DE1060394B - Process for the manufacture of anti-inflammatory steroids - Google Patents
Process for the manufacture of anti-inflammatory steroidsInfo
- Publication number
- DE1060394B DE1060394B DEU4781A DEU0004781A DE1060394B DE 1060394 B DE1060394 B DE 1060394B DE U4781 A DEU4781 A DE U4781A DE U0004781 A DEU0004781 A DE U0004781A DE 1060394 B DE1060394 B DE 1060394B
- Authority
- DE
- Germany
- Prior art keywords
- methyl
- dione
- pregnadiene
- dioxy
- fluoro
- 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 11
- 230000003110 anti-inflammatory effect Effects 0.000 title claims description 9
- 150000003431 steroids Chemical class 0.000 title claims description 5
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000012025 fluorinating agent Substances 0.000 claims description 2
- 229930194542 Keto Natural products 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 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 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 229940096017 silver fluoride Drugs 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 229960000890 hydrocortisone Drugs 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 3
- 239000005977 Ethylene Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003862 glucocorticoid Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000001919 adrenal effect Effects 0.000 description 2
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- -1 from 6-methyl-11ß Chemical class 0.000 description 2
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 2
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- DDAZLRORDOWNBG-YFWFAHHUSA-N (8S,9S,10R,13S,14S,17S)-17-(2-fluoroacetyl)-10,13-dimethyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-one Chemical compound FCC([C@H]1CC[C@H]2[C@@H]3CCC4=CC(C=C[C@]4(C)[C@H]3CC[C@]12C)=O)=O DDAZLRORDOWNBG-YFWFAHHUSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- JKFYKCYQEWQPTM-UHFFFAOYSA-N 2-azaniumyl-2-(4-fluorophenyl)acetate Chemical compound OC(=O)C(N)C1=CC=C(F)C=C1 JKFYKCYQEWQPTM-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 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 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 229910021612 Silver iodide Inorganic materials 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229940045348 brown mixture Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 208000002296 eclampsia Diseases 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000002070 germicidal effect Effects 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 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
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 229940057838 polyethylene glycol 4000 Drugs 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 201000011461 pre-eclampsia Diseases 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229940045105 silver iodide Drugs 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000699 topical effect 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
Verfahren zur Herstellung von entzündungswidrig wirkenden Steroiden Die Erfindung bezieht sich auf ein Verfahren zur Herstellung von entzündungswidrig wirkenden Steroiden, und zwar von 6-Methyl-11ß,17a-dioxy-21-fluor-1,4-pregnadien-3,20-dion und 6-Methyl-17a-oxy-21-fluor-1,4-pregnadien-3,11,20-trion, die wertvolle physiologische Eigenschaften besitzen.Process for the manufacture of anti-inflammatory steroids The invention relates to a method for producing anti-inflammatory effective steroids, namely from 6-methyl-11ß, 17a-dioxy-21-fluoro-1,4-pregnadiene-3,20-dione and 6-methyl-17a-oxy-21-fluoro-1,4-pregnadiene-3,11,20-trione, the valuable physiological Possess properties.
Das erfindungsgemäße Verfahren besteht darin, daß man 6-Methyl-11ß,17a-dioxy-21-jod-1,4-pregnadien-3,20-dion in bekannter Weise mit einem Fluorierungsmittel umsetzt und gegebenenfalls die llständige Hydroxylgruppe in ebenfalls bekannter Weise oxydiert.The process according to the invention consists in that 6-methyl-11ß, 17a-dioxy-21-iodo-1,4-pregnadiene-3,20-dione reacted in a known manner with a fluorinating agent and optionally the permanent Hydroxyl group is also oxidized in a known manner.
Es kann durch folgendes Formelschema wiedergegeben werden: Die verfahrensgemäß herstellbaren neuen Produkte, insbesondere die 6a-Epimeren, sind physiologisch stark wirksam und unterscheiden sich in ihren Wirkungsspektren von denen natürlich vorkommender Nebennierenrindenhormone, wie Hydrocortison und Cortison, vor allem hinsichtlich der Wirkung auf den Mineral- und Wasser-Stoffwechsel. Die neuen Verbindungen bewirken die Ausscheidung von Salz und Wasser, was sie für die Behandlung von chronischen kongestiven Herzbeschwerden und für die Behandlung von Leberzirrhose, nephrotischem Syndrom und die Behandlung von Eclampsien und Präeclampsien besonders wertvoll macht. Sie besitzen ferner entzündungswidrige, glucocorticoide, anästhetische, uterine, ovariale, adrenalwachstumshemmende und adrenalcorticoide Wirksamkeit. Ihre glucocorticoide und entzündungswidrige Wirkung ist der des Hydrocortisons bei weitem überlegen. So ergab der Leberglykogenablagerungstest nach Stafford und Mitarbeiter (Proc. Soc. Exp. Biol. and Med., Bd. 89, 1955, S. 371) für 6a-Methyl-11ß,17a-dioxy-21-fluor-1,4-pregnadien-3,20-dion die 5fache Wirkung des Hydrocortisons, während für das vergleichbare 11ß,17a-Dioxy-21-fluor-4-pregnen-3,20-dion nur29 °/o der Hydrocortisonwirkung beobachtet wurden.It can be represented by the following equation: The new products that can be produced according to the process, in particular the 6a-epimers, are physiologically highly effective and differ in their spectrum of activity from those of naturally occurring adrenal hormones such as hydrocortisone and cortisone, especially with regard to their effect on the mineral and water metabolism. The new compounds cause the excretion of salt and water, which makes them particularly valuable for the treatment of chronic congestive heart problems and for the treatment of cirrhosis of the liver, nephrotic syndrome and the treatment of eclampsia and pre-eclampsia. They also have anti-inflammatory, glucocorticoid, anesthetic, uterine, ovarian, adrenal growth-inhibiting and adrenalcorticoid activity. Its glucocorticoid and anti-inflammatory effects are far superior to that of hydrocortisone. The liver glycogen deposition test according to Stafford and coworkers (Proc. Soc. Exp. Biol. And Med., Vol. 89, 1955, p. 371) for 6a-methyl-11ß, 17a-dioxy-21-fluoro-1,4- pregnadiene-3,20-dione had 5 times the effect of hydrocortisone, while only 29% of the hydrocortisone effect was observed for the comparable 11β, 17a-dioxy-21-fluoro-4-pregnen-3,20-dione.
Die entzündungswidrige Wirkung des 6a-Methyl-11ß,17a-dioxy-21-fluor-1,4-pregnadien-3,20-dions ist nach dem Granulomtest (Andre Robert und Mitarbeiter, Acta Endocrinologica, Bd. 25, 1957, S. 105) 7,6mal so hoch wie die des Hydrocortisons. Das 11ß,17a-Dioxy-21-fluor-4-pregnen-3,20-dion zeigt dagegen keine meßbare entzündungswidrige Wirkung. Die neuen Produkte sind oral, parenteral und örtlich (Haut, Augen) anwendbar. Für die orale Anwendung können sie zusammen mit Polyäthylenglykol 4000 oder 6000 oder Lactose und/oder Sucrose als Träger in die Form von Tabletten gebracht werden. Für die örtliche Anwendung verarbeitet man sie vorteilhaft in Salben, flüssige Präparate, Gelees, Cremes, Suppositorien, Zäpfchen, wäßrige Suspensionen usw. Zur Steigerung und Ergänzung ihrer Wirkung kann man dabei Antibiotika, Sulfonamide und/oder Germicide zumischen.The anti-inflammatory effect of 6a-methyl-11ß, 17a-dioxy-21-fluoro-1,4-pregnadiene-3,20-dione is according to the granuloma test (Andre Robert and coworkers, Acta Endocrinologica, Vol. 25, 1957, p. 105) 7.6 times as high as that of hydrocortisone. In contrast, 11ß, 17a-dioxy-21-fluoro-4-pregnen-3,20-dione shows no measurable anti-inflammatory effect. The new products can be used orally, parenterally and locally (skin, eyes). For oral use they can be brought into the form of tablets together with polyethylene glycol 4000 or 6000 or lactose and / or sucrose as a carrier. For topical use, they are advantageously processed in ointments, liquid preparations, jellies, creams, suppositories, suppositories, aqueous suspensions, etc. To increase and supplement their effect, antibiotics, sulfonamides and / or germicides can be mixed in.
Die erfindungsgemäß herstellbaren Verbindungen, das 6-@Iethyl-11ß,17a-dioxy 21-fluor-1,4-pregnadien-3,20-dion und sein 11-Keto Analoges können in weitere therapeutisch wertvolle Verbindungen, z. B. das 6-Methyl-1lß,17a-dioxy-9,21-difluor-1,4-pregnadien-3,20-dion und sein 11-Keto-Derivat umgewandelt werden, die ebenfalls glucocorticoide und entzündungswidrige Wirkung besitzen und zusammen mit den verfahrensgemäß herstellbaren Verbindungen in Präparate für die medizinische Anwendung verarbeitet werden können. Man geht dabei in der Weise vor, daß man 6-Methyl-llß,17a-dioxy-21-fluor-1,4-pregnadien-3,20-dion in 9(11)-Stellung dehydratisiert, an das erhaltene 6-Methyl-17a-oxy-21-fluor-1,4,9(11)-pregnatrien-3,20-dion unterhalogenige Säure anlagert, aus dem gebildeten 6-Methyl-9a-halögen-llß,17a-dioxy-21-fluor-1,4-pregnadien-3,20-dion Halogenwasserstoff abspaltet und das so erhaltene 6-Methyl-9(11)-oxido-17a-oxy-21-fluor-1,4-pregnadien mit Fluorwasserstoff behandelt.The compounds that can be prepared according to the invention, 6- @ ethyl-11ß, 17a-dioxy 21-fluoro-1,4-pregnadiene-3,20-dione and its 11-keto analogues can be used in further therapeutic applications valuable compounds, e.g. B. 6-methyl-1ß, 17a-dioxy-9,21-difluoro-1,4-pregnadiene-3,20-dione and its 11-keto derivative, which is also glucocorticoid and anti-inflammatory Have effect and together with the compounds that can be produced according to the method can be processed into preparations for medical use. One goes in such a way that 6-methyl-11ß, 17a-dioxy-21-fluoro-1,4-pregnadiene-3,20-dione dehydrated in the 9 (11) position to the 6-methyl-17a-oxy-21-fluoro-1,4,9 (11) -pregnatriene-3,20-dione obtained Hypohalous acid is added, from the 6-methyl-9a-halogen-11ß, 17a-dioxy-21-fluoro-1,4-pregnadiene-3,20-dione formed Splitting off hydrogen halide and the 6-methyl-9 (11) -oxido-17a-oxy-21-fluoro-1,4-pregnadiene thus obtained treated with hydrogen fluoride.
Zur Durchführung des erfindungsgemäßen Verfahrens wird 6-Methyl-11ß,17a-dioxy-21-jod-1,4-pregnadien-3,20-dion in einem geeigneten Lösungsmittel, wie Acetonitril, Hexanen, Heptanen, Benzol, tert. Butylalkohol od. dgl., vorzugsweise in Acetonitril, gelöst und in an sich bekannter Weise mit Silberfluorid behandelt. Die Reaktion wird unter Ausschluß von Licht und unter Rühren durchgeführt. An Stelle von festem Silberfluorid wird vorteilhaft eine 50°/jge wäBrige Silberfluoridlösung verwendet. Die Reaktion wird zweckmäßig zwischen 40 und 60° G durchgeführt. Es können jedoch auch niedrigere oder höhere Temperaturen zwischen 10 und etwa 75° C angewendet werden. Da das bei der Umsetzung gebildete Silberjodid mit dem Silberfluorid eine Molekülverbindung eingeht, müssen mindestens 2 Mol Silberfluorid pro Mol Steroid verwendet werden. Zur Erzielung höherer Ausbeuten verwendet man jedoch vorteilhaft einen 10 bis 50o/jgen Überschuß über diese Menge. Das Silberfluorid wird nach und nach zugegeben. Die Reaktionszeit beträgt 1 2 Stunde bis zu 6 Stunden. Zur Isolierung des Produktes wird das Lösungsmittel verdampft und das rohe Produkt mit einem geeigneten Lösungsmittel, wie Chloroform, Methylenchlorid, Tetrachlorkohlenstoff, Benzol od. dgl., extrahiert. Die Reinigung erfolgt nach üblichen Verfahren, z. B. durch nochmalige Extraktion, Umkristallisieren oder chromatographisch.To carry out the process according to the invention, 6-methyl-11ß, 17a-dioxy-21-iodo-1,4-pregnadiene-3,20-dione is used in a suitable solvent such as acetonitrile, hexanes, heptanes, benzene, tert. Butyl alcohol or the like, preferably in acetonitrile, dissolved and known per se Way treated with silver fluoride. The reaction is in the absence of light and carried out with stirring. Instead of solid silver fluoride, a 50% / y aqueous silver fluoride solution is used. The reaction is conveniently between 40 and 60 ° G carried out. However, lower or higher temperatures can also be used between 10 and about 75 ° C. Because that formed in the implementation Silver iodide with which silver fluoride forms a molecular compound must at least 2 moles of silver fluoride are used per mole of steroid. To achieve higher yields however, it is advantageous to use a 10 to 50% excess over this amount. The silver fluoride is gradually added. The reaction time is 1 2 hours up to 6 hours. The solvent is evaporated to isolate the product and the crude product with a suitable solvent such as chloroform, methylene chloride, Carbon tetrachloride, benzene or the like., Extracted. The cleaning is carried out according to the usual Procedure, e.g. B. by repeated extraction, recrystallization or chromatographically.
Die Oxydation des 6-Methyl-Ilß,17a-dioxy-21-fluor-1,4-pregnadien-3,20-dions wird auf übliche Weise durchgeführt, z. B. in Essigsäurelösung mit der berechneten Menge Chromsäureanhydrid oder einem leichten, beispielsweise 10 bis 30%igen Überschuß. Die Oxydation kann auch mit einem Halogenamid oder Halogenimid, wie N-Bromacetamid, N-Chlorsuccinimid, N-Bromsuccinimid in Pyridin, Dioxan oder anderen Lösungsmitteln erfolgen. Nach beendeter Oxydation wird das Oxydationsmittel zerstört. Bei Verwendung von Chromsäure z. B. durch Zugabe von Methylalkohol, Äthylalkohol usw. oder durch Zugabe eines Alkalibisulfits, wenn Chromsäure oder N-Bromsuccinimid und andere N-Halogenacylamide angewandt wurden. Danach wird das 6-Methyl-17a-oxy-21-fiuor-1,4-pregnadien-3,11,20-trion in der üblichen Weise gewonnen, z. B. durch Extraktion mittels mit Wasser nicht mischbaren Lösungsmitteln, wie Methylenchlorid, Äthylenchlorid, Chloroform, Tetrachlorkohlenstoff, Äther, Benzol, Toluol od. dgl., oder gegebenenfalls chromatographisch.The oxidation of 6-methyl-ILß, 17a-dioxy-21-fluoro-1,4-pregnadiene-3,20-dione is carried out in the usual way, e.g. B. in acetic acid solution with the calculated Amount of chromic anhydride or a slight, for example 10 to 30%, excess. The oxidation can also be carried out with a halogenamide or halogenimide, such as N-bromoacetamide, N-chlorosuccinimide, N-bromosuccinimide in pyridine, dioxane or other solvents take place. When the oxidation is complete, the oxidizing agent is destroyed. Using of chromic acid e.g. B. by adding methyl alcohol, ethyl alcohol, etc. or by Addition of an alkali bisulfite if chromic acid or N-bromosuccinimide and other N-haloacylamides were applied. Then the 6-methyl-17a-oxy-21-fluor-1,4-pregnadiene-3,11,20-trione obtained in the usual way, e.g. B. not by extraction with water miscible solvents such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, Ether, benzene, toluene or the like, or optionally chromatographically.
Der für das erfindungsgemäße Verfahren verwendete Ausgangsstoff, das 6-Methyl-11ß,17a-dioxy-21-jod-1,4-pregnadien-3,20-dion, kann dadurch hergestellt werden, daß man 11ß,17a,21-Trioxy-4-pregnen-3,20-dion-3,20-bis-(äthylenketal) epoxydiert, das erhaltene 5a,6a-Oxido-11ß,17a,21-trioxy-allopregnan-3,20-dion-3,20-bis-(äthylenketal) mit Methylmagnesiumbromid umsetzt, das entstandene 5a,11ß,17a,21-Tetraoxy-6ß-methyl-allopregnan-3,20-dion-3,20-bis-(äthylenketal) entketalisiert, das erhaltene 5a,11ß,17a,21-Tetraoxy-6ß-methyl-allopregnan-3,20-dion dehydratisiert, das gebildete llß,17a,21-Trioxy-6-methyl-4-pregnen-3,20-dion in 1(2)-Stellung fermentativ dehydriert, das derart erhaltene 11ß,17a,21-Trioxy-6-methyl-1,4-pregnadien-3,20-dion in 21-Stellung sulfoniert und das entstandene 21-Sulfonat in Acetonlösung mit Natriumjodid oder Kaliumjodid umsetzt.The starting material used for the process according to the invention, the 6-methyl-11β, 17a-dioxy-21-iodo-1,4-pregnadiene-3,20-dione, can thereby be produced be that 11ß, 17a, 21-trioxy-4-pregnen-3,20-dione-3,20-bis (ethylene ketal) is epoxidized, the obtained 5a, 6a-oxido-11ß, 17a, 21-trioxy-allopregnan-3,20-dione-3,20-bis- (ethylene ketal) reacts with methyl magnesium bromide, the resulting 5a, 11ß, 17a, 21-tetraoxy-6ß-methyl-allopregnan-3,20-dione-3,20-bis (ethylene ketal) The 5a, 11ß, 17a, 21-tetraoxy-6ß-methyl-allopregnan-3,20-dione obtained are decetalised dehydrated, the 11ß, 17a, 21-trioxy-6-methyl-4-pregnen-3,20-dione formed in 1 (2) position fermentatively dehydrated, the 11β, 17a, 21-trioxy-6-methyl-1,4-pregnadiene-3,20-dione obtained in this way sulfonated in the 21-position and the resulting 21-sulfonate in acetone solution with sodium iodide or potassium iodide.
Das folgende Beispiel erläutert das erfindungsgemäße Verfahren Beispiel
6a-Methyl-11ß,17a-dioxy-21-fluor-1,4-pregnadien-3,20-dion 1 g 6a-Methyl-ilß,17a-dioxy-21-jod-1,4-pregnadien-3,20-dion
wurde durch Erhitzen bis zum Siedepunkt in 150 ccm Acetonitril (technisch rein)
gelöst. Nach dem Kühlen auf 40° C wurde die Lösung unter Ausschluß von Licht und
unter Rühren mit 0,8 ccm einer 50°/jgen wäßrigen Silberfluoridlösung versetzt. Die
Lösung wurde darauf trübe und nahm eine braune Farbe an. Unter dauerndem Rühren
bei 40 bis 45° C wurde nach einer Stunde nochmals Silberfluoridlösung zugesetzt,
und zwar zweimal je 0,7 ccm. Dann wurde noch 2 Stunden erhitzt und gerührt. Das
braune Gemisch wurde darauf durch eine Schicht aus Celite-Diatomeenerde filtriert
und das Filtrat zu einem Bad bei reduziertem Druck und einer Temperatur von 50°
C eingedampft. Der braune Rückstand wurde gründlich zweimal mit je 100 ccm warmem
Methylenchlorid extrahiert, die Methylenchloridextrakte wurden auf ein Volumen von
etwa 100 ccm eingeengt und über 50 g synthetisches Magnesiumsilikat, Handelsbezeichnung
»Florisih,, chromatographiert. Es wurden Fraktionen von 200 ccm der nachfolgend
angegebenen Zusammensetzung verwendet.
Analyse für C22 Hsa 04F Berechnet ..... C 70,18,H 7,76, F 5,05; gefunden....... C 70,43,H 7,91,F 3,78.Analysis for C22 Hsa 04F Calculated ..... C 70.18, H 7.76, F 5.05; found....... C 70.43, H 7.91, F 3.78.
Die erhaltene Verbindung kann anschließend mit thromsäureanhydrid in Essigsäure zu 6a-Methyl-17a-oxy-21-fluor-1,4-pregnadien-3,11,20-trion oxydiert werden.The compound obtained can then with thromic anhydride oxidized in acetic acid to 6a-methyl-17a-oxy-21-fluoro-1,4-pregnadiene-3,11,20-trione will.
Verwendet man als Ausgangsstoff im obigen Verfahren 6ß-Methyl-11ß,17a-dioxy-21-j od-1,4-pregnadien-3,20-dion und hält die Reaktionsbedingungen nahe am Neutralpunkt, so erhält man das entsprechende 6ß-Isomere, das durch Behandlung mit einer Säure oder Base in einem organischen Lösungsmittel, z. B. Äthanol, in das 6a-Epimere umgewandelt werden kann.If the starting material used in the above process is 6ß-methyl-11ß, 17a-dioxy-21-j od-1,4-pregnadiene-3,20-dione and keeps the reaction conditions close to the neutral point, in this way the corresponding 6β-isomer is obtained, which is obtained by treatment with an acid or base in an organic solvent, e.g. B. ethanol, converted into the 6a-epimer can be.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1060394XA | 1956-09-10 | 1956-09-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1060394B true DE1060394B (en) | 1959-07-02 |
Family
ID=22309142
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEU4781A Pending DE1060394B (en) | 1956-09-10 | 1957-09-09 | Process for the manufacture of anti-inflammatory steroids |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1060394B (en) |
-
1957
- 1957-09-09 DE DEU4781A patent/DE1060394B/en active Pending
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