DE1907804C3 - 4-chloro-1alpha, 2alpha; 6alpha, 7alphadimethylene-3-keto-4-pregnene, processes for their preparation and agents containing them - Google Patents
4-chloro-1alpha, 2alpha; 6alpha, 7alphadimethylene-3-keto-4-pregnene, processes for their preparation and agents containing themInfo
- Publication number
- DE1907804C3 DE1907804C3 DE19691907804 DE1907804A DE1907804C3 DE 1907804 C3 DE1907804 C3 DE 1907804C3 DE 19691907804 DE19691907804 DE 19691907804 DE 1907804 A DE1907804 A DE 1907804A DE 1907804 C3 DE1907804 C3 DE 1907804C3
- Authority
- DE
- Germany
- Prior art keywords
- chloro
- acid
- keto
- pregnene
- preparation
- 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.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 3
- 239000002253 acid Substances 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000005822 methylenation reaction Methods 0.000 claims description 4
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 2
- 150000003431 steroids Chemical class 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- FUZZWVXGSFPDMH-UHFFFAOYSA-N Hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 238000007127 saponification reaction Methods 0.000 description 4
- 229960000583 Acetic Acid Drugs 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- -1 dimethylethylene sulfonium oxide Chemical compound 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- 230000001264 neutralization Effects 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N Oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-M Perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N Perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- DNXIASIHZYFFRO-UHFFFAOYSA-N Pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N Trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N ethoxyethane;trifluoroborane Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- 238000010575 fractional recrystallization Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 230000016087 ovulation Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- SJSYJHLLBBSLIH-SDNWHVSQSA-N (E)-3-(2-methoxyphenyl)-2-phenylprop-2-enoic acid Chemical compound COC1=CC=CC=C1\C=C(\C(O)=O)C1=CC=CC=C1 SJSYJHLLBBSLIH-SDNWHVSQSA-N 0.000 description 1
- HXUIDZOMTRMIOE-UHFFFAOYSA-N 3-oxo-3-phenylpropionic acid Chemical compound OC(=O)CC(=O)C1=CC=CC=C1 HXUIDZOMTRMIOE-UHFFFAOYSA-N 0.000 description 1
- HHXVJSCSDJBUGP-UHFFFAOYSA-N 4-chloro-1$l^{3},2-dithia-3,5-diazacyclopenta-3,5-diene Chemical compound ClC1=NS[S]=N1 HHXVJSCSDJBUGP-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N Chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- PKVJHHYQLHOKDK-FDLPIURMSA-N ClC1=C2C=C[C@H]3[C@@H]4CC[C@](C(C)=O)([C@]4(CC[C@@H]3[C@]2(C=CC1=O)C)C)O Chemical compound ClC1=C2C=C[C@H]3[C@@H]4CC[C@](C(C)=O)([C@]4(CC[C@@H]3[C@]2(C=CC1=O)C)C)O PKVJHHYQLHOKDK-FDLPIURMSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N Cypionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- JXTHNDFMNIQAHM-UHFFFAOYSA-N Dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N Heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- CQBIFASRYMRWLF-UHFFFAOYSA-O O=[SH3+] Chemical compound O=[SH3+] CQBIFASRYMRWLF-UHFFFAOYSA-O 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N Phenylacetic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N Phenylpropanoic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N Pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- BPLKQGGAXWRFOE-UHFFFAOYSA-M Trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N Undecylic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001476 alcoholic Effects 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- AVGAIPMGSIOHFZ-UHFFFAOYSA-N dichloromethane;2-propan-2-yloxypropane Chemical compound ClCCl.CC(C)OC(C)C AVGAIPMGSIOHFZ-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 230000003152 gestagenic Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- PKHMTIRCAFTBDS-UHFFFAOYSA-N hexanoyl hexanoate Chemical compound CCCCCC(=O)OC(=O)CCCCC PKHMTIRCAFTBDS-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- ODGCEQLVLXJUCC-UHFFFAOYSA-O tetrafluoroboric acid Chemical compound [H+].F[B-](F)(F)F ODGCEQLVLXJUCC-UHFFFAOYSA-O 0.000 description 1
- YRYSAWZMIRQUBO-UHFFFAOYSA-N trimethylsulfoxonium Chemical class C[S+](C)(C)=O YRYSAWZMIRQUBO-UHFFFAOYSA-N 0.000 description 1
Description
3535
4040
worin R die oben angegebene Bedeutung hat. gemäß Hauptpatent, dadurch gekennzeichnet, daß man nach an sich bekannten Methoden aus dem erhaltenen Isomerengemisch das 6a,7o-Isomere abscheidet und, je nach der Bedeutung, die R im Endprodukt haben soll, gegebenenfalls vor oder nach der Isomerentrennung die Reaktionsprodukte einer Veresterung oder Verseifung unterwirft. wherein R has the meaning given above. according to the main patent, characterized in that the 6a, 7o isomer is obtained from the mixture of isomers obtained by methods known per se separates and, depending on the meaning that R should have in the end product, optionally before or after the isomers have separated, the reaction products are subjected to esterification or saponification.
50 einer in der Steroidchemie üblichen Carbonsäure mit bis zu 15 Kohlenstoffatomen bedeutet. 50 means a carboxylic acid customary in steroid chemistry with up to 15 carbon atoms.
Bevorzugte Säuren sind niedere und mittlere aliphatische Carbonsäuren. Weiterhin können die Säuren auch ungesättigt, verzweigt, mehrbasisch oder in üblicher Weise, z. B. durch Hydroxyl-, Aminogruppen oder Halogenatome, substituiert sein. Geeignet sind auch cycloaliphatische, aromatische, gemischt aromatisch-aliphatische und heterocyclische Säuren, die ebenfalls in üblicher Weise substituiert sein kennen. Ais bevorzugte Säuren seien beispielsweise genannt: Essigsäure, Propionsäure, Capronsäure, önanthsäure, Undecylsäure, ölsäure, Trimethylessigsäure Monochloressigsäure, Dichloressigsäure, Cyclopentylpropionsäure, Phenylpropionsäure, Phenylessigsäure, Phenoxyessigsäure, Dialkylaminoessigsäure, Piperindinoessigsäure, Bernsteinsäure, Benzoesäure u. a.Preferred acids are lower and middle aliphatic Carboxylic acids. Furthermore, the acids can also be unsaturated, branched, polybasic or in usual way, e.g. B. by hydroxyl, amino groups or halogen atoms, may be substituted. Suitable are also cycloaliphatic, aromatic, mixed aromatic-aliphatic and heterocyclic acids, who also know to be substituted in the usual way. Preferred acids are, for example: Acetic acid, propionic acid, caproic acid, oenanthic acid, undecylic acid, oleic acid, trimethylacetic acid, monochloroacetic acid, Dichloroacetic acid, cyclopentylpropionic acid, phenylpropionic acid, phenylacetic acid, Phenoxyacetic acid, dialkylaminoacetic acid, piperindinoacetic acid, succinic acid, benzoic acid and others.
Die in 6,7-Stellung isomeren 4-Chlor-1 «,2«;6/i,7/-;-dimethylen-3-keto-4-pregnene sind bereits im Hauptpatent beschrieben. Sie besitzen starke gestagene und ovulationshemmende Wirksamkeit.The 4-chloro-1 ", 2"; 6 / i, 7 / -; - dimethylene-3-keto-4-pregnene isomeric in the 6,7-position are already described in the main patent. They have strong gestagenic and ovulation-inhibiting effects.
Es wurde nun gefunden, daß die neuen 4-Chlorl(i,2./;6«,7a-dimethylen-3-kelo-4-pregnene der allgemeinen Formel I in ihrer ovulationshemmenden Wirksamkeit die isomeren 6f>',7/i-Methylenverbindungen des Hauptpatents übertreffen. Auf Grund ihrer wertvollen pharmakologischen Eigenschaften können die neuen Wirkstoffe beispielsweise zur Konzeptionsverhütung und in der Gynäkologie Verwendung finden.It has now been found that the new 4-chloro (i, 2 ./; 6 ", 7a-dimethylene-3-kelo-4-pregnene of the general formula I the isomeric 6f> ', 7 / i-methylene compounds in their ovulation-inhibiting activity of the main patent. Due to their valuable pharmacological properties, the new active ingredients, for example for contraception and in gynecology use Find.
Die erfindungsgemäßen Verbindungen werden nach an sich bekannten Methoden hergestellt. Sie werden beispielsweise nach dem Verfahren des Hauptpatents durch Methylenierung eines entsprechenden 4-ChIor-3-keto-l,4,6-pregnatriens erhalten. Das Methylenierungsprodukt besteht aus einem lsomerongemisch von 6/1,7/*- und 6«,7a-Methy]enverbindung, aus dem sich das 6</,7r-Isomere durch die üblichen Trennungsverfahren isolieren läßt. Die Abtrennung wird beispielsweise durch Chromatographieren und/oder fraktioniertes Umkristallisieren erreicht.The compounds according to the invention are prepared by methods known per se. you will be for example by the method of the main patent by methylenating a corresponding 4-chloro-3-keto-1,46-pregnatriene receive. The methylenation product consists of an isomerone mixture of 6 / 1,7 / * - and 6 «, 7a-methylene compound from which the 6 </, 7r isomer can be isolated by the usual separation processes. The separation is for example achieved by chromatography and / or fractional recrystallization.
Die Erfindung betrifft demnach außerdem ein Verfahren zur Herstellung der Verbindungen der allgemeinen Formel 1 durch Methylenierung eines 4-Chlor-3-keto-l,4,6-pregnatriens der allgemeinen Formel IIThe invention accordingly also relates to a process for the preparation of the compounds of the general Formula 1 by methylenation of a 4-chloro-3-keto-l, 4,6-pregnatriene of the general formula II
CH3 CH 3
Die Erfindung betrifft neue 4-Chlor- lu,2u;6a,7<«-dimethylen-3-keto-4-pregnene der allgemeinen Formel IThe invention relates to new 4-chloro-lu, 2u; 6a, 7 <«- dimethylene-3-keto-4-pregnene of the general formula I.
CH3 CH 3
5555
C = OC = O
(II)(II)
(D(D
6060
6565
worin R ein Wasserstoffatom oder den Säurerest worin R die vorstehend angegebene Bedeutung hat, gemäß Hauptpalent 15 93 516, dadurch gekennzeichnet, daß man aus dem erhaltenen Isomerengemisch das 6u,7ri-Isomere abscheidet und, je nach der Bedeutung, die R im Endprodukt haben soll, gegebenenfalls vor oder nach der Isomerentrennung die Reaktionsprodukte einer Veresterung oder Verseifung unterwirft. in which R is a hydrogen atom or the acid radical in which R has the meaning given above, according to Hauptpalent 15 93 516, characterized in that the mixture of isomers obtained the 6u, 7ri-isomer separates and, depending on the meaning that R should have in the end product, optionally subjecting the reaction products to esterification or saponification before or after isomer separation.
Die Veresterung und die Verseifung können nach den bekannten Methoden durchgeführt werden. Spe-The esterification and the saponification can be carried out by the known methods. Spe-
ziell genannt seien für die Veresterung der Umsatz mit Säureanhydriden oder -Chloriden In Gegenwart einer Säure oder der Umsatz der gewünschten Säure in Gegenwart von Trifluoressigsäureanhydrid.The conversion with acid anhydrides or chlorides in the presence may be mentioned specifically for the esterification an acid or the conversion of the desired acid in the presence of trifluoroacetic anhydride.
Die Verseifung wird beispielsweise mit Basen in alkoholischer Lösung durchgerührt.The saponification is carried out, for example, with bases in an alcoholic solution.
Die Methylenierung erfolgt in an sich bekannter Weise. Als Methylenierungsmiltel sind beispielsweise Diniethylmethylensulfoniumoxid und Diazomethan geeignet.The methylenation takes place in a manner known per se. Methylenating agents are, for example Diniethylmethylene sulfonium oxide and diazomethane are suitable.
Dimethylmelhylensulfoniumoxid kann aus einem Trimethylsulfoxoniumsalz, wie z. B. dem Halogenid, Perchlorat oder Methylsulfat, in einem aprotonischen Lösungsmittel wie Dimethylsulfoxid oder Dimethylformamid mit einer wasserfreien Base freigesetzt werden. Zur Durchführung des Verfahrens bringt man das so erhältliche Dimethylnethylensulfoniumoxid ohne lsolie- ung bei Temperaturen von —40 bis 100 C, vorzugsweise bei Raumtemperatur, mit dem 4-Chlor-1,4,6-trien-3-Keton zur Reaktion, wobei je nach den Reaktionsbedingungen ein Isomerengemisch 6/7\7/i-Methylen- zu 6/z,7i/-Methylenverbindungen von 70:30 bis 80:20 entsteht. Eine weitere Möglichkeit zur Methylenierung besteht darin, daß man auf das ungesättigte Keton Diazomethan einwirken läßt und aus der erhaltenen 1,2;6,7-Bis-(diazomethylen)-Verbindung thermisch oder katalytisch Stickstoff abspaltet. Die thermische Abspaltung wird bei etwa 200 bis 250 C, vorzugsweise im Hochvakuum vorgenommen. Die katalytische Pyrazolinspaltung erfolgt mit sauren Katalysatoren wie Fluorborsäure, Bortrifluoridätherat oder Perchlorsäure in organischen Lösungsmitteln wie Aceton, vorzugsweise bei Raumtemperatur. Die Pyrazolinspaltung kann außerdem mit hochsiedenden Basen wie Chinolin oder Anilin in der Siedehitze erfolgen.Dimethylmelhylenesulfonium oxide can consist of a Trimethylsulfoxonium salt, e.g. B. the halide, perchlorate or methyl sulfate, in an aprotic Solvents such as dimethyl sulfoxide or dimethylformamide be released with an anhydrous base. To carry out the process one brings the so obtainable dimethylethylene sulfonium oxide without isolation at temperatures from -40 to 100 ° C, preferably at room temperature, with the 4-chloro-1,4,6-triene-3-ketone for the reaction, depending on the reaction conditions, an isomer mixture 6/7 \ 7 / i-methylene to 6 / z, 7i / -methylene compounds of 70:30 to 80:20 arises. Another way to methylenate is to click on the Unsaturated ketone lets diazomethane act and from the 1,2; 6,7-bis (diazomethylene) compound obtained thermally or catalytically eliminates nitrogen. The thermal cleavage is at about 200 to 250 C, preferably carried out in a high vacuum. The catalytic pyrazoline cleavage takes place with acidic catalysts such as fluoroboric acid, boron trifluoride etherate or perchloric acid in organic Solvents such as acetone, preferably at room temperature. The pyrazoline cleavage can also with high-boiling bases such as quinoline or aniline at the boiling point.
250 g Trimethylsulfoxoniumjodid werden in 2,5 1 Dimethylsulfoxid unter Rühren und Stickstoffbegasung gelöst. Nach Zugabe von 40 g Natriumhydroxidpulver rührt man 30 Minuten unter Stickstoffbegasung. 180 g 4-Chlor-17-hydroxy-1,4,6-pregnatrien-3,20-dion werden eingetragen und 75 Minuten bei Raumtemperatur gerührt. Das Reaktionsgemisch wird in 35 1 Eiswasser, dem 250 ml Essigwasser zugesetzt sind, eingerührt, der Niederschlag abgesaugi, mit Wasser gewaschen und getrocknet. Das erhaltene Rohprodukt (185 g) schmilzt bei 222 bis 228 C; UV: f276 = 11700.250 g of trimethylsulfoxonium iodide are dissolved in 2.5 l of dimethyl sulfoxide with stirring and a nitrogen gas supply. After adding 40 g of sodium hydroxide powder, the mixture is stirred for 30 minutes under a nitrogen blanket. 180 g of 4-chloro-17-hydroxy-1,4,6-pregnatriene-3,20-dione are added and the mixture is stirred for 75 minutes at room temperature. The reaction mixture is stirred into 35 l of ice water to which 250 ml of acetic water have been added, and the precipitate is filtered off with suction, washed with water and dried. The crude product obtained (185 g) melts at 222 to 228 C; UV: f 276 = 11700.
Nach Umkristallisation aus Methanol/Methylenchlorid (2:1) erhält man 90,9 g 4-Chlor-17-hydroxyl«,2«;6,7-dimethylen-4-pregnen-3,20-dion; F. 260 bis 265 C. UV: ,276 = 12 960.Recrystallization from methanol / methylene chloride (2: 1) gives 90.9 g of 4-chloro-17-hydroxyl, 2 ";6,7-dimethylene-4-pregnen-3,20-dione; F. 260 to 265 C. UV :, 276 = 12,960.
74 g dieser Substanz werden in 740 ml Eisessig suspendiert, 139 ml Essigsäureanhydrid und 6,55 g p-Toluolsulfonsäure zugegeben und 17 Stunden bei Raumtemperatur unter Stickstoffatmosphäre gerührt. Man fällt das Reaklionsgemisch in 15 i Eiswasser, saugt den entstandenen Niederschlag ab, wäscht mit Wasser neutral und trocknet. Das erhaltene rohe !7-Acetat wird in 400 ml Essigester suspendiert, 30 Minuten unter Rückfluß erhitzt, gekühlt, abgesaugt, mit Essigester gewaschen und getrocknet. Man erhält 73,2 g 4 - Chlor - 17 - acetoxy - 1 «,2«;6,7 - dimethylen-4-pregnen-3,20-dion; F. 269 bis 272''C, UV: ;275 = 12 950; [α] 0 = —19,4' (Chloroform).74 g of this substance are suspended in 740 ml of glacial acetic acid, 139 ml of acetic anhydride and 6.55 g of p-toluenesulfonic acid are added and the mixture is stirred for 17 hours at room temperature under a nitrogen atmosphere. The reaction mixture is precipitated in 15 l of ice water, the precipitate formed is filtered off with suction, washed neutral with water and dried. The crude! 7-acetate obtained is suspended in 400 ml of ethyl acetate, heated under reflux for 30 minutes, cooled, filtered off with suction, washed with ethyl acetate and dried. 73.2 g of 4-chloro-17-acetoxy-1 ", 2"; 6,7-dimethylene-4-pregnen-3,20-dione are obtained; F. 269 to 272 "C, UV :; 275 = 12,950; [α] 0 = -19.4 ' (chloroform).
Durch wiederholte fraktionierte Umkristallisation aus Methylenchlorid/Diisopropyläther erhält man 4-Chlor- 17-acetoxy- l«,2(i;6//,7/i-dimethylen-4-pregnen-3,20-dion vom Schmelzpunkt 279 bis 280'C, UV: T276 = 15 250; [«]0 = -77° (Chloroform).Repeated fractional recrystallization from methylene chloride / diisopropyl ether gives 4-chloro-17-acetoxy- 1,2 (i; 6 //, 7 / i-dimethylene-4-pregnen-3,20-dione with a melting point of 279 to 280 ' C, UV: T 276 = 15,250; [«] 0 = -77 ° (chloroform).
Aus den eingeengten Mutterlaugen erhält man durch weitere fraktionierte Kristallisation aus Essigester 4 - Chlor -17 - acetoxy -1 α,2«;6«,7« - dimethylen-4-pregnen-3,20-dion vom Schmelzpunkt 264 bis 266° C. UV:f2ft8 = 10400: [«], = +233° (Chloroform).From the concentrated mother liquors, further fractional crystallization from ethyl acetate gives 4-chloro-17-acetoxy-1 α, 2 ";6", 7 "- dimethylene-4-pregnen-3,20-dione with a melting point of 264 to 266 ° C UV: f2ft8 = 10400: [«], = + 233 ° (chloroform).
1 g 4-Chlor-17-acetoxy- l«,2a;6(i,7«-dimethylen-4-pregnen-3,20-dion werden in 40 m! Methanol und 1 ml Tetrahydrofuran suspendiert, in die Suspension wird eine Lösung von 1,6 g Natriumhydroxid in 5 ml Wasser zugegeben und unter Stickstoff 17 Stunden bei Raumtemperatur gerührt. Das Reaktionsgemisch wird in 800 ml Eiswasser, das 5 ml Essigsäure enthält, eingerührt. Der entstandene Niederschlag wird auf einer Nutsche abgesaugt, mit Wasser neutral gewaschen und bei 50JC im Vakuum getrocknet. Man erhält 1,6g 4-Chlor-17-hydroxy- l«,2«;6«,7«-dimethylen-4-pregnen-3,20-dion. Die durch Umkristallisation aus Essigester erhaltene reine Verbindung schmilzt bei 269 bis 271°C, UV: ,·269 = 10 300; [«]<> = +269,5 (Chloroform). 1 g of 4-chloro-17-acetoxy- 1 ", 2a; 6 (i, 7" -dimethylene-4-pregnen-3,20-dione are suspended in 40 ml of methanol and 1 ml of tetrahydrofuran, and a A solution of 1.6 g of sodium hydroxide in 5 ml of water was added and the mixture was stirred under nitrogen for 17 hours at room temperature. The reaction mixture was stirred into 800 ml of ice water containing 5 ml of acetic acid. The precipitate formed was filtered off with suction on a suction filter and washed neutral with water and dried at 50 J C in vacuo to give 1.6 g of 4-chloro-17-hydroxy-l ', 2',. 6 ', 7' -dimethylen-4-pregnene-3,20-dione by recrystallization from. The pure compound obtained from ethyl acetate melts at 269 to 271 ° C, UV: · 269 = 10,300; [«] <> = +269.5 (chloroform).
B e i s ρ i e 1 3B e i s ρ i e 1 3
2,5 ml Capronsäureanhydrid und 100 mg p-Toluolsulfonsäure werden unter Feuchtigkeitsausschluß verrührt. Unter Stickstoff und Rühren gibt man 1 g 4-Chlor-17- hydroxy -1 α,2α ;6α,7α - dimethylen - 4 - pregnen-3,20-dion und 2,5 ml Capronsäure hinzu. Nach 4 Stunden Reaktionszeit bei Raumtemperatur fällt man in Eiswasser, das 5 g Natriumhydrogencarbonat enthält. Man saugt den erhaltenen Niederschlag ab, wäscht ihn mit Wasser neutral und trocknet ihn im Vakuum bei 400C. Durch Behandeln des rohen Capronats mit Diisopropyläther entfernt man die noch anhaftende Capronsäure. Man erhält 1 g 4-Chlor- ! 7 - hexinoyloxy -1 «,2u ;6a,7u- dimethylen - 4 - pregnen-3,20-dion. Nach Umkristallisation aus Methanol schmilzt die Substanz bei 194 bis 195°C, UV: t2bS = 10 600; [u]0 = +206,2c (Chloroform).2.5 ml of caproic anhydride and 100 mg of p-toluenesulfonic acid are stirred with the exclusion of moisture. 1 g of 4-chloro-17-hydroxy-1 α, 2α; 6α, 7α-dimethylene-4-pregnen-3,20-dione and 2.5 ml of caproic acid are added under nitrogen and with stirring. After a reaction time of 4 hours at room temperature, it is precipitated into ice water which contains 5 g of sodium hydrogen carbonate. Is filtered off the precipitate obtained, it is washed neutral with water and dried in vacuo at 40 0 C. By treating the crude Capronats with diisopropyl ether, remove the still adhering caproic acid. 1 g of 4-chlorine is obtained! 7 - hexinoyloxy -1 ", 2u; 6a, 7u-dimethylene - 4 - pregnen-3,20-dione. After recrystallization from methanol, the substance melts at 194 ° to 195 ° C., UV: t 2bS = 10,600; [ u ] 0 = + 206.2 c (chloroform).
Claims (4)
Priority Applications (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19691907804 DE1907804C3 (en) | 1969-02-13 | 4-chloro-1alpha, 2alpha; 6alpha, 7alphadimethylene-3-keto-4-pregnene, processes for their preparation and agents containing them | |
| DK25470AA DK123712B (en) | 1969-02-13 | 1970-01-20 | Analogous process for the preparation of 4-chloro-1α, 2α, 6α, 7α-dimethylene-4-pregnen-17α-ol-3,20-dione or esters thereof. |
| CS528A CS167272B2 (en) | 1969-02-13 | 1970-01-23 | |
| JP45011419A JPS4920563B1 (en) | 1969-02-13 | 1970-02-09 | |
| US11013A US3691213A (en) | 1969-02-13 | 1970-02-12 | 4-chloro-1alpha,2alpha,6alpha,7alpha-dimethylene-3-keto-4-pregnene and method of making the same |
| FR707004917A FR2034545B2 (en) | 1969-02-13 | 1970-02-12 | |
| CH1620472A CH532564A (en) | 1969-02-13 | 1970-02-13 | Ovulation inhibiting pregnenes |
| GB706670A GB1304698A (en) | 1969-02-13 | 1970-02-13 | |
| CH210270A CH531489A (en) | 1967-08-11 | 1970-02-13 | Ovulation inhibiting pregnenes |
| BE745966D BE745966A (en) | 1969-02-13 | 1970-02-13 | PREGNENES, THEIR PREPARATIONS AND THEIR USES |
| NL7002112A NL7002112A (en) | 1969-02-13 | 1970-02-13 | |
| DK612371AA DK126501B (en) | 1969-02-13 | 1971-12-15 | 4-chloro-1,2,6,7-dimethylene-3-keto-4-pregnenes for use in contraception. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19691907804 DE1907804C3 (en) | 1969-02-13 | 4-chloro-1alpha, 2alpha; 6alpha, 7alphadimethylene-3-keto-4-pregnene, processes for their preparation and agents containing them |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1907804A1 DE1907804A1 (en) | 1970-08-20 |
| DE1907804B2 DE1907804B2 (en) | 1976-02-05 |
| DE1907804C3 true DE1907804C3 (en) | 1976-12-02 |
Family
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