DE1468894A1 - Process for the preparation of optically active 3-oxo-13 beta-ethyl-17 beta-hydroxy-17 alpha-ethynyl-gonen - Google Patents
Process for the preparation of optically active 3-oxo-13 beta-ethyl-17 beta-hydroxy-17 alpha-ethynyl-gonenInfo
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- DE1468894A1 DE1468894A1 DE19641468894 DE1468894A DE1468894A1 DE 1468894 A1 DE1468894 A1 DE 1468894A1 DE 19641468894 DE19641468894 DE 19641468894 DE 1468894 A DE1468894 A DE 1468894A DE 1468894 A1 DE1468894 A1 DE 1468894A1
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
- C07C59/46—Unsaturated compounds containing hydroxy or O-metal groups containing rings other than six-membered aromatic rings
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/80—Unsaturated compounds containing keto groups containing rings other than six-membered aromatic rings
- C07C59/82—Unsaturated compounds containing keto groups containing rings other than six-membered aromatic rings the keto group being part of a ring
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C62/30—Unsaturated compounds
- C07C62/38—Unsaturated compounds containing keto groups
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J15/00—Stereochemically pure steroids containing carbon, hydrogen, halogen or oxygen having a partially or totally inverted skeleton, e.g. retrosteroids, L-isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J61/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one or two atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/16—Benz[e]indenes; Hydrogenated benz[e]indenes
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Description
Verfabren s Herstellung von optisch aktiven ====================== : ====================== 3-Oxo-13#-õthyl-17#-hydroxy-17αõthinyl-genenen Die Erfindung betrifft ein Verfahren zur Herstellung von optisch aktiven 3-Oxo-13#-õthyl-17#-hydroxy-17α-õthinyl-genonen der allgemeinen ? omel in der aioh die durch Punkte symbolisierte Doppelbindung in 4 (5)- oder 5C)-Stellung befindet.Procedure s production of optically active ======================: ===================== = 3-Oxo-13 # -õthyl-17 # -hydroxy-17αõthynyl-genes The invention relates to a process for the production of optically active 3-oxo-13 # -õthyl-17 # -hydroxy-17α-õthynyl-genones of the general? omel in which aioh the double bond symbolized by dots is in the 4 (5) or 5C) position.
Das vorlisgende Verfahren zur Totalsynthese von 13#-~thyl-18,19-dinor-testosteron-derivaten weist gegen³ber den bekannten Synthesen den Vorteil auf, da# es k³rzer ist, nicht aber Zwischenprodukte führt, die einen aromatischen Kern A enthaltes, und ou den optiaoh aktiven Verbindungen f³hrt.The present process for the total synthesis of 13 # - ~ ethyl-18,19-dinor-testosterone derivatives points towards the known Syntheses the advantage on that # it is shorter, but does not lead to intermediate products which contain an aromatic nucleus A, and leads to the optically active compounds.
Die nach dem neuen Verfahren gemõ# der Erfindung erhaltenen Verbindungen besitzen eine steriache Konfiguration, die mit der-Jenig der nat³rlichen Steroide identisch ist, und weisen demnach eine doppelt so starke hormonale Wirkung auf als die aus den bekanntgemachten Unterlagen der belgischen Patente 632 347 und 623 844 bekannten racemiachen Produkte.The compounds obtained by the new process according to the invention have a sterile configuration similar to that of natural steroids is identical, and therefore have a hormonal effect that is twice as strong as those from the published documents of Belgian patents 632 347 and 623 844 well-known racemic products.
So ist aus R. A. Edgren, Steroids 2 (1963) t Seite 731-736, bekannt, da# daß Steroide, die eine der natürlichen Konfiguration entgegengesetzte Konfiguration aufweisen, frei von Aktivitõt sind. Daraus ergibt sich, daß die racemischen Verbindungen eine Aktivitõt aufweisen, die aus der Kombination eines aktiven mit einem inaktiven Enantiomer resultiert. In der genannten Literaturstelle wird hervorgehoben, da# die biologisch aktiven Racemate Kombinationen darstellen müssen aus einem inerten Enantiomer und einem aktiven Enantiomer, das doppelt so wirksam wie das Racemat sein muß Es hei#t weiter, da# die Spaltung des Racemats auf mikrobiologischem Wege bewirkt wurde. Wie der US-Patentschrift 3 189 528 entnommen werden kann, gelingt die mikrobiologische Racematspaltung nur mit ungewöhnlicb geringen Ausbeuten.It is known from R. A. Edgren, Steroids 2 (1963) t page 731-736, that # that steroids have a configuration opposite to the natural configuration are free from activity. It follows that the racemic compounds have an activity that results from the combination of an active with an inactive Enantiomer results. In the cited reference it is emphasized that # the biologically active racemates must represent combinations of an inert Enantiomer and an active enantiomer that is twice as effective as the racemate Must be It goes on to say that the cleavage of the racemate is microbiological was effected. As can be seen from US Pat. No. 3,189,528, it succeeds the microbiological resolution only with unusually low yields.
Daraus ergibt sich der ³berraschende Vorteil des erfindungage-Bäßen mõ#en Verfahrens, nach dem die gesamte Synthese mit Verbindungen durchgef³hrt wird, die die Konfiguration der nat³rlichen Steroide aufweisen, wohingegen bei den bekannten Verfahren die erhaltenen raceaiaohen Verbindungen am Schluß der Synthese mit sehr schlechten Ausbeuten optisch gespalten werden.This results in the surprising advantage of the inventive basses mõ # en process by which the entire synthesis is carried out with compounds, which have the configuration of the natural steroids, whereas the known ones Process the raceaiaohen compounds obtained at the end of the synthesis with very poor yields are optically split.
Dem erfindungsgemõ#en 3-Oxo-17#-hydroxy-17α-õthinyl-13#-õthyl-5 10)-gonen, [α]D20 = +95# + 2# (c = 1% Dioxan), und 3-Oxo-17#-hydroxy-17 -õthinyl-13#-õthyl-4-gonen oder 17 -~thinyl-13#-õthyl-18,19-dinor-testosteron, [α]D20 = -26 # 1,5# (c = 0,5 % Chloroform) kommt im Hinblick auf ihre bemerkenswerten progestetiven Eigenohaften ein besonderes Interesse za. The 3-oxo-17 # -hydroxy-17α-thynyl-13 # -ethyl-5 according to the invention 10) -gonen, [α] D20 = + 95 # + 2 # (c = 1% dioxane), and 3-oxo-17 # -hydroxy-17 -õthynyl-13 # -õthyl-4-gonen or 17 - ~ thinyl-13 # -õthyl-18,19-dinor-testosteron, [α] D20 = -26 # 1,5 # (c = 0.5% chloroform) comes in view of their remarkable progestational inherentities a special interest za.
Das erfindungsgemõ#e Verfahren zur Herstellung von optisch aktiven 3-Oxo-13#-õthyl-17#-hydroxy-17α-õthinyl-gonanen der allgemeinen Formel in der sich die durch Punkte symbolisierte Doppelbindung in 4 (5)-der 5 (10)-Stellung befindet, ist dadurch charakterisiert, da8 man 3-Oxo-17#-hydroxy-13#-õthyl-gona-4,9-dien der Einwirkung eines Alkalimetalle oder von Calcium in Segenwart von fl³ssigem AeMBonisk und einem Protonendonator unterwirft, das 3-Oxo-17#-hydroxy-13ß-athyl-gona-5(0)-enerhält,dessen17-AlkohoI-funktion mit Chromsõureanhydrid sum 3,17-Dioxo-13#-õthyl-gona-5(10)-en oxydiert, auf die erhaltene Verbindung ein ~thinylierungsmittel einwirken lõ#t und das erhaltene 3-Oxo-17#-hydroxy-17α-õthinyl-13#-õthyl-gona-5(10)-en gegebenenfalls durch Sõurebehandlung zum 3-Oxo-17#-hydroxy-17α-õthinyl-13#-õthyl-gona-4-en isomerisiert, welches man gegebenenfalls durch Einwirkung einer niederen organischen Carbonsõure bder eines funktionellen Derivats derselben verestert.The process according to the invention for the preparation of optically active 3-oxo-13 # ethyl-17 # -hydroxy-17α-thynylgonanes of the general formula in which the double bond symbolized by dots is in the 4 (5) or 5 (10) position is characterized by the fact that 3-oxo-17 # -hydroxy-13 # -ethyl-gona-4,9-diene is used subjected to the action of an alkali metal or calcium in the presence of liquid AeMBonisk and a proton donor, which 3-oxo-17 # -hydroxy-13ß-ethyl-gona-5 (0) -contains, whose 17-alcohol function with chromic anhydride sum 3, 17-Dioxo-13 # -õthyl-gona-5 (10) -en is oxidized, a thynylating agent acts on the compound obtained and the 3-oxo-17 # -hydroxy-17α-thynyl-13 # -thyl obtained -gona-5 (10) -en, optionally by acid treatment, isomerized to 3-oxo-17 # -hydroxy-17α-thynyl-13 # -thyl-gona-4-ene, which is optionally isomerized by the action of a lower organic carboxylic acid Esterified derivative of the same.
PUr die Ausführung der Reduktion des 3-Oxo-17#-hydroxy-13#-õthyl-4, 9-gonadiene-ist es vorteilhaft, einen kleinen ~berschu# an Metall einzusetzen. Vorteilhaft arbeitet man mit einer Menge, die 3 Atome Metall pro Molek³l Diensteroid der Formel t cht überschreitet und die vorzugsweise zwischen 2, 1 und 2,5 Atomen liegt.To carry out the reduction of 3-oxo-17 # -hydroxy-13 # -õthyl-4, 9-gonadiene-it is advantageous to use a small excess of metal. Advantageous one works with an amount of 3 atoms of metal per mole of diene steroid of the formula t exceeds cht and which is preferably between 2.1 and 2.5 atoms.
Besonders vorteilhaft ist es, unter den oben erwõhnten Metallen Lithium zu wählen.It is particularly advantageous to use lithium among the metals mentioned above to choose.
Als Protonendonatoren sind die niederen aliphatiacben Alkohole, beispielsweise Methanol, ~thanol, tert.-Butanol usw. sebr gut geeignet die nat³rlich gleichzeitig die Rolle des Lösungsmittels spielen.The lower aliphatic benzene alcohols are, for example, proton donors Methanol, ~ ethanol, tert-butanol etc. are also well suited to the natural at the same time play the role of the solvent.
B e Umsetzung kann in Gegenwart oder Abwesenheit eines dritten, gegenüber don verwendeten Metallen inerten L~sungsmittels durchgef³hrt werden. Das L~sungsmittel kann unter den aliphatischen und cyclischen Xthern gewählt werden. Ala Beispiele heirf³r können Xthyläther oder isopropylõther, Dioxan oder Tetrahydrofuran angefahrt werden.B e implementation can be in the presence or absence of a third, opposite the metals used are inert solvents. The solvent can be chosen from aliphatic and cyclic ethers. Ala examples Ethyl ether or isopropyl ether, dioxane or tetrahydrofuran can be used here will.
Man arbeitet bei Temperaturen, die zwischen -30 und -80#C, vorzugsweise zwichen -60 und -70#C liegen.Temperatures between -30 and -80 ° C. are preferably used lie between -60 and -70 # C.
Die Heratellung von Derivaten des 13#-~thyl-18, 9-ordo testosterons der allgemeinen Formel V erfolgt ausgehend von einem 3-Oxo-17#-hydroxy-13#-õthy-5(10)-gonen (II), welches durch Reduktion der dienischen Varbindung I erhalten wird. So oxydiert man beispielsweise die Alkoholgrkuppe in Stellung 17 dieser Verbindung mit Chromsõureanhydrid in Gegeenwart von Schwefelsõure, unterwirft das so gebildete 3,17-Dioxo-13#-õthyl-5 10)-gonen III der Einwirkung eines ~thinylierungsmittels, führt eine Isomerisierung eines 3-Oxo-17#-hydroxy-17#-õthinyl-13#-õthyl-5(10)-gonens IV durch, wobei man vorzugsweise in salzsaurem Medium in Tetrabydrofuran arbeitet, und erhält das gesuchte 13#-~thyl-18,19-dinor-testosteron der Formel V, welches man gegebenenfalls mit dam Ohlorid oder Anhydrid der gewählten Säure verestert. Als Ester k~nnen das Formiat, Acetat, Trimethylacetat, Propionat, Cyclopentylpropionat, Isobutyrat, Hexanoat, Undecylenst, Hemisuccinat, Benzoat, Cyclohexylcarbonat, @-Sulfobenzoat usw. angef³hrt werden.The preparation of derivatives of 13 # - ~ ethyl-18, 9-ordo testosterone of the general formula V is based on a 3-oxo-17 # -hydroxy-13 # -õthy-5 (10) -gonen (II), which is obtained by reducing the dienic compound I. So oxidized for example, the alcohol group in position 17 of this compound with chromic acid anhydride In the presence of sulfuric acid, the 3,17-Dioxo-13 # -õthyl-5 thus formed subdues 10) -gonen III the action of a thynylating agent, leads to an isomerization of a 3-oxo-17 # -hydroxy-17 # -õthynyl-13 # -õthyl-5 (10) -gonens IV through, preferably works in hydrochloric acid medium in tetrabydrofuran, and receives the sought-after 13 # - ~ ethyl-18,19-dinor-testosterone of the formula V, which can optionally be mixed with the selected fluoride or anhydride Esterified acid. Formate, acetate, trimethyl acetate, propionate, Cyclopentyl propionate, isobutyrate, hexanoate, Undecylenst, hemisuccinate, Benzoate, cyclohexyl carbonate, @ -sulfobenzoate, etc. are listed.
Die aarenEster,wiedasHemisncoinat,sindvorteilhaft,da man von ihnen ausgehend die Alkali-und Erdalkalisalse herstellen kann, indem man sie mit molaren Mengen einer Base, wie z.B. Natriumbicarbonat, Kaliumbicarbonat oder Calciumbicarbonat, behandelt. Dieae Salze sind nicht nur physiologisch aktiv, sondern auch wasserl~slich, ein Vorzug, den die gewöhnlichen Steroidester nicht besitzen.The aarenEster, like the Hemisncoinat, are advantageous as one of them starting from the alkali and alkaline earth salts can be prepared by treating them with molar Amounts of a base such as sodium bicarbonate, potassium bicarbonate, or calcium bicarbonate, treated. The salts are not only physiologically active, but also water-soluble, a benefit that ordinary steroid esters do not have.
Bas folgende Beispiel erlõutert die Erfindun, ohne sie zu beschrõnken.The following example explains the invention without limiting it.
Beispiel Herstellungvon3-Oxo-17B-'hydroxy-n%M-äthinyl-3B-äthyl--ßonen (oder 17α-~thinyl-13#-õthyl-18,19-dinor-testosteron) (Verbindung V Stufe A: 3-Oxo-17#-hydroxy-13#-õthyl-5(10)-gonen (II) Zu 175 ml fl³ssigem Ammoniak, der auf etwa -70#C abgek³hult wurde, gibt man langsam unter R³hren eine Mischung von 100 ml tert.-Butanol und 150 ml Testrahydrofuran, fgt danaeb 1, 4 g Lithium und 5 Minuten opliter 25 g 33-Oxo-17#-hydroxy-13#-õthyl-4,9-gonadien (I) zu. Die Reaktionsmischung wird 10 Minuten ger³hrt, dann werden 25 ml Essigsõure und 25 ml Tetrahydrofuran sugeaetzt. Example Preparation of 3-oxo-17B-'hydroxy-n% M-ethinyl-3B-ethyl-ions (or 17α- ~ thinyl-13 # -õthyl-18,19-dinor-testosteron) (Compound V Level A: 3-Oxo-17 # -hydroxy-13 # -õthyl-5 (10) -gonen (II) To 175 ml of liquid ammonia, which on has cooled to about -70 ° C, a mixture of 100 is slowly added with stirring ml of tert-butanol and 150 ml of testrahydrofuran, then add 1, 4 g of lithium and 5 minutes opliter 25 g of 33-oxo-17 # -hydroxy-13 # -ethyl-4,9-gonadiene (I). The reaction mixture the mixture is stirred for 10 minutes, then 25 ml of acetic acid and 25 ml of tetrahydrofuran are added sugeaetzt.
Man glaßt auf eisgek³hltes Wasser, startet die Kristallisation aerob Kratzen und lõ#t eine Stunde unter R³hren stehen.The mixture is poured into ice-cold water and the crystallization starts aerobically Scrape and stir for an hour.
Dam nutecht man ab, wilriobt mit Wasser, trocknet und erhõlt 22,6 g des Produktes, welches nach Reinigung durch Aufl~sen in 25 Volumen Methylenchlorid, Leiten ³ber Aluminiumoxyd und anschlie#ender Umkristallisation aus Isopropylõther 15 g 3-Oxo-17#-hydroxy-13#-õthyl-5(10) gonem (II) von F. 110#C ergibt; [α]D20 = + 151# # 1,5# (c = 1 % in Dioxan).Damage is peeled off, wilted with water, dried and obtained 22.6 g of the product, which after purification by dissolving in 25 volumes of methylene chloride, Passing over aluminum oxide and subsequent recrystallization from isopropyl ether 15 g of 3-oxo-17 # -hydroxy-13 # -õthyl-5 (10) gonem (II) of F. 110 # C gives; [α] D20 = + 151 # # 1.5 # (c = 1% in dioxane).
Das Prodokt fällt in For farbloser Prismen an, die in Wasser unlöslich, in Kther und Benzol wenig löslich, in Alkohol, Aceton und Chloroform l~slich sind.The product is obtained in form of colorless prisms, which are insoluble in water, are sparingly soluble in ether and benzene, and are soluble in alcohol, acetone and chloroform.
Analyse: C19H28O2 = 288,41 berechnet: C 79, 12 H 9, 78% gefunden : 78, 9 9, 5 Die Verbindung wurde bisher in der literatur noch nicht beschrieben.Analysis: C19H28O2 = 288.41 calculated: C 79, 12 H 9, 78% found: 78, 9 9, 5 The compound has not yet been described in the literature.
Stufe B: 3,17-Dioxo-13#-õthyl-5(10)-gonen (III) 20 g de mie in der vorhergehenden Stufe beaehrieben erhaltenon 3-Oxo-17#-hydroxy-13#-õthyl-5(10)-genons (III) werden in 400 ml Aceton gel~s, auf -25#C abgek³hlt und tropfenweise mit 23 al einer Ldaung von 27 g Chromtrioxyd (in einer ausreichenden Menge Wasser gel~st, 23 ml Schwefelsõure und soviel Waeser, da8 Snsgesamt 100 ml Lboung erhalten werden, veraetzt.Level B: 3,17-Dioxo-13 # -õthyl-5 (10) -gonen (III) 20 g de mie in the in the previous step, 3-oxo-17 # -hydroxy-13 # -õthyl-5 (10) -genons (III) are dissolved in 400 ml of acetone, cooled to -25 ° C. and washed dropwise with 23 al a solution of 27 g chromium trioxide (dissolved in a sufficient amount of water, 23 ml of sulfuric acid and so much water that a total of 100 ml of solution are obtained, scratched.
Die Reaktionsmischuing wird danach eine Stunde bei-10 ger³hrt, worauf 20 ml Natriumbisulfitl~sund und 60 ml Wasser zugegeben werden.The reaction mixture is then stirred for one hour at -10, whereupon 20 ml of sodium bisulfite solution and 60 ml of water are added.
Dann lliert man das Aceton im Vakuum ab, nutscht ab, sp³lt mit Wasser, trocknet und erhõlt 17,9 g eines Produktes, welches nach Umkristallisieren aus Methylõthylketon 8, 157 g 3, 17-Dioxo-13#-õthyl-5(10)-gonen (III) vom F. 138#C ergibt: [α]D20 = +214# # 2# (c = 1% in Dioxan).Then the acetone is removed in vacuo, suction filtered, rinsed with water, dries and receives 17.9 g of a product which, after recrystallization from methyl ethyl ketone 8, 157 g 3, 17-Dioxo-13 # -õthyl-5 (10) -gonen (III) from F. 138 # C gives: [α] D20 = + 214 # # 2 # (c = 1% in dioxane).
Das Produkt fällt in Form farbloser Prismen an, die in tasser unl~slich, in Alkohol, thylacetat und Methyläthylketon wenig ldslich und in Aceton, das 50 eN Waaaer enthält, Benzol und Chloroform l~slich sind.The product is obtained in the form of colorless prisms, which are insoluble in not very soluble in alcohol, thylacetate and methyl ethyl ketone and in acetone, the 50 If it contains water, benzene and chloroform are soluble.
Stafe ufe C: 3-Oxo-17#-hyrdroxy- 17@-õth 1-13#-õthyl-5(10)-2 g frisch von den Krusten befreites Kalium werden in 80 ml fl³ssigem Ammoniak, der auf -35#C abgek³hlt wurde, eingebraoht und 10 Mimsten gerührt. lam leitet man eine Stunde lang einen Aoetylenstrom ein.Level C: 3-Oxo-17 # -hyrdroxy- 17 @ -õth 1-13 # -õthyl-5 (10) -2 g fresh Potassium freed from the crusts is dissolved in 80 ml of liquid ammonia, which is set to -35 ° C Was cooled, brewed and stirred 10 Mimsten. lam leads an hour a stream of acetylene for a long time.
Anschlie#end gibt man 20 ml ~ther zu, f³hrt 4 g 3, 17-Dioxo-13#-õthyl-5(10)-gonen (III) ein und leitet 4 Stunden lang einen Acetylenstrom ein, wobei man die Mischung bei etwa -35#C hõlt.Then 20 ml of ether are added and 4 g of 3,17-dioxo-13-ethyl-5 (10) -gonen are added (III) and passing in a stream of acetylene for 4 hours, whereby the mixture at around -35 # C.
Da der Ammoniak im Verlauf der Reaktion stark verdampft, ist es notwendig, dus Volumen mehrere Male wieder aufzuf³llen.Since the ammonia vaporizes strongly in the course of the reaction, it is necessary to Replenish the volume several times.
Anschlie#end gibt man Ammoniumchlorid zu, r³hrt nochmals 15 Minuten und beendet dann die Acetyleneinleitung.Then ammonium chloride is added and the mixture is stirred for another 15 minutes and then terminates the introduction of acetylene.
Man extrahiert mit Methylenchlorid, wõscht die Extrakte mit Nasser, trocknet und verdampft lm m Vakuum zur Trockne, wobei man 1,42 g 3-Oxo-17#-hydroxy-17α-õthinyl-13#-õthyl-5(10)-gonon (IV erhält,daemiteinesViertelWolekSlethylenahlorid solvatisiert ist, F. 190#C: [α]D20 = +89# #2# (c = 1% in Dioxan); dies entzprischt einem [α]D20 = +95# #2, berechnet auf das desolvatisierte Produkt.Extract with methylene chloride, wash the extracts with water, dries and evaporates to dryness in a vacuum, giving 1.42 g of 3-oxo-17 # -hydroxy-17α-thynyl-13 # -thyl-5 (10) -gonone (IV obtained that it is solvated with a quarter of a molecular weight ethylene aahloride, F. 190 # C: [α] D20 = + 89 # # 2 # (c = 1% in dioxane); this corresponds to a [α] D20 = + 95 # # 2, calculated on the desolvated product.
DZ Verbindung fõllt in Form farbloser Pismen an, die in Tasser onloslich, in Alkohol, Aoeton und Benzol wenig loalioh und in Chloroform l~slich sind.DZ connection accumulates in the form of colorless pisms that dissolve in tasser, are not very soluble in alcohol, acetone and benzene and are soluble in chloroform.
Analyse: C21H28O2 . 1/4 CH2Cl2 = 333,69 berechnet : C 76,49 H 8,61 Cl 5,31% gefunden 6 5, 2 Die Verbindung svurde bisher in der Literatur noch nicht beschrieben.Analysis: C21H28O2. 1/4 CH2Cl2 = 333.69 calcd: C 76.49 H 8.61 Cl 5.31% found 6 5, 2 The compound has not yet been found in the literature described.
Stufe D: 3-Oxo-17#-hydroxy-17α-õthinyl-13#-õthyl-4-gonen (oder 17α-~thinyl-13#-õthyl-18,19-dinor-testosteron).Level D: 3-Oxo-17 # -hydroxy-17α-õthinyl-13 # -õthyl-4-gonen (or 17α- ~ thinyl-13 # -ethyl-18,19-dinor-testosterone).
Verbindung V 1 g @droxy-17α-õthinyl-13-õthyl-5(10)-gonen (IV) wird 10 10 ml reines Tetrahydrofuran eingebracht. 0,2 ml n-salzsõure werden zugegeben, und danach wird 5 Stunden bei Zimmertemperatur ger³hrt. Compound V 1 g @ droxy-17α-õthynyl-13-õthyl-5 (10) -gonen (IV) 10 10 ml of pure tetrahydrofuran is introduced. 0.2 ml n-hydrochloric acid are added, and then stirred for 5 hours at room temperature.
Dann gie#t man auf eisgek³hltes Wasser, lõ#t die Reaktionsmischung 10 Minuten stehen, nutscht ab, wõscht, trocknet und erhõlt 0,9 g 3-Oxo-17#-hydroxy-17α-õthinyl-13#-õthyl-4-gonen oder ~thinyl-13#-õthyl-18,19-dinortestosteron vom F. 240#C ; [α]D20 20 # 1,5# (c = 0,5% in Chloroform).Then it is poured into ice-cold water and the reaction mixture is dissolved Stand for 10 minutes, soak off, wash, dry and obtain 0.9 g of 3-oxo-17 # -hydroxy-17α-õthynyl-13 # -õthyl-4-gonen or ~ thinyl-13 # -õthyl-18,19-dinortestosterone from F. 240 # C; [α] D20 20 # 1.5 # (c = 0.5% in chloroform).
Dab Produkt fõllt in Form farbloser Prismen an, die in Wasser unl~slich, in Kther und Benzol sehr wenig l~slich, in Alkohol wenig löslich und in Chloroform ziemlich l~slich sind.The product accumulates in the form of colorless prisms, which are insoluble in water, Very little soluble in ether and benzene, sparingly soluble in alcohol and in chloroform are quite soluble.
Analyse : 1H28O2 = 312,43 berechnet: C 80,72 F 9,03% gefunden : 80,7 9,1 Die Verbindung wurde in der Literatur bisher noch nicht beschrieben.Analysis: 1H28O2 = 312.43 calculated: C 80.72 F 9.03% found: 80.7 9.1 The compound has not yet been described in the literature.
Claims (2)
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR890184A FR1364556A (en) | 1962-03-06 | 1962-03-06 | New process for the synthesis of steroids and related compounds and products used in this process |
| FR957406A FR1378463A (en) | 1963-12-17 | 1963-12-17 | Method of wet grading or sludge removal of fine-grained or fine and medium-grained solids, with simultaneous removal of water from the coarse fraction |
| FR957460A FR1476509A (en) | 1962-03-06 | 1963-12-17 | New process for the synthesis of steroids and related compounds and products used in this process |
| FR957406 | 1963-12-17 | ||
| FR960254 | 1964-01-14 | ||
| FR960254A FR1512318A (en) | 1962-03-06 | 1964-01-14 | Optically active derivatives of 19-nor testosterone and method of preparation |
| FR964517A FR91612E (en) | 1962-03-06 | 1964-02-20 | Optically active derivatives of 19-nor testosterone and method of preparation |
| FR964517 | 1964-02-20 | ||
| DER0039479 | 1964-12-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE1468894A1 true DE1468894A1 (en) | 1969-02-06 |
| DE1468894C3 DE1468894C3 (en) | 1976-07-01 |
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| C3 | Grant after two publication steps (3rd publication) | ||
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