NO135835B - - Google Patents
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- NO135835B NO135835B NO753445A NO753445A NO135835B NO 135835 B NO135835 B NO 135835B NO 753445 A NO753445 A NO 753445A NO 753445 A NO753445 A NO 753445A NO 135835 B NO135835 B NO 135835B
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- Norway
- Prior art keywords
- ether
- group
- ethynyl
- melting point
- dioxane
- Prior art date
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- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000003377 acid catalyst Substances 0.000 claims description 3
- 230000004071 biological effect Effects 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 20
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000002844 melting Methods 0.000 description 14
- 230000008018 melting Effects 0.000 description 14
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- 229960003387 progesterone Drugs 0.000 description 10
- 239000000186 progesterone Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 150000002084 enol ethers Chemical class 0.000 description 5
- DBPWSSGDRRHUNT-CEGNMAFCSA-N 17α-hydroxyprogesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DBPWSSGDRRHUNT-CEGNMAFCSA-N 0.000 description 4
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 4
- 239000005977 Ethylene Substances 0.000 description 4
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 description 4
- 230000000757 progestagenic effect Effects 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 3
- -1 ethyl orthoformic acid ester Chemical class 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229960004719 nandrolone Drugs 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IMONTRJLAWHYGT-ZCPXKWAGSA-N Norethindrone Acetate Chemical compound C1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CC[C@](C#C)(OC(=O)C)[C@@]1(C)CC2 IMONTRJLAWHYGT-ZCPXKWAGSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 230000002254 contraceptive effect Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- QLSSITLVZFHSJT-UHFFFAOYSA-N 1-(3-chlorophenyl)-n-methylpropan-2-amine Chemical compound CNC(C)CC1=CC=CC(Cl)=C1 QLSSITLVZFHSJT-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- JAJIPIAHCFBEPI-UHFFFAOYSA-N 9,10-dioxoanthracene-1-sulfonic acid Chemical class O=C1C2=CC=CC=C2C(=O)C2=C1C=CC=C2S(=O)(=O)O JAJIPIAHCFBEPI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 230000001548 androgenic effect Effects 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- VMPVEPPRYRXYNP-UHFFFAOYSA-I antimony(5+);pentachloride Chemical compound Cl[Sb](Cl)(Cl)(Cl)Cl VMPVEPPRYRXYNP-UHFFFAOYSA-I 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000001072 progestational effect Effects 0.000 description 1
- LBUSGXDHOHEPQQ-UHFFFAOYSA-N propane-1,1,1-triol Chemical compound CCC(O)(O)O LBUSGXDHOHEPQQ-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- E—FIXED CONSTRUCTIONS
- E04—BUILDING
- E04F—FINISHING WORK ON BUILDINGS, e.g. STAIRS, FLOORS
- E04F10/00—Sunshades, e.g. Florentine blinds or jalousies; Outside screens; Awnings or baldachins
- E04F10/02—Sunshades, e.g. Florentine blinds or jalousies; Outside screens; Awnings or baldachins of flexible canopy materials, e.g. canvas ; Baldachins
- E04F10/06—Sunshades, e.g. Florentine blinds or jalousies; Outside screens; Awnings or baldachins of flexible canopy materials, e.g. canvas ; Baldachins comprising a roller-blind with means for holding the end away from a building
- E04F10/0611—Sunshades, e.g. Florentine blinds or jalousies; Outside screens; Awnings or baldachins of flexible canopy materials, e.g. canvas ; Baldachins comprising a roller-blind with means for holding the end away from a building with articulated arms supporting the movable end of the blind for deployment of the blind
- E04F10/0614—Sunshades, e.g. Florentine blinds or jalousies; Outside screens; Awnings or baldachins of flexible canopy materials, e.g. canvas ; Baldachins comprising a roller-blind with means for holding the end away from a building with articulated arms supporting the movable end of the blind for deployment of the blind whereby the pivot axis of the articulation is parallel to the roller
Landscapes
- Engineering & Computer Science (AREA)
- Architecture (AREA)
- Civil Engineering (AREA)
- Structural Engineering (AREA)
- Building Awnings And Sunshades (AREA)
- Steroid Compounds (AREA)
Description
Fremgangsmåte for fremstilling av enoletere av A <4>-3-ketosteroider. Process for the preparation of enol ethers of A<4>-3-ketosteroids.
Nærværende oppfinnelse angår en The present invention relates to a
fremgangsmåte for fremstilling av enoletere av A4-3-ketosteroider med den generelle method for the preparation of enoleters of A4-3-ketosteroids with the general
formel: formula:
hvor R' er hydrogen eller en metylgruppe, where R' is hydrogen or a methyl group,
R er en alifatisk, likekjedet eller forgrenet R is an aliphatic, straight chain or branched
hydrocarbongruppe med 4—7 carbonatomer hydrocarbon group with 4-7 carbon atoms
eller en cykloalifatisk hydrocarbongruppe or a cycloaliphatic hydrocarbon group
med 5—6 carbonatomer, idet X, når R' er with 5-6 carbon atoms, being X when R' is
hydrogen, er en hydroksygruppe eller en hydrogen, is a hydroxy group or a
acetoksygruppe, mens Y er en etinylgruppe, acetoxy group, while Y is an ethynyl group,
eller når R' er en metylgruppe, er X en or when R' is a methyl group, X is a
acetylgruppe, mens Y er hydrogen, en acetyl group, while Y is hydrogen, a
hydroksy- eller acetoksygruppe. hydroxy or acetoxy group.
Disse hittil ukjente enoletere har These hitherto unknown enolets have
uventede biologiske egenskaper, som er unexpected biological properties, which are
bedre enn egenskapene til de frie ketoner. better than the properties of the free ketones.
Disse egenskaper beskrives nærmere neden-for. These properties are described in more detail below.
Fremgangsmåten ifølge oppfinnelsen The method according to the invention
er karakterisert ved at man omsetter etylenoleteren av et tilsvarende A4-3-keto-steroid med en alkohol ROH, hvor R har is characterized by reacting the ethylene ether of a corresponding A4-3-keto-steroid with an alcohol ROH, where R has
den ovenfor nevnte betydning i nærvær av en sur katalysator. the above meaning in the presence of an acid catalyst.
Den sure katalysator, som benyttes ved ombytningsreaksjonen, kan være en av de til dannelse av enoletere vanlig anvendte syrer, slik som toluensulfonsyre eller en annen syre av samme art, slik som benzensulfonsyre eller naftalensulfonsyrer eller antrakinonsulfonsyrer. Som katalysator kan også anvendes en Lewissyre, slik som SnCl4, SbCl5 eller salter av organiske baser med mineralsyrer, slik som pyridinhydro-klorid. The acid catalyst, which is used in the exchange reaction, can be one of the acids commonly used for the formation of enol ethers, such as toluenesulfonic acid or another acid of the same kind, such as benzenesulfonic acid or naphthalene sulfonic acids or anthraquinonesulfonic acids. A Lewis acid, such as SnCl4, SbCl5 or salts of organic bases with mineral acids, such as pyridine hydrochloride, can also be used as a catalyst.
Ombytningsreaksjonen forløper i al-minnelighet i et organisk fortrinnsvis ikke polart oppløsningsmiddel. Det anvendes fortrinnsvis oppløsningsmidler som benzen, cykloheksan, isooktan eller tetrahydrofuran. Også halogenholdige oppløsningsmid-ler, slik som etylenbromid, kloroform og tetrakloretan kan anvendes alene eller i blanding med et av de ovenfor nevnte opp-løsningsmidler. The exchange reaction generally takes place in an organic, preferably non-polar, solvent. Solvents such as benzene, cyclohexane, isooctane or tetrahydrofuran are preferably used. Halogen-containing solvents, such as ethylene bromide, chloroform and tetrachloroethane can also be used alone or in admixture with one of the above-mentioned solvents.
Reaksjonsblandingen som består av etylenoleteren av 3-keto-A4-steroidet, som er suspendert eller oppløst i et av den ovenfor nevnte oppløsningsmidler av alkoholen og som velges til utførelse av ombytningsreaksjonen, og av den sure katalysator, bringes til kokning i en kolbe forsynt med stigende eller fallende kjøler. Hvis blandin-gen destilleres en viss tid, fjernes all etanolen som danner seg under ombytningsreaksjonen ved medrivning eller ved azeo-trbpisk blanding med oppløsningsmidlet. Varigheten av destillasjonen avhenger na-turligvis av volumet av det anvendte opp-løsningsmiddel og av mengden av den om-satte etylenoleter. The reaction mixture consisting of the ethylene ol ether of the 3-keto-A4 steroid, which is suspended or dissolved in one of the above-mentioned solvents of the alcohol and which is chosen to carry out the exchange reaction, and of the acidic catalyst, is brought to boiling in a flask provided with rising or falling cooler. If the mixture is distilled for a certain time, all the ethanol formed during the exchange reaction is removed by entrainment or by azeotropic mixing with the solvent. The duration of the distillation naturally depends on the volume of the solvent used and on the quantity of the converted ethylene ether.
Minst 2/3 av oppløsningens begynnel-sesvolum skal avdestilleres. Man kan så være sikker på at etanolen er blitt fullkom-men avdestillert fra reaksjonsblandingen. Oppløsningsremanensen gjøres svakt alka-lisk ved tilsetning av en svak organisk base, f. eks. pyridin og konsentreres deretter til et lite volum. Man kan med fordel lette krystallisasjonen av enoleteren i remanensen ved tilsetning av metanol, etanol eller heksan. At least 2/3 of the initial volume of the solution must be distilled off. One can then be sure that the ethanol has been completely distilled from the reaction mixture. The solution residue is made slightly alkaline by adding a weak organic base, e.g. pyridine and then concentrated to a small volume. Crystallization of the enol ether in the residue can be facilitated by adding methanol, ethanol or hexane.
Den som utgangsstoff anvendte etylenoleter fås ved omsetning av et 3-keto-A4-steroid med ortomaursyreetylester. Det er ikke absolutt nødvendig å fremstille etylenoleteren særskilt og derpå etter rensning å underkaste den den ovennevnte ombytningsreaksjon. Reaksjonen kan også utføres i den oppløsning inneholdende etylenoleteren, som fås ved reaksjon mel-lom 3-keto-A4-steroidet og ortomaursyre-etylesteren. I så fall lar man et overskudd av den ønskede alkohol i nærvær av en sur katalysator i et ikke polart oppløsnings-middel innvirke på oppløsningen. Denne reaksjonen gir utbytter av enoleter, som overstiger de som fås, når man går ut fra ren 3-enoletyleter. The ethylene ether used as starting material is obtained by reacting a 3-keto-A4-steroid with ethyl orthoformate. It is not absolutely necessary to prepare the ethylene ether separately and then, after purification, subject it to the above-mentioned exchange reaction. The reaction can also be carried out in the solution containing the ethylene ether, which is obtained by reaction between the 3-keto-A4 steroid and the ethyl orthoformic acid ester. In that case, an excess of the desired alcohol in the presence of an acidic catalyst in a non-polar solvent is allowed to affect the solution. This reaction gives yields of enolets, which exceed those obtained when starting from pure 3-enole ethyl ether.
Enoleterene av progesteron og dennes 17-hydroksy- og acetoksyderivat utmerker seg ved verdifull gestagen virkning, idet de administrert per os er meget virksommere enn de tilsvarende A4-3-ketosteroider og fri for bivirkninger. Især utviser de ingen androgen virkning, ingen follikel-springshindring og fremkaller ingen hyp-nose. The enol ethers of progesterone and its 17-hydroxy and acetoxy derivative are distinguished by their valuable progestogenic effect, as they are much more effective when administered per os than the corresponding A4-3-ketosteroids and free of side effects. In particular, they exhibit no androgenic effect, no follicle-bursting inhibition and induce no hypo-nosis.
For å prøve den gestagene virkning av disse forbindelser i sammenlikning med de tilsvarende A4-3-ketoner ble det anvendt Claubergprøven, og den gestagene virkning betegnes med Mc. Phail indekset (The journal of Physiology, bind 83, 1935, side 145). To test the progestogenic effect of these compounds in comparison with the corresponding A4-3 ketones, the Clauberg test was used, and the progestogenic effect is denoted by Mc. The Phail index (The journal of Physiology, volume 83, 1935, page 145).
Resultatene av forsøkene er sammen-fattet i tabell I og II. The results of the experiments are summarized in Tables I and II.
Resultatene viser at 3-n-amylenoleter og 3-cyklopentylenoleter av progesteron er 10 henholdsvis 7 ganger virksommere enn progesteron, og 3-cyklopentyl- og n-amylenoleter av 17a-acetoksyprogesteron er 10 henholdsvis 4 ganger virksommere enn den tilsvarende A4-3-ketoforbindelse. The results show that 3-n-amylenol ether and 3-cyclopentylenol ether of progesterone are 10 and 7 times more effective than progesterone, and 3-cyclopentyl and n-amylenol ether of 17a-acetoxyprogesterone are 10 and 4 times more effective than the corresponding A4-3-keto compound .
Enoleterene av 17a-etinyl-19-nortesto-steron og deres ester har verdifulle biologiske egenskaper. Farmakologiske forsøk har vist at enolforetringen av 17|3-etinyl-19-nortestosteronet bevirker en fraskillelse av utgangsketonets gestagene og kontra-septive virkning. Især har cyklopentylenoleteren av 17a-etinyl-19-nortestosteronace-tat en forøket antiøstrogen og antikonsep-tionel virkning og en nedsatt progestesjo-nalverdi. The enol ethers of 17α-ethynyl-19-nortestosterone and their esters have valuable biological properties. Pharmacological experiments have shown that the enol esterification of 17|3-ethynyl-19-nortestosterone causes a separation of the starting ketone's progestogenic and contraceptive effects. In particular, the cyclopentylenol ether of 17α-ethynyl-19-nortestosterone acetate has an increased antiestrogenic and contraceptive effect and a reduced progestational value.
De følgende eksempler belyser fremgangsmåten ifølge oppfinnelsen. The following examples illustrate the method according to the invention.
Eksempel 1. Example 1.
En oppløsning av 3-etylenoleteren av progesteron fremkommet ved å behandle 20 g progesteron i 18 ems tetrahydrofuran med 12 cm^ ortomaursyreetylester og 170 mg benzensulfonsyre helles i en 3-liters kolbe, inneholdende 1500 cm» vannfritt benzen, 30 ems n-amylalkohol og 100 mg benzensulfonsyre, og deretter avdampes oppløsningsmidlet inntil 1/4 av det opprinnelige volum. Til den tilbakeblivne opp-løsning settes noen få dråper pyridin for å nøytralisere den tilstedeværende sulfon-syre, og oppløsningsmidlet fjernes i vakuum ved en temperatur på ikke over 30°C. Remanensen opptas i metanol og omkrystalliseres av metanol inneholdende noen få dråper pyridin. Derved får man den rene n-amylenoleter av progesteron, smeltepunkt 66,5—68°C, [<x]D = -=-49° (dioksan). A solution of the 3-ethyleneoleether of progesterone obtained by treating 20 g of progesterone in 18 ems of tetrahydrofuran with 12 cm^ of orthoformic ethyl ester and 170 mg of benzenesulfonic acid is poured into a 3-liter flask, containing 1500 cm» of anhydrous benzene, 30 ems of n-amyl alcohol and 100 mg of benzenesulfonic acid, and then the solvent is evaporated to 1/4 of the original volume. A few drops of pyridine are added to the remaining solution to neutralize the sulphonic acid present, and the solvent is removed in vacuo at a temperature not exceeding 30°C. The residue is taken up in methanol and recrystallized from methanol containing a few drops of pyridine. This gives the pure n-amylenol ether of progesterone, melting point 66.5-68°C, [<x]D = -=-49° (dioxane).
Eksempel 2. Example 2.
Til en blanding av 50 mg sulfosalicylsyre og 500 ems vannfritt tetrahydrofuran settes 3 g metylenoleter av progesteron i 5 cm3 cyklopentylalkohol og deretter avdestilleres oppløsningsmidlet, inntil 1/4 av det opprinnelige volum. Det settes pyridin til den tilbakeblivende oppløsning, og man konsentrerer i vakuum. Remanensen opptas i fortynnet metanol, frasuges og tørres. Derved får man cyklopentylenoleteren av progesteron, smeltepunkt 105—106°C [a]D = -=-47,5° (dioksan). To a mixture of 50 mg of sulfosalicylic acid and 500 ems of anhydrous tetrahydrofuran, 3 g of methylene ether of progesterone are added to 5 cm 3 of cyclopentyl alcohol and then the solvent is distilled off, up to 1/4 of the original volume. Pyridine is added to the remaining solution and concentrated in vacuo. The residue is taken up in diluted methanol, suctioned off and dried. This gives the cyclopentylenol ether of progesterone, melting point 105-106°C [a]D = -=-47.5° (dioxane).
På samme måte fremstiller man cykloheksylenoleteren av progesteron, smeltepunkt 115—116°C [ct]D = 52,5° (dioksan) In the same way, the cyclohexyl enol ether of progesterone is prepared, melting point 115-116°C [ct]D = 52.5° (dioxane)
og cykloheksenyl-2-enoleteren av progesteron, smeltepunkt 105—106°C [a]D = -=-55° and the cyclohexenyl-2-enoleter of progesterone, melting point 105—106°C [a]D = -=-55°
(dioksan). (dioxane).
Eksempel 3. Example 3.
En oppløsning inneholdende etylenoleteren av 17a-acetoksyprogesteron fremkommet ved behandling av 2 g 17<x-acetoksyprogesteron i 3 cma tetrahydrofuran med 2 ems ortomaursyreetylester, 4 ems absolutt etanol og 50 mg sulfosalicylsyre, helles i en kokende oppløsning av 10 cm» N-amylalkohol i 800 cm» benzen og man avdestillerer deretter, inntil all etanolen er fjernet. Det tilbakeblivende produkt iso-leres på vanlig måte og renses. Den derved fremkomne n-amylenoleter av 17a-acetoksyprogesteron smelter ved 125—126°C [a]D = -i-126,5° (dioksan). A solution containing the ethylene oleether of 17a-acetoxyprogesterone obtained by treating 2 g of 17<x-acetoxyprogesterone in 3 cma of tetrahydrofuran with 2 ems of ethyl orthoformic acid, 4 ems of absolute ethanol and 50 mg of sulfosalicylic acid, is poured into a boiling solution of 10 cm» of N-amyl alcohol in 800 cm" of benzene and then distill off until all the ethanol has been removed. The remaining product is isolated in the usual way and purified. The resulting n-amylenol ether of 17a-acetoxyprogesterone melts at 125-126°C [a]D = -i-126.5° (dioxane).
På samme måte fremstilles cyklopentylenoleteren, smeltepunkt 157—158°C [a]n = -f-124", cykloheksylenoleteren, smel-smeltepunkt 154—156°C [a]D = h-142,5, n-heksylenoleteren, smeltepunkt 93—94°C [a]D = h-124°, cykloheksylenoleteren, smeltepunkt 162—164°C [a]n = -=-131° og cyk-loheksenyl-2-enoleteren, smeltepunkt 154— 156,5°C [a]i, = -=-145,5°. Alle optiske rota-sjoner er målt i dioksan. In the same way, the cyclopentylenol ether, melting point 157—158°C [a]n = -f-124", the cyclohexylenol ether, melting point 154—156°C [a]D = h-142.5, the n-hexylenol ether, melting point 93 is prepared —94°C [a]D = h-124°, the cyclohexylenol ether, melting point 162—164°C [a]n = -=-131° and the cyclohexenyl-2-enol ether, melting point 154— 156.5°C [ a]i, = -=-145.5° All optical rotations are measured in dioxane.
Eksempel 4. Example 4.
En oppløsning inneholdende etylenoleteren av 17a-hydroksyprogesteron fremkommet ved behandling av 2,5 g 17a-hydroksyprogesteron i 2,5 cm» absolutt etanol og 25 mg p-toluensulfonsyre, helles i en kolbe inneholdende 450 cm? benzen, 8 ems cyklopentanol og 50 mg -p-toluensulfonsyre, og det arbeides videre som beskrevet i eksempel 1. Derved får man cyklopentylenoleteren av 17a-hydroksyprogesteron, smeltepunkt 184,5—186,5°C [a]D = -7-115° (dioksan). A solution containing the ethylene oleether of 17a-hydroxyprogesterone obtained by treating 2.5 g of 17a-hydroxyprogesterone in 2.5 cm» of absolute ethanol and 25 mg of p-toluenesulfonic acid is poured into a flask containing 450 cm? benzene, 8 ems cyclopentanol and 50 mg -p-toluenesulfonic acid, and the work is continued as described in example 1. This gives the cyclopentylenol ether of 17a-hydroxyprogesterone, melting point 184.5—186.5°C [a]D = -7- 115° (dioxane).
På liknende måte får man n-amyl-enoletereh av 17a-hydroksyprogesteron, smeltepunkt 102—104°C [a]D = -r-95" (dioksan). In a similar way, n-amyl-enole ether is obtained from 17a-hydroxyprogesterone, melting point 102-104°C [a]D = -r-95" (dioxane).
Eksempel 5. Example 5.
Til en blanding av 600 ems vannfritt benzen og 6 cm3 cyklopentanol settes 0,15 g benzensulfonsyre. Man avdestillerer en del av oppløsningsmidlet for å fjerne even-tuelle spor av fuktighet azeotropisk. Til reaksjonsblandingen settes så 3 g 3-enoletyleter av 17a-etinyl-19-nortestosteron-acetat, og destillasjonen fortsettes i ca. 30 0.15 g of benzenesulfonic acid is added to a mixture of 600 ems of anhydrous benzene and 6 cm3 of cyclopentanol. Part of the solvent is distilled off to remove any traces of moisture azeotropically. 3 g of 3-enole ethyl ether of 17a-ethynyl-19-nortestosterone acetate is then added to the reaction mixture, and the distillation is continued for approx. 30
minutter, således at den under reaksjonen minutes, so that during the reaction
dannede etanol fjernes helt. Til den tilbakeblivende oppløsning setter man noen få formed ethanol is completely removed. A few are added to the remaining solution
dråper pyridin og inndamper den i vakuum. drops of pyridine and evaporate it in vacuo.
Remanensen opptas i eter, tørres, frasuges The residue is taken up in ether, dried, filtered off with suction
og omkrystalliseres så av metanol inneholdende noen dråper pyridin. Derved opp-står cyklopentylenoleteren av 17a-etinyl-19-nortestosteronacetat, smeltepunkt 180— and then recrystallized from methanol containing a few drops of pyridine. This results in the cyclopentylenol ether of 17a-ethynyl-19-nortestosterone acetate, melting point 180—
183°C [a]D = -=-212° (dioksan). 183°C [a]D = -=-212° (dioxane).
På samme måte får man n-amylenol-eteren av 17a-etinyl-19-nortestosteronace-tat, smeltepunkt 108—110°C [a]D = --194° In the same way, the n-amylenol ether of 17a-ethynyl-19-nortestosteronacetate is obtained, melting point 108—110°C [a]D = --194°
(dioksan), n-heptylenoleteren av 17a-eti-nyl-19-nortestosteronacetat, smeltepunkt (dioxane), the n-heptylenol ether of 17α-ethynyl-19-nortestosterone acetate, m.p.
38—40°C [a]n = -=-153° (dioksan) og n-oktylenoleteren av 17a-etinyl-19-nortesto-steronacetat, en olje med [<x]D = -=-58° (dioksan). 38—40°C [a]n = -=-153° (dioxane) and the n-octylenol ether of 17a-ethynyl-19-nortestosterone acetate, an oil with [<x]D = -=-58° (dioxane) .
Eksempel 6. Example 6.
Ved å arbeide som beskrevet i eksempel 5 får man utfra etylenoleteren av 17a-etinyl-19-nortestosteron cyklopentylenoleteren av 17a-etinyl-19-nortestosteron, By working as described in example 5, one obtains from the ethylene oleether of 17a-ethynyl-19-nortestosterone the cyclopentylenolether of 17a-ethynyl-19-nortestosterone,
smeltepunkt 149—151 °C [a]„ = -=-242° melting point 149—151 °C [a]„ = -=-242°
(dioksan). (dioxane).
Claims (1)
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO753445A NO753445L (en) | 1975-10-10 | 1975-10-10 | Locking device for awning fittings. |
| FI762855A FI57818C (en) | 1975-10-10 | 1976-10-07 | SPA MARKETING |
| SE7611237A SE420434B (en) | 1975-10-10 | 1976-10-08 | LOCKING DEVICE, Separate by marquise fitting |
| DK454276A DK144386C (en) | 1975-10-10 | 1976-10-08 | AWNING HARDWARE |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO753445A NO753445L (en) | 1975-10-10 | 1975-10-10 | Locking device for awning fittings. |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO135835B true NO135835B (en) | 1977-02-28 |
| NO753445L NO753445L (en) | 1977-04-13 |
| NO135835C NO135835C (en) | 1977-06-08 |
Family
ID=19882494
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO753445A NO753445L (en) | 1975-10-10 | 1975-10-10 | Locking device for awning fittings. |
Country Status (4)
| Country | Link |
|---|---|
| DK (1) | DK144386C (en) |
| FI (1) | FI57818C (en) |
| NO (1) | NO753445L (en) |
| SE (1) | SE420434B (en) |
-
1975
- 1975-10-10 NO NO753445A patent/NO753445L/en unknown
-
1976
- 1976-10-07 FI FI762855A patent/FI57818C/en not_active IP Right Cessation
- 1976-10-08 SE SE7611237A patent/SE420434B/en unknown
- 1976-10-08 DK DK454276A patent/DK144386C/en active
Also Published As
| Publication number | Publication date |
|---|---|
| NO135835C (en) | 1977-06-08 |
| DK144386C (en) | 1982-07-26 |
| FI762855A (en) | 1977-04-11 |
| DK144386B (en) | 1982-03-01 |
| SE7611237L (en) | 1977-04-11 |
| NO753445L (en) | 1977-04-13 |
| DK454276A (en) | 1977-04-11 |
| FI57818C (en) | 1980-10-10 |
| SE420434B (en) | 1981-10-05 |
| FI57818B (en) | 1980-06-30 |
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