-UHFFFAOYSA-B 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
Verfahren zur Herstellung von 17a-Methyl-17,B-hydroxyandrostan-11-on Die Erfindung betrifft ein Verfahren zurHerstellung von 17a-Methyl-17ß-hydroxyandrostan-11-on der folgenden Formel: Diese Verbindung übt in hohem Maße eine orale anabolische Aktivität aus und besitzt den Vorteil, nur eine geringe oder gar keine orale androgene Aktivität bei demselben Dosierungsspiegel aufzuweisen.Process for the production of 17a-methyl-17, B-hydroxyandrostan-11-one The invention relates to a process for the production of 17a-methyl-17ß-hydroxyandrostan-11-one of the following formula: This compound exerts high levels of oral anabolic activity and has the advantage of having little or no oral androgenic activity at the same dosage level.
3-Desoxysteroide sind bekannt (vgl. Kochakian, »Proc. Soc. Exptl. Biol. und Med.«, 80, S. 386 [l952]; »Am. J. Physiol.«, 158, S. 51 [1949]; Inhoffen et a1., »Ann.«, 568, S. 52 [1950]; Klyne et a1., »J. Chem. Soc.«, S. 4545 ff. [1958], und Sondheimer et a1., »Journ. Org. Chem.«, 22, S. l090 ff. [1957]). Ein 3-Desoxysteroid der in 11-Stellung oxydierten Androstanreihe, welches außerdem in 17-Stellung eine Methylgruppe aufweist, ist dagegen neu. Diese Art der Substitution in 17-Stellung ist aber sowohl für die pharmakologische Aktivität als auch für das chemische Reaktionsvermögen von entscheidender Bedeutung. Im Hinblick auf den merklichen Aktivitätsabfall, den viele Hormone, z. B. Testosteron, bei Oxydation in 11 -Stellung erleiden, stellt die physiologische Aktivität des gemäß Erfindung zugänglichen, in 11-Stellung oxydierten Steroids eine besondere Überraschung dar. Weiterhin war man bislang der Ansicht, daß eine Hydroxyfunktion in 3-Stellung für die Aktivität von in 11 -Stellung oxydierten Steroiden wesentlich sei.3-Deoxysteroids are known (cf. Kochakian, »Proc. Soc. Exptl. Biol. And Med. ", 80, p. 386 [1952]; "At the. J. Physiol. ", 158, p. 51 [1949]; I hope et a1., "Ann.", 568, p. 52 [1950]; Klyne et a1., »J. Chem. Soc. ", Pp. 4545 ff. [1958], and Sondheimer et al., »Journ. Org. Chem. ", 22, pp. 1090 ff. [1957]). A 3-deoxysteroid the androstane series oxidized in the 11-position, which also has a Having a methyl group, on the other hand, is new. This type of substitution in the 17-position but is for both pharmacological activity and chemical reactivity vital. With regard to the noticeable decrease in activity, the many hormones, e.g. B. Testosterone, suffer from oxidation in 11 position, provides the physiological activity of the accessible according to the invention, oxidized in the 11-position Steroids are a particular surprise. Furthermore, it was previously of the opinion that a hydroxyl function in the 3-position was oxidized for the activity of in the 11 -position Steroids is essential.
Das erfindungsgemäß zugängliche 17a-Methyl-17ß-hydroxyandrostan-11-onunterscheidet sich gegenüber dem entsprechenden 11-Hydroxysteroid dadurch, daß es eine bedeutende anabolische und androgene Aktivität ausübt, die nicht von starken Effekten auf das Zentralnervensystem und neuromuskulären Wirkungen, die das bekannte 17a-Methyl-11 ß,17ß-dihydroxyandrostan kennzeichnen, begleitet wird. Die erfindungsgemäß zugängliche Verbindung kann in den üblichen Dosierungsformen, wie Pillen, Tabletten und Kapseln, für orale Anwendung oder in den üblichen flüssigen Formen, wie sie mit natürlichen und synthetischen Corticosteroidhormonen für injizierbare Präparate verwendet werden, appliziert werden.The 17α-methyl-17β-hydroxyandrostan-11-one accessible according to the invention is different compared to the corresponding 11-hydroxysteroid in that it is a significant one Exerts anabolic and androgenic activity that does not have strong effects on the Central nervous system and neuromuscular effects that the well-known 17a-methyl-11 ß, 17ß-dihydroxyandrostane is accompanied. The accessible according to the invention Compound can be in the usual dosage forms, such as pills, tablets and capsules, for oral use or in the usual liquid forms such as those with natural ones and synthetic corticosteroid hormones are used for injectable preparations, be applied.
Zur Durchführung des erfindungsgemäßen Verfahrens setzt man llß-Hydroxyandrostan-17-on mit einem geeigneten Methyl-Grignard-Reagens zu 17a-Methylandrostan-lIß,17ß-diol um, das bei Oxydation in 11-Stellung 17a-Methyl-17-hydroxyandrostan-11-on ergibt.To carry out the process according to the invention, 11β-hydroxyandrostan-17-one is used with a suitable methyl Grignard reagent to 17α-methylandrostane-lIß, 17ß-diol um, which on oxidation in the 11-position gives 17a-methyl-17-hydroxyandrostan-11-one.
Die nachfolgenden Beispiele erläutern das erfindungsgemäße Verfahren. Beispiele a) 17a-Methylandrostan-llß,17ß-diol Eine Lösung von Methyhnagnesiumjodid wird durch Reaktion von 1 g Methyljodid mit 290 mg Magnesium in 20 ccm wasserfreiem Äther hergestellt. Zu dieser Lösung läßt man eine Lösung von 500 mg 11ß - Hydroxxandrostan - 17 - an in einer Mischung von 30 ccm Äther und 12 ccm Benzol zutropfen. Die Mischung wird unter Stickstoffatmosphäre 7 Stunden gerührt, sodann durch Zutropfen einer gesättigten, wäßrigen Ammoniumchloridlösung zuersetzt. Man dekantiert die Lösung von dem anorganischen Niederschlag ab, trocknet sie und dampft sie zur Trockene ein, wobei man einen Rückstand erhält, der praktisch aus 17a-Methylandrostan-llß,17ß-diol besteht. Bei Chromatographie dieses Produktes über eine Kolonne von synthetischem Magnesiumsilikat (bekannt unter dem Handelsnamen Florisil) wird ein praktisch reines Produkt mit einem Schmelzpunkt von 178 bis 178,5-C erhalten.The following examples explain the process according to the invention. Examples a) 17α-Methylandrostan-llβ, 17β-diol A solution of methyl magnesium iodide is prepared by reacting 1 g of methyl iodide with 290 mg of magnesium in 20 cc of anhydrous ether. A solution of 500 mg of 11β-Hydroxxandrostane-17-an in a mixture of 30 cc of ether and 12 cc of benzene is added dropwise to this solution. The mixture is stirred under a nitrogen atmosphere for 7 hours, and then a saturated aqueous ammonium chloride solution is added dropwise. The solution is decanted from the inorganic precipitate, dried and evaporated to dryness, whereby a residue is obtained which consists practically of 17α-methylandrostane-llß, 17ß-diol. When this product is chromatographed over a column of synthetic magnesium silicate (known under the trade name Florisil), a practically pure product with a melting point of 178 to 178.5 ° C. is obtained.
b) 17a-Methyl-17-hydroxyandrostan-ll-on Eine Lösung von 1 g Chromsäureanhydrid in 2 ccm Wasser und 9 ccm Essigsäure wird zu 2 g 17a - Methylandrostan - l lß,17ß - diol in 30 ccm Essigsäure zugegeben. Die Mischung läßt man bei Raumtemperatur 1 Stunde stehen, verdünnt sie mit 10 bis 15 ccm Methanol und fällt das Steroid durch Zusatz von Wasser, wobei man 1,6 g 17a-Methyl-17-hydroxyandrostan-11-on mit einem Schmelzpunkt zwischen 125 und 128'C erhält. Bei Umkristallisation aus verdünntem Methanol erhält man eine polymorphe Form, die bei 157 bis 159°C schmilzt. [a]D -I-38° in Chloroform.b) 17a-methyl-17-hydroxyandrostan-II-one A solution of 1 g of chromic anhydride in 2 cc of water and 9 cc of acetic acid, 2 g of 17a - methylandrostane - lb, 17b - added diol in 30 cc acetic acid. The mixture is left at room temperature Stand for 1 hour, dilute it with 10 to 15 cc of methanol and the steroid will fail Addition of water, 1.6 g of 17a-methyl-17-hydroxyandrostan-11-one with a Melting point between 125 and 128'C is obtained. When recrystallized from dilute Methanol is obtained in a polymorphic form which melts at 157 to 159 ° C. [a] D -I-38 ° in chloroform.
Wenn die Schmelze des niedriger schmelzenden Produktes mit höher schmelzendem Material angeimpft wird, verflüssigt es sich wieder und schmilzt bei 151 bis 157'C. Analyse für C2oHs202: Berechnet ..... C 78,89, H 10,60; gefunden ..... C 79,21, H 10,75.If the melt of the lower melting product is inoculated with higher melting material, it liquefies again and melts at 151 to 157 ° C. Analysis for C2oHs202: Calculated ..... C 78.89, H 10.60; found ..... C 79.21, H 10.75.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1147225XA | 1959-01-09 | 1959-01-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1147225B true DE1147225B (en) | 1963-04-18 |
Family
ID=22357038
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEU6747A Pending DE1147225B (en) | 1959-01-09 | 1959-12-17 | Process for the preparation of 17ª ‡ -Methyl-17ª ‰ -hydroxyandrostan-11-one |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1147225B (en) |
-
1959
- 1959-12-17 DE DEU6747A patent/DE1147225B/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| None * |
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