DE1088489B - Process for the production of 6,9á-difluoro-21-deoxyhydrocortisone - Google Patents
Process for the production of 6,9á-difluoro-21-deoxyhydrocortisoneInfo
- Publication number
- DE1088489B DE1088489B DEU5791A DEU0005791A DE1088489B DE 1088489 B DE1088489 B DE 1088489B DE U5791 A DEU5791 A DE U5791A DE U0005791 A DEU0005791 A DE U0005791A DE 1088489 B DE1088489 B DE 1088489B
- Authority
- DE
- Germany
- Prior art keywords
- difluoro
- pregnen
- dione
- deoxyhydrocortisone
- dioxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 150000003461 sulfonyl halides Chemical class 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 7
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- -1 steroid compound Chemical class 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000005228 aryl sulfonate group Chemical group 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone 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 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000001860 Eye Infections Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 208000005141 Otitis Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000004133 Sodium thiosulphate Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- FGRVOLIFQGXPCT-UHFFFAOYSA-L dipotassium;dioxido-oxo-sulfanylidene-$l^{6}-sulfane Chemical compound [K+].[K+].[O-]S([O-])(=O)=S FGRVOLIFQGXPCT-UHFFFAOYSA-L 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 208000019258 ear infection Diseases 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 208000011323 eye infectious disease Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical class CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- XCOBTUNSZUJCDH-UHFFFAOYSA-B lithium magnesium sodium silicate Chemical compound [Li+].[Li+].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Na+].[Na+].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3 XCOBTUNSZUJCDH-UHFFFAOYSA-B 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- DJEHXEMURTVAOE-UHFFFAOYSA-M potassium bisulfite Chemical compound [K+].OS([O-])=O DJEHXEMURTVAOE-UHFFFAOYSA-M 0.000 description 1
- 229940099427 potassium bisulfite Drugs 0.000 description 1
- 235000010259 potassium hydrogen sulphite Nutrition 0.000 description 1
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Inorganic materials [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000003014 reinforcing effect Effects 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000005406 washing Methods 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
Verfahren zur Herstellung von 6,9 a-Difluor-21-desoxyhydrocortison Gegenstand der Erfindung ist ein Verfahren zur Herstellung von Verbindungen 6,9a-Difluor-21-desoxyhydrocortison (6,9a-Difluor-l lß,17a-dioxy-4-pregnen-3,20-dion).Process for the preparation of 6,9α-difluoro-21-deoxyhydrocortisone The invention relates to a process for the preparation of compounds 6,9a-difluoro-21-deoxyhydrocortisone (6,9a-difluoro-lß, 17a-dioxy-4-pregnen-3,20-dione).
Die erfindungsgemäß herstellbare Verbindung besitzt wertvolle therapeutische Eigenschaften und eignet sich zur Behandlung von rheumatischen und artbritischen Erkrankungen sowie zur Behandlung von Entzündungserscheinungen. Besonders ausgeprägt ist ihre glucocorticoide Wirkung. So besitzt das 6a,9a-Difluor-21-desoxyhydrocortison die dreiundzwanzigfache glucocorticoide Wirkung des Hydrocortisons, ferner etwa dessen zwölffache entzündungshemmende Wirkung. Außerdem übt es einen günstigen Einfluß auf den Salz- und Wasserhaushalt des Körpers aus. Es kann insbesondere zur Behandlung von Haut-, Augen- und Ohrenentzündungen beim Menschen und bei wertvolleren Haustieren sowie zur Bekämpfung von Kontaktdermatitis und anderen allergischen Erscheinungen verwendet werden. Hierfür bringt man es in die üblichen Dosierungsformen, beispielsweise in die Form von Pillen, Tabletten, Kapseln, Sirups oder Elixieren für den oralen Gebrauch oder in die Form flüssiger Präparate, wie sie für natürliche und synthetische Corticosteroidhormone üblich sind, für die parenterale Applikation. Zur örtlichen Anwendung wird es in die Form von Salben, Cremes, Lotionen u. dgl. gebracht. Bei der Herstellung der obengenannten Dosierungsformen können auch die Wirkung der Steroidverbindung ergänzende und verstärkende Antibiotika und Sulfonamide, ferner Konservierungsmittel verwendet werden.The compound that can be prepared according to the invention has valuable therapeutic properties Properties and is suitable for the treatment of rheumatic and Artbritic Diseases and for the treatment of symptoms of inflammation. Particularly pronounced is their glucocorticoid effect. It has 6a, 9a-difluoro-21-deoxyhydrocortisone twenty-three times the glucocorticoid action of hydrocortisone, and also about its twelve-fold anti-inflammatory effect. It also has a beneficial influence on the body's salt and water balance. It can be used in particular for treatment of skin, eye and ear infections in humans and more valuable pets as well as to combat contact dermatitis and other allergic phenomena be used. For this it is brought into the usual dosage forms, for example in the form of pills, tablets, capsules, syrups or elixirs for the oral Use or in the form of liquid preparations such as those for natural and synthetic Corticosteroid hormones are common for parenteral administration. To the local It is used in the form of ointments, creams, lotions and the like. at The preparation of the above dosage forms can also reduce the effects of the steroidal compound complementary and reinforcing antibiotics and sulfonamides, as well as preservatives be used.
Die erfindungsgemäß herstellbare Steroidverbindung wird nach folgendem-Reaktionsschema erhalten: in dem R einen organischen Rest, insbesondere einen 1 bis 10 Kohlenstoffatome enthaltenden Kohlenwasserstoffrest, z. B. den Methyl-, Äthyl-, Phenyl-, Tolyl-, Näphthyl-, vorzugsweise den Methylrest, bedeutet und der Fluorsubstituent in 6-Stellung a- wie ß-ständig sein kann.The steroid compound which can be prepared according to the invention is obtained according to the following reaction scheme: in which R is an organic radical, in particular a hydrocarbon radical containing 1 to 10 carbon atoms, e.g. B. denotes the methyl, ethyl, phenyl, tolyl, naphthyl, preferably the methyl radical, and the fluorine substituent in the 6-position can be a- or ß-position.
Das erfindungsgemäße Verfahren umfaßt die Umsetzung von 6,9a-Difluor-11ß,17a,21-trioxy 4-pregnen-3,20-dion (6,9a-Difluor-hydrocortison) (I) mit einem organischen Sulfonylhalogenid zum entsprechenden 21-Alkyl- oder Arylsulfonat des 6,9a-Difluor-11ß,17a,21-trioxy-4-pregnen-3,20-dioris, das nachfolgend mit einem Jodierungsmittel, wie Natriumj odid, in Acetonlösung zum entsprechenden 6,9a-Difluor 21-jod-11ß,17a-dioxy-4-pregnen-3,20-dion (III) umgesetzt und anschließend mit einem Reduktionsmittel, wie Zinkstaub, Natriumthiosulfat, Natriumbisulfit, Kaliumbisulfit od. dgl., vorzugsweise mit einem wäßrigen organischen Lösungsmittel zu dem entsprechenden 6,9a-Difluor-11ß,17a-dioxy-4-pregnen-3,20-dion (IV) umgewandelt wird. Das obengenannte 6,9a-Difluor-4-pregnen-Derivat kann gegebenenfalls zu 6,9a-Difluor-17a-oxy-4-pregnen-3,11,20-trion (V) oxydiert werden. Alle Verfahrensmaßnahmen werden in an sich bekannter Weise durchgeführt.The process according to the invention comprises the reaction of 6,9a-difluoro-11ß, 17a, 21-trioxy 4-pregnen-3,20-dione (6,9a-difluoro-hydrocortisone) (I) with an organic sulfonyl halide to the corresponding 21-alkyl or aryl sulfonate of 6,9a-difluoro-11ß, 17a, 21-trioxy-4-pregnen-3,20-dioris, which is subsequently used with an iodizing agent such as sodium iodide in acetone solution corresponding 6,9a-difluoro 21-iodine-11ß, 17a-dioxy-4-pregnen-3,20-dione (III) implemented and then with a reducing agent such as zinc dust, sodium thiosulfate, sodium bisulfite, Potassium bisulfite or the like, preferably with an aqueous organic solvent converted to the corresponding 6,9a-difluoro-11ß, 17a-dioxy-4-pregnen-3,20-dione (IV) will. The above-mentioned 6,9a-difluoro-4-pregnene derivative can optionally be 6,9a-difluoro-17a-oxy-4-pregnene-3,11,20-trione (V) are oxidized. All procedural measures are carried out in a manner known per se carried out.
Die Umsetzung der 21-Oxyverbindung mit dem organischen Sulfonylhalogenid wird vorzugsweise in einem Lösungsmittel, wie Pyridin, Benzol, Toluol od. dgl., durchgeführt, vorteilhaft in Pyridin, da dieses gleichzeitig den während der Reaktion entstehenden Chlorwasserstoff abfängt. Die Reaktionstemperatur -liegt je nach dem angewandten Lösungsmittel zwischen - 10 und + 60°C. Die Umsetzung ist nach etwa 4 bis 24 Stunden beendet, worauf man das Reaktionsprodukt 6,9a-Difluor-llß,17a, 21-trioxy-4-pregnen-3,20-dion-21-alkyl- oder -arylsulfonat (II) auf übliche Weise gewinnt, z. B. durch Verdampfen des Lösungsmittels, bis einfester Rückstand erhalten ist, oder durch Verdünnen der Reaktionsmischung mit Wasser und Ausfällen des Produktes -mit verdünnter Salzsäure.The reaction of the 21-oxy compound with the organic sulfonyl halide is preferably in a solvent such as pyridine, benzene, toluene or the like. carried out, advantageously in pyridine, since this is at the same time during the reaction intercepts resulting hydrogen chloride. The reaction temperature depends on the applied solvent between - 10 and + 60 ° C. The implementation is after about Completed 4 to 24 hours, whereupon the reaction product 6,9a-difluoro-llß, 17a, 21-trioxy-4-pregnen-3,20-dione-21-alkyl or aryl sulfonate (II) in the usual way wins, e.g. B. by evaporation of the solvent until a solid residue is obtained is, or by diluting the reaction mixture with water and precipitating the product -with dilute hydrochloric acid.
Das 21-Sulfonat wird darauf in einem Lösungsmittel, z. B. in Aceton, mit einem Überschuß eines Jodierungsmittels, wie Natrium-, Kalium- oder Lithiumjodid, 3 bis 30 Minuten unter Rückfluß erhitzt. Das auf diese Weise gebildete 6,9a-Difluor-21-jod-11ß,17a-dioxy-4-pregnen-3,20-dion kann durch Verdampfen des Lösungsmittels isoliert werden. Es wird in roher oder durch Umkristallisation gereinigter Form für die nachfolgende Reduktionsstufe verwendet, die vorzugsweise in Essigsäure bei Zimmertemperatur unter Verwendung von Natrium- oder Kaliumthiosulfat, Natriumsulfit oder Zinkstaub in Essigsäure im Überschuß erfolgt, wobei man 30 Minuten bis 1 Stunde rührt. Das Produkt 6,9a-Difluor-11ß,17a-dioxy-4-pregnen-3,20-dion wird auf übliche Weise gewonnen, z. B. durch Umkristallisieren oder Extrahieren und anschließendes Umkristallisieren oder Chromatographieren.The 21-sulfonate is then dissolved in a solvent, e.g. B. in acetone, with an excess of an iodizing agent such as sodium, potassium or lithium iodide, Heated to reflux for 3 to 30 minutes. The 6,9a-difluoro-21-iodine-11β, 17a-dioxy-4-pregnen-3,20-dione formed in this way can be isolated by evaporation of the solvent. It comes in raw or used by recrystallization of purified form for the subsequent reduction stage, preferably in acetic acid at room temperature using sodium or potassium thiosulphate, sodium sulphite or zinc dust in acetic acid in excess, stirring for 30 minutes to 1 hour. The product 6,9a-difluoro-11ß, 17a-dioxy-4-pregnen-3,20-dione is obtained in the usual way, e.g. B. by recrystallization or extraction and subsequent recrystallization or chromatography.
Die obengenannten Umsetzungen können auch mit dem entsprechenden 11-Koto-Analogen durchgeführt werden. Anschließend kann die llß-ständige Hydroxylgruppe in bekannter Weise, z. B. in Essigsäure mit Chromtrioxyd, oder mit einem Halogenamid oder -imid einer Säure, wie N-Bromacetamid, N-Chlorsuccinimid, oder N-Bromsuccinimid in geeigneten Lösungsmitteln zur 11-Ketogruppe oxydiert werden.The above reactions can also be carried out with the corresponding 11-Koto analogs be performed. The 11β-position hydroxyl group can then be used in a known manner Way, e.g. B. in acetic acid with chromium trioxide, or with a halogenamide or imide an acid such as N-bromoacetamide, N-chlorosuccinimide, or N-bromosuccinimide in suitable Solvents are oxidized to the 11-keto group.
In sämtlichen Stufen des erfindungsgemäßen Verfahrens kann jeweils das 6a- oder 6ß-Fluorepimere verwendet werden. Aus der 6ß-Fluorverbindung kann in an sich bekannter Weise das 6a-Fluorsteroid erhalten werden, wenn man ersteres in einem organischen Lösungsmittel, wie Chloroform, in Gegenwart von Alkohol mit einer wasserfreien Mineralsäure; - mqe -Salzsäure, bei Temperaturen von O' C oder etwas darunter behandelt. Das Reaktionsgemisch kann dann mit mehreren Teilen verdünntem Alkali und Wasser gewaschen und unter vermindertem Druck eingedampft werden, worauf man das 6a-Epimere in hoher Ausbeute erhält.The 6α or 6β-fluoroepimer can be used in all stages of the process according to the invention. From the 6β-fluorine compound, the 6α-fluoro steroid can be obtained in a manner known per se if the former is obtained in an organic solvent such as chloroform in the presence of alcohol with an anhydrous mineral acid; - mqe hydrochloric acid, treated at temperatures of O 'C or slightly below. The reaction mixture can then be washed with several parts of dilute alkali and water and evaporated under reduced pressure, whereupon the 6a-epimer is obtained in high yield.
Das folgende Beispiel erläutert das erfindungsgemäße 5 Verfahren. Beispiel 6a,9a-Difluor-11ß,17a,21-trioxy-4-pregnen-3,20-dion-21-methansulfonat (II) Einer Lösung von 500 mg 6a,9a-Difluor-11ß,17a,21-triio oxy-4-pregnen-3,20-dion (I) in 6 ccm Pyridin, die zuvor auf 0 bis 5°C abgekühlt worden war, wurden 0,55 ccm Methansulfonylchlorid zugefügt. Das Reaktionsgemisch wurde bei 6°C 16 Stunden gerührt und dann in 100 ccm kalte 5°/oige Salzsäurelösung gegossen. Das ausfallende 15 6a,9a-Difluor-11ß,17a,21-trioxy-4-pregnen-3,20-dion-21-methansulfonat wog nach dem Filtrieren, Waschen mit Wasser und Trocknen 620 mg. b) 6a,9a-Difluor-llß,17a-dioxy-21-jod-l-pregnen-3,20-dion (III) und 6a,9a-Difluor-11ß,17a-dioxy-4-pregnen-3,20-dion (IV) Einer Lösung von 370 mg rohem 6a,9a-Difluor-11ß,17a,21-trioxy-4-pregnen-3,20-dion-21-methansulfonat (II) in 10 ccm Aceton wurde eine Lösung von 370 mg Natriumjodid in 4 ccm Aceton zugesetzt. Das Gemisch wurde bei Zimmertemperatur 20 Minuten gerührt und 15 Minuten unter Rückfluß gekocht. Darauf wurde unter vermindertem Druck zur Trockne eingedampft. Der 6a,9a-Difluor-llß,17a-dioxy-21-jod-4-pregnen-3,20-dion (III) enthaltende Rückstand wurde in 5 ccm Essigsäure gelöst und 45 Minuten gerührt. Der Essigsäurelösung wurde zuerst eine Lösung von 600 mg Natriumthiosulfat in 7,2 ccm Wasser und sodann 70 ccm Eis und Wasser zugefügt. Der ausgeschiedene abfiltrierte Feststoff wog 185 mg. Er wurde über synthetisches Magnesiumsilikat chromatographiert und aus Aceton-Hexanen (bekannt unter dem Handelsnamen Skellysolve B) umkristallisiert, worauf man 137 mg 6a,9a-Difluor-11ß,17a-dioxy-4-pregnen-3,20-dion (IV) erhielt; Schmelzpunkt 220 bis 240°C. Zusätzliche 59 mg Produkt mit einem Schmelzpunkt von 200 bis 220°C wurden dadurch gewonnen, daß man die wäßrige Phase aus der obigen Fällstufe mit Methylenchlorid extrahierte und den Extrakt, wie oben beschrieben, chromatographierte und kristallisierte. Das gesammelte kristalline Material wurde mehrmals aus Äthylacetat umkristallisiert. Eine Analysenprobe hatte den Schmelzpunkt 253 bis 256°C. [a]D = -@- 109° (Aceton).The following example explains the method according to the invention. Example 6a, 9a-Difluoro-11ß, 17a, 21-trioxy-4-pregnen-3,20-dione-21-methanesulfonate (II) A solution of 500 mg 6a, 9a-difluoro-11ß, 17a, 21-triio oxy-4-pregnen-3,20-dione (I) in 6 cc of pyridine, which had previously been cooled to 0 to 5 ° C, was 0.55 cc Methanesulfonyl chloride added. The reaction mixture was stirred at 6 ° C. for 16 hours and then poured into 100 cc of cold 5% hydrochloric acid solution. The precipitating 15 6a, 9a-difluoro-11ß, 17a, 21-trioxy-4-pregnen-3,20-dione-21-methanesulfonate weighed 620 mg after filtering, washing with water and drying. b) 6a, 9a-difluoro-llß, 17a-dioxy-21-iodine-1-pregnen-3,20-dione (III) and 6a, 9a-difluoro-11ß, 17a-dioxy-4-pregnen-3,20-dione (IV) a solution of 370 mg of crude 6a, 9a-difluoro-11β, 17a, 21-trioxy-4-pregnene-3,20-dione-21-methanesulfonate (II) in 10 cc of acetone was a solution of 370 mg of sodium iodide in 4 cc of acetone added. The mixture was stirred at room temperature for 20 minutes and 15 minutes refluxed. It was then evaporated to dryness under reduced pressure. The residue containing 6a, 9a-difluoro-11ß, 17a-dioxy-21-iodo-4-pregnen-3,20-dione (III) was dissolved in 5 cc acetic acid and stirred for 45 minutes. The acetic acid solution was first a solution of 600 mg of sodium thiosulphate in 7.2 cc of water and then 70 cc of ice and water were added. The precipitated, filtered solid weighed 185 mg. It was chromatographed on synthetic magnesium silicate and from acetone-hexanes (known under the trade name Skellysolve B) recrystallized, whereupon 137 mg 6a, 9a-difluoro-11ß, 17a-dioxy-4-pregnen-3,20-dione (IV) received; Melting point 220 up to 240 ° C. An additional 59 mg of product with a melting point of 200-220 ° C was added obtained by the fact that the aqueous phase from the above precipitation stage with methylene chloride extracted and the extract chromatographed and crystallized as described above. The collected crystalline material was recrystallized several times from ethyl acetate. An analysis sample had a melting point of 253 to 256 ° C. [a] D = - @ - 109 ° (acetone).
Analyse für C"H"O,F2 Berechnet ... C 65,95, H 3,38, F 9,94; gefunden ... C 66,26, H 7,49, F 9,10.Analysis for C "H" O, F2 Calculated ... C 65.95, H 3.38, F 9.94; Found ... C 66.26, H 7.49, F 9.10.
Das 6a, 9a-Difluor-11ß,17a-dioxy-21-jod-4-pregnen-3,20-dion (III) kann vor der weiteren Umsetzung auch durch Umkristallisieren aus Methylenchlorid gereinigt werden.The 6a, 9a-difluoro-11ß, 17a-dioxy-21-iodine-4-pregnen-3,20-dione (III) can also be carried out by recrystallization from methylene chloride before the further reaction getting cleaned.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1088489X | 1957-11-29 |
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| Publication Number | Publication Date |
|---|---|
| DE1088489B true DE1088489B (en) | 1960-09-08 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEU5791A Pending DE1088489B (en) | 1957-11-29 | 1958-11-28 | Process for the production of 6,9á-difluoro-21-deoxyhydrocortisone |
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| DE (1) | DE1088489B (en) |
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1958
- 1958-11-28 DE DEU5791A patent/DE1088489B/en active Pending
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