DE1070177B - - Google Patents
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- Publication number
- DE1070177B DE1070177B DENDAT1070177D DE1070177DA DE1070177B DE 1070177 B DE1070177 B DE 1070177B DE NDAT1070177 D DENDAT1070177 D DE NDAT1070177D DE 1070177D A DE1070177D A DE 1070177DA DE 1070177 B DE1070177 B DE 1070177B
- Authority
- DE
- Germany
- Prior art keywords
- dione
- fluoro
- saturated
- epoxy
- pregnen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- NROKBHXJSPEDAR-UHFFFAOYSA-M Potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 10
- 150000003431 steroids Chemical class 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 235000003270 potassium fluoride Nutrition 0.000 claims description 5
- 239000011698 potassium fluoride Substances 0.000 claims 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 claims description 4
- 125000000468 ketone group Chemical group 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000012433 hydrogen halide Substances 0.000 claims description 3
- 229910000039 hydrogen halide Inorganic materials 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- WUKWITHWXAAZEY-UHFFFAOYSA-L Calcium fluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 claims description 2
- 229910001634 calcium fluoride Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 2
- CPUKWYXYHPOQJH-RDQPJNLGSA-N (8R,9S,10S,13S,14S)-17-ethenyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15-dodecahydro-1H-cyclopenta[a]phenanthrene Chemical compound C1CCC[C@]2(C)[C@H]3CC[C@](C)(C(=CC4)C=C)[C@@H]4[C@@H]3CCC21 CPUKWYXYHPOQJH-RDQPJNLGSA-N 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000000875 corresponding Effects 0.000 description 3
- 229960004544 cortisone Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000002024 ethyl acetate extract Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- KRVSOGSZCMJSLX-UHFFFAOYSA-L Chromic acid Chemical compound O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 2
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 description 2
- BYSGBSNPRWKUQH-UJDJLXLFSA-N Glycogen Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](O)[C@@H](O[C@@H]2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)O1 BYSGBSNPRWKUQH-UJDJLXLFSA-N 0.000 description 2
- 229940096919 Glycogen Drugs 0.000 description 2
- 229920002527 Glycogen Polymers 0.000 description 2
- 210000004185 Liver Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229960003290 cortisone acetate Drugs 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- JWMFYGXQPXQEEM-WZBAXQLOSA-N (8S,9S,10S,13R,14S,17S)-17-ethyl-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene Chemical class C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](CC)[C@@]1(C)CC2 JWMFYGXQPXQEEM-WZBAXQLOSA-N 0.000 description 1
- 229960000583 Acetic Acid Drugs 0.000 description 1
- 241001261858 Alsodes Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- JYGXADMDTFJGBT-VWUMJDOOSA-N Cortisol Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001886 cortisols Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- SSVFMICWXDVRQN-UHFFFAOYSA-N ethanol;sodium Chemical compound [Na].CCO SSVFMICWXDVRQN-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003128 pregnanes Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
deutschesGerman
patentamtpatent office
kl 12 ο 25/05kl 12 ο 25/05
BEKANNTMACHUNG
OEB ANMELDUNG
UND AUSGABE DER
AUS LEGESCHRIFT:NOTICE
OEB REGISTRATION
AND ISSUE OF THE
FROM LEGEND:
0 54581Yb/12o0 54581Yb / 12o
11. APRIL 19 S 7
3. DEZEMBER 1959APRIL 11, 19 S 7
DECEMBER 3, 1959
Die Erfindung betrifft ein Verfahren zur Synthese wertvoller neuer Steroide der allgemeinen FormelThe invention relates to a process for the synthesis of valuable new steroids of the general formula
CH2FCH 2 F
in welcher die 1(2)-Stellung gesättigt oder doppelt gebunden ist,· R Wasserstoff, R' /J-Oxy- oder R und R' zusammen Keto- und X Halogen bedeuten. Die erfindungsgemäß erhaltenen Verbindungen sind wertvolle Arzneimittel, die an Stelle von Cortison oder Hydrocortison angewendet werden können, jedoch um ein Vielfaches wirksamer sind als die entsprechenden Cortisonpräparate. in which the 1 (2) position is saturated or double bonded, R is hydrogen, R '/ J-oxy- or R and R' together denote keto and X denote halogen. The compounds obtained according to the invention are valuable Medicines that can be used in place of cortisone or hydrocortisone, however, are a Are many times more effective than the corresponding cortisone preparations.
Das erfindungsgemäße Verfahren kennzeichnet sich dadurch, daß man entweder ein Steroid der allgemeinen FormelThe inventive method is characterized in that either a steroid of the general formula
CH8YCH 8 Y
Anmelder:
Olin Mathieson Chemical Corporation,
New York, N.Y. (V.St.A.)Applicant:
Olin Mathieson Chemical Corporation,
New York, NY (V.St.A.)
Vertreter: Dipl.-Ing. E. Prinz
und Dr. rer. nat. G. Hauser, Patentanwälte,
München-Pasing, Bodenseestr. 3 aRepresentative: Dipl.-Ing. E. Prince
and Dr. rer. nat. G. Hauser, patent attorneys,
Munich-Pasing, Bodenseestr. 3 a
Beanspruchte Priorität:
V. St. v. Amerika vom 16. Mai 1956Claimed priority:
V. St. v. America May 16, 1956
Josef Edward Herz und Josef Fried,
New Brunswick, N. J. (V. St A.),
sind als Erfinder genannt wordenJosef Edward Herz and Josef Fried,
New Brunswick, NJ (V. St A.),
have been named as inventors
R-R'' R-R ''
C=OC = O
-OH-OH
a1 a 1
o-j:o-j:
in welcher die 1(2)-Stellung gesättigt oder doppelt gebunden ist, Y eine Alkansulfonyloxygruppe, Chlor oder Brom bedeutet und R, R' und X die vorstehend angegebene Bedeutung haben, in bekannter Weise mit KaUumfluorid in einem organischen Lösungsmittel mit hoher Dielektrizitätskonstante umsetzt oder daß man ein Steroid der allgemeinen Formelin which the 1 (2) position is saturated or double bonded, Y is an alkanesulfonyloxy group, chlorine or Is bromine and R, R 'and X have the meaning given above, in a known manner with calcium fluoride in an organic solvent with a high dielectric constant or that one is a steroid the general formula
CH8YCH 8 Y
I II I
C=OC = O
OHOH
in welcher die !^-Stellung gesättigt und doppelt gebunden ist und Y die vorstehend angegebene Bedeutung besitzt, zunächst in bekannter Weise mit Kaliumfluorid und dann ebenfalls in bekannter Weise mit einem Halogenwasserstoff umsetzt und anschließend gegebenenfalls die 11 ständige Hydroxylgruppe zur Ketogruppe oxydiert.in which the! ^ position is saturated and doubly bonded and Y has the meaning given above possesses, first in a known manner with potassium fluoride and then likewise in a known manner with a Reacts hydrogen halide and then optionally the 11 hydroxyl group to the keto group oxidized.
Die erfindungsgemäß erhaltenen, neuen Verbindungen besitzen durch das in 21-Stellung eingeführte Fluoratom überraschenderweise eine um ein Mehrfaches gesteigerte Wirkung gegenüber dem entsprechenden bekannten, das Fluoratom nicht enthaltenden Cortison- oder Hydrocortisonverbindungen. The novel compounds obtained according to the invention have the fluorine atom introduced in the 21-position Surprisingly, an effect that is several times greater than that of the corresponding known, the Cortisone or hydrocortisone compounds not containing fluorine atom.
Die neuen Verbindungen gemäß dieser Erfindung umfassen:The new compounds according to this invention include:
B. 21-Fluor-9a-halogen-ll/?-oxy-(oder ll-keto)-steroide der Pregnanreihe.B. 21-fluoro-9a-halogen-II /? - oxy (or II-keto) steroids of the pregnane series.
Die erfindungsgemäßen Umsetzungen erfolgen vorzugsweise in Dimethylformamid oder Dimethylsulfoxyd als organisches Lösungsmittel, am besten bei erhöhter Temperatur; ein Temperaturbereich von 100 bis 130°C So wird bevorzugt.The reactions according to the invention are preferably carried out in dimethylformamide or dimethyl sulfoxide as organic solvent, preferably at an elevated temperature; a temperature range of 100 to 130 ° C So is preferred.
Geeignete Ausgangsmaterialien für die zuletzt angegebene Ausführungsform des ernndungsgemäßen Verfahrens sind unter anderem die 21 -Alkansulfonsäureester des 9^,ll^-Erx)xy-^^pregnen-17a^l-diol-3iO-dions (z. B.Suitable starting materials for the last-mentioned embodiment of the method according to the invention include the 21 -alkanesulfonic acid esters of 9 ^, ll ^ -Erx) xy - ^^ pregnen-17a ^ l-diol-3iO-dione (e.g.
90» 687/42290 »687/422
das 21-Mesylat> und 9/},ll/i-Epoxy-/41'*-pregnadien-17a, 21-diol-3,20-dions, ferner das 21-Chlor-9/3,ll/3-epoxy-4*-pregnen-17ot-ol-3,20-dion, 21 -Chlor-9/3,ll/3-epoxy-Δ *·«-pregnadien-17a-ol-S,20-dion, 21 -Brom-9/3,1 1/3-epoxy-44-pregnen-17a-ol-3,20-dion und 21-Brom-9/3-ll/3-epoxy-Δ 1^pregnadien-17a-ol-3,20-dion.the 21-mesylate> and 9 /}, ll / i-epoxy- / 4 1 '* -pregnadien-17a, 21-diol-3,20-dione, furthermore the 21-chloro-9/3, ll / 3- epoxy-4 * -pregnen-17ot-ol-3,20-dione, 21 -Chlor-9/3, ll / 3-epoxy- Δ * · «-pregnadien-17a-ol-S, 20-dione, 21 - Bromo-9 / 3,1 1/3-epoxy-4 4 -pregnen-17a-ol-3,20-dione and 21-bromo-9/3-II / 3-epoxy- Δ 1 ^ pregnadien-17a-ol -3,20-dione.
Wird als Endprodukt des erfindungsgemäßen Verfahrens ein entsprechendes Il-Ketosteroid gewünscht, so kann auf übliche Weise oxydiert werden, z. B. durch Behandlung mit Chromsäure in Eisessig.If a corresponding II-ketosteroid is desired as the end product of the process according to the invention, so can be oxidized in the usual way, e.g. B. by treatment with chromic acid in glacial acetic acid.
Geeignete Ausgangssteroide für die zuerst angegebene Ausführungsform des erfindungsgemäßen Verfahrens umfassen: die 21-Alkansulfonsäureester des 9a-Fluorhydrocortisons (z. B. das 21-Mesylat), 9ct-Fluorcortisons, 9a-Fluor-l-dehydro-hydrocortisons und 9a-Fluor-l-dehydrocortisons; femer des 9a-Fluor-21-chlor-J4-pregnenll/3,17a-diol-3,20-dion, 9a-Fluor-21-chlor-Zl4-pregnen-17a-ol-3,ll,20-trion, 9a-Fluor-21-chlor-<d1-4-pregnadienll/3,17a-diol-3,20-dion, 9a-Fluor-21-chlor-J1.*-pregnadien-17a-ol-3,ll,20-trion, 9a-Fluor-21-brom-^J4-pregnenll/3,17a-diol-3,20-dion, 9a-Fluor-21 -brom-zl4-pregnen-17a-ol-3,ll,20-trion, 9a-Fluor-21-brom-,dM-pregnadien-11/3,17a-diol-3,20-dion und 9a-Fluor-21 -brom-4 x-4-pregnadien-17a-ol-3,l 1,20-trion.Suitable starting steroids for the first specified embodiment of the method according to the invention include: the 21-alkanesulfonic acid esters of 9a-fluorohydrocortisone (e.g. the 21-mesylate), 9ct-fluorocortisone, 9a-fluoro-1-dehydro-hydrocortisone and 9a-fluoro-1 -dehydrocortisone; also des 9a-fluoro-21-chloro-J 4 -pregnenll / 3,17a-diol-3,20-dione, 9a-fluoro-21-chloro-Zl 4 -pregnen-17a-ol-3, ll, 20- trione, 9a-fluoro-21-chloro- < d 1 - 4 -pregnadienII / 3,17a-diol-3,20-dione, 9a-fluoro-21-chloro-I 1. * - pregnadien-17a-ol-3 , ll, 20-trione, 9a-fluoro-21-bromo- ^ J 4 -pregnenll / 3,17a-diol-3,20-dione, 9a-fluoro-21-bromo-zl 4 -pregnen-17a-ol- 3, ll, 20-trione, 9a-fluoro-21-bromo-, dM-pregnadiene-11 / 3,17a-diol-3,20-dione and 9a-fluoro-21-bromo-4 x - 4 -pregnadiene- 17a-ol-3, l 1,20-trione.
a) ga^l-Difluor-J^pregnen-ll/J.lTa-diol-S^-diona) ga ^ l-Difluor-J ^ pregnen-ll / J.lTa-diol-S ^ -dion
Zu einer Lösung von 200 mg 9a-Fluor-hydrocortison-21-mesylat in 5 ecm von wiederholt destilliertem Dimethylformamid werden 200 mg wasserfreies Kaliumfluorid gegeben, und die erhaltene Suspension wird unter Rühren 18 Stunden auf IlO0C erhitzt. Die Mischung wird auf ein kleines Volumen konzentriert, in Wasser aufgenommen und mit Äthylacetat extrahiert. Der Äthylacetatextrakt wird dann mit Wasser wieder extrahiert und das Lösungsmittel im Vakuum entfernt. Der Rückstand wird mit Chloroform verrieben, und der chloroformunlösliche Niederschlag wird aus 95°/oigem Alkohol umkristallisiert. Reines 9et,21-Difluor-Zl4-pregnen-l 1/3,17o-diol-3,20-dion hat die folgenden Eigenschaften: Schmelzpunkt etwa 259 bis 261°C; [α]£ + 147° (c = 0,3 in Dioxan); + 134° (c = 0,53 in Aceton); 239 πιμ (e = 16400), λ**' 2,89 μ, 3,04 μ, 5,84 μ, 6,01 bis 6,05 μ.To a solution of 200 mg of 9a-fluoro-hydrocortisone 21-mesylate in 5 cc of distilled repeated dimethylformamide are added 200 mg of anhydrous potassium fluoride, and the resulting suspension is heated 0 C with stirring for 18 hours ILO. The mixture is concentrated to a small volume, taken up in water and extracted with ethyl acetate. The ethyl acetate extract is then extracted again with water and the solvent is removed in vacuo. The residue is triturated with chloroform, and the chloroform-precipitate is recrystallized ° / oig em alcohol from 95th Pure 9et, 21-Difluor-Zl 4 -pregnen-l 1 / 3,17o-diol-3,20-dione has the following properties: melting point about 259 to 261 ° C; [α] £ + 147 ° (c = 0.3 in dioxane); + 134 ° (c = 0.53 in acetone); 239 πιμ (e = 16400), λ ** '2.89 μ, 3.04 μ, 5.84 μ, 6.01 to 6.05 μ.
Berechnet .... C 65,95, H 7,38, F 9,94; gefunden C 65,96, H 7,43, F 9,87.Calculated .... C 65.95, H 7.38, F 9.94; Found C 65.96, H 7.43, F 9.87.
9α,21 -Difluor-d4-pregnen-110,17a-diol-3,2O-dion besitzt etwa 5- bis 7mal die Aktivität von Cortisonacetat in der Leber-Glykogen-Probe.9α, 21-difluoro-d 4 -pregnen-110,17a-diol-3,2O-dione has about 5 to 7 times the activity of cortisone acetate in the liver glycogen sample.
Bei der Konzentration der Chloroformlösung, aus welcher die unlösliche 21-Fluor-Verbindung entfernt worden ist, im Vakuum und der Umkristallisation des Rückstandes aus 95°/0igem Äthanol wurde ein Produkt erhalten, das folgende Eigenschaften hat: Schmelzpunkt etwa 272 bis 274°C; [a]? + 162° (c = 0,57 in Chloroform); A* 237 πιμ (e = 18300); 3,00 μ, 5,55 μ, 6,05 μ, 6,10 μ, 6,10 μ.Melting point about 272-274 ° C: When the concentration of the chloroform solution from which the insoluble 21-fluoro compound has been removed, in vacuo and recrystallization of the residue from 95 ° / 0 sodium ethanol, a product was obtained which has the following properties ; [a]? + 162 ° (c = 0.57 in chloroform); A * 237 πιμ (e = 18300); 3.00 µ, 5.55 µ, 6.05 µ, 6.10 µ, 6.10 µ.
Berechnet .... C 69.61, H 7,51, F 5,37; gefunden C 69,77, H 7,77, F 5,65.Calculated .... C 69.61, H 7.51, F 5.37; Found C 69.77, H 7.77, F 5.65.
Das Verfahren von Beispiel I kann mit Dimethylsulfoxyd anstatt Dimethylformamid durchgeführt werden ur.d ergibt dieselben Resultate.The procedure of Example I can be carried out with dimethyl sulfoxide in place of dimethylformamide ur.d gives the same results.
9a,21-Difiuor-J M-pregnadien-l ljS,17a-diol-3,20-dion9a, 21-Difluor-J M-pregnadien-1 ljS, 17a-diol-3,20-dione
Zu einer Lösung von 217 mg 9a-Fluor-zJ ^-pregnadienllj8,17a,21-triol-3,20-dion-21-mesylat in IOccm Dimethylformamid werden 220 mg wasserfreies Kaliumfluorid gegeben. Reaktionsbedingungen sind dieselben wie im Beispiel I. Der Rückstand des Äthylacetatextrakts wird ίο mit Chloroform verrieben und das unlösliche Pulver aus 95 °/oigem Äthylalkohol umkristallisiert. Das resultierende reine 9a,21-Difluor-J1.4-pregnadien-ll/3,17a-diol-3,20-dion hat folgende Eigenschaften: Schmelzpunkt etwa 281 bis 283° C; [a]* + 115° (c = 0,35 in Dioxan); A*:, 238 ma (ε = 15500); X£> 3,03 μ, 5,75 μ, 6,05 μ, 6,21 μ, 6,26 μ.220 mg of anhydrous potassium fluoride are added to a solution of 217 mg of 9a-fluoro-zJ ^ -pregnadienllj8,17a, 21-triol-3,20-dione-21-mesylate in 10ccm dimethylformamide. The reaction conditions are the same as in Example I. The residue of the ethyl acetate extract is triturated with chloroform and the insoluble powder is recrystallized from 95% ethyl alcohol. The resulting pure 9a, 21-difluoro-J 1 . 4 -pregnadiene-II / 3,17a-diol-3,20-dione has the following properties: melting point about 281 to 283 ° C; [a] * + 115 ° (c = 0.35 in dioxane); A *: 238 ma (ε = 15500); X £> 3.03 µ, 5.75 µ, 6.05 µ, 6.21 µ, 6.26 µ.
Berechnet .... C66,30, H6,79, F9,99; gefunden C 65,90, H 7,17, F 9,79.Calculated .... C66.30, H6.79, F9.99; Found C 65.90, H 7.17, F 9.79.
ga^l-Difluor-J^^pregnadien-ll/S.^a-diol-S.^-dion besitzt etwa 15mal die Aktivität des Cortisonacetats in der Ratten-Leber-Glykogen-Probe.ga ^ l-Difluor-J ^^ pregnadien-ll / S. ^ a-diol-S. ^ - dione has about 15 times the activity of cortisone acetate in the rat liver glycogen sample.
Aus dem Chloroformfiltrat obiger 21-Fluor-Verbindung wird durch Verdampfen des Lösungsmittels im Vakuum und Umkristallisation aus 95°/oigem Äthanol eine Verbindung isoliert von einer Struktur, die der im zweiten Teil des Beispiels I erhaltenen ähnelt, die aber eine zusätzliche Doppelbindung in der 1 (2)-Stellung enthält. Ihre Eigenschaften sind folgende: Schmelzpunkt etwa 227 bis 228°C; [a]£ + 181° (c = 0,47 in Chloroform); AS" 2,95 μ, 5.52 μ, 6,04 μ, 6,17 μ, 6,24 μ.The above 21-fluorine compound is obtained from the chloroform filtrate by evaporating the solvent in vacuo and recrystallization from 95% ethanol isolates a compound of a structure similar to that in the second Part of Example I obtained is similar, but contains an additional double bond in the 1 (2) position. Their properties are as follows: melting point about 227 to 228 ° C; [a] £ + 181 ° (c = 0.47 in chloroform); AS "2.95 µ, 5.52 µ, 6.04 µ, 6.17 µ, 6.24 µ.
a) 21-Fluor-9/3,l l/3-epoxy-J4-pregnen-17a-ol-3,20-diona) 21-Fluoro-9/3, II / 3-epoxy-J 4 -pregnen-17a-ol-3,20-dione
200 mg 9/3,1 l/3-epoxy-J4-pregnen-17a,21-diol-3,20-dion-21-mesylat und 200 mg wasserfreies Kaliumfluorid werden in 12 ecm frisch destilliertem Dimethylformamid zur Reaktion gebracht, wie im Beispiel I beschrieben. Zwei Umkristallisationen des gesamten Rückstandes von dem Äthylacetatextrakt aus Acetonhexan ergeben reines 21-Fluor-9£,ll/3-epoxy-d4-pregnen-17a-ol-3,20-dion mit folgenden Eigenschaften: Schmelzpunkt etwa 245 bis 246°C; [a]? — 11,5° (c = 0,37 in Aceton); A^x 243πιμ (ε = 15500); Xlf 2,87 μ, 5,80 μ, 6,10 μ.200 mg of 9 / 3.1 l / 3-epoxy-J 4 -pregnen-17a, 21-diol-3,20-dione-21-mesylate and 200 mg of anhydrous potassium fluoride are reacted in 12 ecm of freshly distilled dimethylformamide, as described in Example I. Two recrystallizations of the entire residue from the ethyl acetate extract from acetone hexane give pure 21-fluoro-9 £, ll / 3-epoxy-d 4 -pregnen-17a-ol-3,20-dione with the following properties: melting point about 245 to 246 ° C ; [a]? - 11.5 ° (c = 0.37 in acetone); A ^ x 243πιμ (ε = 15500); Xlf 2.87 µ, 5.80 µ, 6.10 µ.
Berechnet .... C 69,59, H 7,51, F 5,24; gefunden C 69,50, H 7,63, F 5,26.Calculated .... C 69.59, H 7.51, F 5.24; Found C 69.50, H 7.63, F 5.26.
b) 9a-Chlor-21-fluor-zl4-pregnen-ll/3,17a-diol-3,20-dionb) 9a-chloro-21-fluoro-zl 4 -pregnen-II / 3,17a-diol-3,20-dione
Zu einer Lösung von 42 mg 21-Fluor-9/3,ll/8-epoxyzl4-pregnen-17a-ol-3,20-dion in Aceton werden bei O0C 1,8 ecm 0,5 η-Salzsäure zugesetzt. Nach 60 Minuten werden Eis und verdünnte Bicarbonatlösung zugegeben, um überschüssige Säure auszuwaschen; nach Trennung der Schichten wird die Acetonlösung mit Wasser gewaschen, über Natriumsulfat getrocknet und zur Trockne eingedampft. Der kristalline Rückstand wird aus 95°/oigem Äthylalkohol umkristallisiert; man erhält reines 9a-Chlor-21-fluor-J4-pregnen-110,17a-diol-3,2O-dion. 1.8 ecm of 0.5 η hydrochloric acid are added at 0 ° C. to a solution of 42 mg of 21-fluoro-9/3, 11/8-epoxyzl 4 -pregnen-17a-ol-3,20-dione in acetone . After 60 minutes, ice and dilute bicarbonate solution are added to wash off excess acid; after separating the layers, the acetone solution is washed with water, dried over sodium sulphate and evaporated to dryness. The crystalline residue is recrystallized from 95% ethyl alcohol; pure 9a-chloro-21-fluoro-J 4 -pregnen-110,17a-diol-3,2O-dione is obtained.
Ähnlich werden, wenn man einen äquivalenten Wert von Bromwasserstoff- oder Jodwasserstoffsäure an Stelle der Salzsäure verwendet, die 9et-Brom- bzw. 9a-Jod-Similarly, if you put an equivalent value of hydrobromic or hydroiodic acid in place hydrochloric acid, the 9et-bromine or 9a-iodine
Claims (3)
Journ. Amer. Chem. Soc., Bd. 77, 1955, S. 4899;
Act. Chem. Scand., Bd. 9, 1955, S. 587.Considered publications:
Journ. Amer. Chem. Soc., Vol. 77, 1955, p. 4899;
Act. Chem. Scand., Vol. 9, 1955, p. 587.
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