DD210694A5 - PROCESS FOR THE PREPARATION OF 6ALPHA-METHYL PREDNISOLONE DERIVATIVES - Google Patents
PROCESS FOR THE PREPARATION OF 6ALPHA-METHYL PREDNISOLONE DERIVATIVES Download PDFInfo
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- DD210694A5 DD210694A5 DD83258236A DD25823683A DD210694A5 DD 210694 A5 DD210694 A5 DD 210694A5 DD 83258236 A DD83258236 A DD 83258236A DD 25823683 A DD25823683 A DD 25823683A DD 210694 A5 DD210694 A5 DD 210694A5
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- Prior art keywords
- methyl
- dione
- derivatives
- benzoyloxy
- pregnadiene
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims description 7
- VHRSUDSXCMQTMA-PJHHCJLFSA-N 6alpha-methylprednisolone Chemical class C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 title abstract description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- LEVJVKGPFAQPOI-UHFFFAOYSA-N phenylmethanone Chemical compound O=[C]C1=CC=CC=C1 LEVJVKGPFAQPOI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003246 corticosteroid Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[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 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims 1
- 229960005205 prednisolone Drugs 0.000 claims 1
- 208000010668 atopic eczema Diseases 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 2
- 208000017520 skin disease Diseases 0.000 abstract description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 abstract 2
- 230000000172 allergic effect Effects 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 230000000241 respiratory effect Effects 0.000 abstract 1
- 210000002345 respiratory system Anatomy 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- -1 isobutyryl group Chemical group 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229960001334 corticosteroids Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 229960004584 methylprednisolone Drugs 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- JAFMOTJMRSZOJE-UHFFFAOYSA-N 1,1,1-trimethoxybutane Chemical compound CCCC(OC)(OC)OC JAFMOTJMRSZOJE-UHFFFAOYSA-N 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 206010012455 Dermatitis exfoliative Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241001303601 Rosacea Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- RKHQGWMMUURILY-UHRZLXHJSA-N cortivazol Chemical compound C([C@H]1[C@@H]2C[C@H]([C@]([C@@]2(C)C[C@H](O)[C@@H]1[C@@]1(C)C2)(O)C(=O)COC(C)=O)C)=C(C)C1=CC1=C2C=NN1C1=CC=CC=C1 RKHQGWMMUURILY-UHRZLXHJSA-N 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000008505 nuclear pathway Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- C07J5/0046—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 substituted in position 17 alfa
- C07J5/0053—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 substituted in position 17 alfa not substituted in position 16
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
" ' Berlin, den 6· 10. 1983 62 998 18Berlin, the 6th 10th 1983 62 998 18
Verfahren zur Herstellung \on oiX-Methylprednisolon-DerivatenProcess for the preparation of oiX-methylprednisolone derivatives
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von βα,-Methylprednisolon-Derivaten der nachfolgend genannten allgemeinen Formel I.The present invention relates to a process for the preparation of βα, -methylprednisolone derivatives of the general formula I.
Der am nächsten liegende Stand der Technik ist in den DE-Patentanmeldungen Nr. 26 45 104, 26 45 105 und 23 40 591 und 19 58 549 sowie in der US-PS 33 83 394 oder in der. Publikation J. Amer. Soc, 79, 1957, 1515 beschrieben.The closest prior art is in DE Patent Application Nos. 26 45 104, 26 45 105 and 23 40 591 and 19 58 549 and in the US-PS 33 83 394 or in the. Publication J. Amer. Soc, 79, 1957, 1515.
Es wurde gefunden, daß die erfindungsgemäßen Derivate des ό<Χ'-Me thy !prednisolone überraschenderweise oft bei topischer Applikation eine signefikant stärkere Y/irksamkeit besitzen als die vorbekannten Derivate des 60^-Methylprednisolons· Diese Wirksamkeit ist oft sogar noch signifikant stärker als diejenige difluorierter "Edelkortikoide", wie etwa das 6 »χ, 9<x -Difluor-11 ß-hydroxy-16 ο-methyl-21 -valeryloxy-1,4-pregnadien-3,20-dion.Surprisingly, it has been found that the derivatives according to the invention of the ό <Χ'-methyl thy- prednisone often have a signifi- cantly stronger activity when applied topically than the previously known derivatives of the 60-methylprednisolone. This activity is often even significantly greater than that difluorinated "corticosteroids", such as the 6 »χ, 9 < -difluoro-11β-hydroxy-16α-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione.
Bei systemischer Applikation sind diese Derivate des Methylprednisolons überraschenderweise oft schwächer wirksam als die entsprechenden vorbekannten Derivate des 6cC-Methy!prednisolone.When administered systemically, these derivatives of methylprednisolone are surprisingly often less effective than the corresponding prior art derivatives of 6cC-methyl prednisolone.
62 998 1862 998 18
Der Erfindung liegt die Aufgabe zugrunde, neue 6cL-läethylprednisolon-Derivate zur Verfügung zu stellen·The invention has the object to provide novel 6 cL -läethylprednisolon derivatives available ·
Gegenstand der Erfindung ist ein Verfahren zur Herstellung von ooC-Methylprednisolon-Derivaten der allgemeinen Pormel IThe invention relates to a process for the preparation of ooC-methylprednisolone derivatives of the general Pormel I.
GH2OR2 GH 2 OR 2
HOHO
(D,(D,
CH-CH-
worin .. \ \ : / : //':' : ' -../^, ;. ;;-.;. ' . ' '' . R1 einen 1-Oxoalkylrest mit 2 bis ß Kohlenstoffatomen oder einen Benzoylrest undwhere .. \\ : /: // ':': ' - .. / ^,;. ;; -. ; , '. '''. R 1 is a 1-oxoalkyl radical having 2 to ß carbon atoms or a benzoyl radical and
R2 ein Wasserstoffatom, einen 1-Oxoalkylrest mit 2 bis 6 Kohlenstoffatomen oder einen Benzoylrest bedeuten, welches sich dadurch auszeichnet, daß man in an sich bekannter Weise aus einem Kortikoid der allgemeinen Formel IIIR 2 is a hydrogen atom, a 1-oxoalkyl radical having 2 to 6 carbon atoms or a benzoyl radical, which is characterized in that in a conventional manner from a corticoid of the general formula III
CH9OR0 =0CH 9 OR 0 = 0
"OR."OR.
(Ill),(Ill),
62 998 18 ' . - 3 -62 998 18 '. - 3 -
R. und Rp die obengenannte Bedeutung besitzen, Bromwasserstoff abspaltet·R. and Rp have the abovementioned meaning, splits off hydrogen bromide ·
Die neuen 6ty.~Methylprednisolon-Derivate können nach dem erfindungsgemäßen Verfahren hergestellt werden, welches unter den Bedingungen durchgeführt werden kann, wie sie in den deutschen Patentanmeldungen Ur. 26 45 104, 26 45 und 23 40 591 und 19 58 549 sowie im US-Patent Nr. 3 383 oder in der Publikation J. Amer. Chem. Soc.,72, Ί957, 1515 beschrieben sind.The new 6ty.-methylprednisolone derivatives can be prepared by the process according to the invention, which can be carried out under the conditions described in German Patent Applications Ur. 26 45 104, 26 45 and 23 40 591 and 19 58 549 and in US Pat. No. 3,383 or in the publication J. Amer. Chem. Soc., 72, Ί957, 1515.
Die neuen öcc-Methylprednisolon-Derivate der allgemeinen i'ormel I können als 2 bis 6 Kohlenstoffatome enthaltende 1-Oxoalkyigruppen R. und Rp beispielsweise eine Acetylgruppe, eine Propionylgruppe, eine Butyrylgruppe, eine Isobutyrylgruppe, eine Valerylgruppe, eine 3-Methylbutyrylgruppe, eine Irimethylacetylgruppe oder eine Hexanoylgruppe tragen.The new α-methylprednisolone derivatives of the general formula I can be 1- to 1-carbonyl-containing 1-oxoalkyl groups R. and Rp, for example, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, a 3-methylbutyryl group, an irimethylacetyl group or carry a hexanoyl group.
Die neuen 6saC-Methylprednisolon-Derivate der allgemeinen Formel I eignen sich demzufolge in Kombination mit den in der galenischen Pharmazie üblichen Trägermitteln zur lokalen Behandlung von Kontaktdermatitis, Ekzemen der verschiedensten Art, lieurodermatosen, Erythrodermie, Verbrennungen, Pruritis vulvae et ani, Rosacea, Erythematodes cutaneus, Psorasis, Liehen ruber planus et verrueosus und ähnlichen Hauterkrankungen·The new 6saC-methylprednisolone derivatives of the general formula I are accordingly suitable in combination with the carriers customary in galenic pharmacy for the local treatment of contact dermatitis, eczema of the most diverse types, lieurodermatoses, erythroderma, burns, pruritis vulvae et ani, rosacea, cutaneous erythematosus , Psorasis, lichen planus and verruosus and similar skin diseases ·
Me Herstellung der Arzneimittelspezialitäten erfolgt in üblicher Weise, indem man die Wirkstoffe mit geeigneten Zusätzen in die gewünschte Applikationsform, wie zum Beispiel: Lösungen, Lothionen, Salben, Cremen oder Pflaster, überführt. In den so formulierten Arzneimitteln ist dieMe preparation of the drug specialties in a conventional manner, by converting the active ingredients with suitable additives in the desired application form, such as: solutions, lotions, ointments, creams or patches. In the drugs formulated in this way, the
62 998 18 -4-62 998 18 -4-
Wirkstoffkonzentration von der Applikationsform abhängig· Bei Lotionen und Salben wird vorzugsweise eine Wirkstoffkonzentration von 0,001 ίο bis 1 % verwendet.Active substance concentration depends on the application form · For lotions and ointments an active substance concentration of 0.001 to 1 % is preferably used.
Darüber hinaus sind die neuen Verbindungen gegebenenfalls in Kombination mit den üblichen Trägermitteln und Hilfsstofi'en auch gut zur Herstellung von Inhalationsmitteln geeignet, welche zur Therapie allergischer Erkrankungen der Atomwege wie zum Beispiel des Bronchialasthmas oder der Rhinitis verwendet werden können.In addition, the novel compounds, optionally in combination with the usual carriers and excipients, are also well-suited for the preparation of inhalants which can be used to treat allergic diseases of the nuclear pathways such as bronchial asthma or rhinitis.
Ferner eignen 3ich die neuen Kortikoide auch in Form von Kapseln, Tabletten oder Dragees, die vorzugsweise 10 bis 200 mg Wirkstoff enthalten und oral appliziert werden oder in Form von Suspensionen, die vorzugsweise 100 bis 500 mg Wirkstoff pro Dosiseinheit enthalten und rektal appliziert werden. Auch zur Behandlung allergischer Erkrankungen des Darmtraktes, wie der Kolitis ulcerosa und der Kolitis granulomatosa.Furthermore, the new corticosteroids are also suitable in the form of capsules, tablets or dragees which preferably contain 10 to 200 mg of active ingredient and are administered orally or in the form of suspensions which preferably contain 100 to 500 mg of active ingredient per dose unit and are rectally applied. Also for the treatment of allergic diseases of the intestinal tract, such as ulcerative colitis and granulomatous colitis.
Die nachfolgenden Ausführungsbeispiele dienen zur Erläuterung de3 erfindungsgemäßen Verfahrens.The following exemplary embodiments serve to explain the method according to the invention.
Ausführungsbeispiele Beispiel 1Exemplary embodiments Example 1
A) Eine Suspension von 34,0 g 21-Acetoxy-9%-brom-1iß,i7-dihydroxy-6^-methyl-1,4-pregnadien-3»20-dion in 1,36 Methanol und 120 ml 70%iger Perchlorsäure wird 20 h bei Raumtemperatur gerührt. Nach der Eiswasserfällung wird der niederschlag abgesaugt, mit Wasser neutralgewaschen und im Vakuumtrockenschrank getrocknet. Man erhält 28,3 g 9t*/-Brom-11ß, 17»21~trihydroxy-6üü-methyl-i,4-pregnadien-3,20-dion. Schmp. 159-160 0C.A) A suspension of 34.0 g of 21-acetoxy-9% bromo-1β, i7-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione in 1,36 methanol and 120 ml 70%. iger perchloric acid is stirred for 20 h at room temperature. After the ice water precipitation, the precipitate is filtered off, washed neutral with water and dried in a vacuum oven. This gives 28.3 g of 9t * / - bromo-11ß, 17 »21 ~ trihydroxy-6üü-methyl-i, 4-pregnadiene-3,20-dione. M.p. 159-160 0 C.
62 998 18 - 5 -62 998 18 - 5 -
B) Aus einer Lösung von 4,3 g 9t\/-Brom-11ß,17,21-trihydroxy-6 λ-methyl-1,4-pregnadien-3,20-dion und 430mg Pyridiniumtosylat in 34,5 ml Dimethylformamid und 300 ml Benzol werden bei 130 0C über einen Wasserabscheider 129 ml Benzol abdestilliert. In die heiße Reaktionslösung läßt man 10,3 ml Orthobuttersäuretrimethylester hinzutropfen und destilliert anschließend weiter Benzol und andere leichtflüchtige Reaktionskomponenten ab. Man fügt 5 ml Pyridin hinzu und engt i· Vak. zur Trockne ein· Es wird 9 oi-Brom-11 ß-hydroxy-17 <X, 21 - (1-methoxybutylidendioxy)-6x-methyl-l,4-pregnadien-3,20-dion als 01 isoliert.B) From a solution of 4.3 g of 9t / bromo-11β, 17,21-trihydroxy-6λ-methyl-1,4-pregnadiene-3,20-dione and 430 mg of pyridinium tosylate in 34.5 ml of dimethylformamide and 300 ml of benzene are distilled off at 130 0 C via a water separator 129 ml of benzene. 10.3 ml of trimethyl orthobutyrate are added dropwise to the hot reaction solution and benzol and other readily volatile reaction components are subsequently distilled off. Add 5 ml of pyridine and concentrate in vacuo. It is isolated to dryness 9 o -bromo-11β-hydroxy-17 <X, 21 - (1-methoxybutylidendioxy) -6x-methyl-l, 4-pregnadiene-3,20-dione.
C) Das rohe 9<jC-Brom~i Iß-hydroxy-i7o^.21-(i-methoxybutyliden-dioxy)-6^-methyl-1,4-pregnadien-3,20~dion wird in 129 ml Methanol gelöst und mit einem Gemisch aus 46,4 ml 0,1H wäßriger Essigsäure und 5,2 ml O,1M wäßriger Natriumacetatlösung 1 h bei 00 0C Badtemperatur gerührt. Man engt die Lösung auf v/3 ihres Volumens ein, gibt auf Wasser und wäscht die Bssigesterextrakte neutral. iJach dem Irocknen und Einengen wird das Rohprodukt an 200 g Kieselgel mit einem Hexan-Aceton-Gradienten (0-60 % Aceton) gereinigt. Man isoliert 3,7 g 9<£-Brom-17<a/-butyryloxy-11ß,21-dihydroxy-6 &-methyl-1,4-pregnadi en-3,20-dion. Schmp. 158-159 0CC) The crude 9 <jC-bromo-1β-hydroxy-i7o ^ .21- (i-methoxybutylidene-dioxy) -6 ^ -methyl-1,4-pregnadiene-3,20 ~ dione is dissolved in 129 ml of methanol and stirred with a mixture of 46.4 ml of 0.1H aqueous acetic acid and 5.2 ml of O, 1M aqueous sodium acetate solution for 1 h at 00 0 C bath temperature. The solution is concentrated to v / 3 of its volume, added to water and washed the Bssigesterextrakte neutral. After drying and concentration, the crude product is purified on 200 g of silica gel with a hexane-acetone gradient (0-60 % acetone). 3.7 g of 9 £ -bromo-17 <a / -butyryloxy-11β, 21-dihydroxy-6 & -methyl-1,4-pregnadiene-3,20-dione are isolated. M. 158-159 0 C
D) Eine Suspension von 3,0 g 9o£~Brom-i7iX"-butyryloxy-11ß,21-dihydroxy-6cx -methyl-1,4-pregnadien-3,20-dion in 60 ml Hexamethylphosphorsäuretriamid wird mit 3,0 g Lithiumchlorid 1 h bei 80 0C Badtemperatur gerührt. JMach der Eiswasserfällung wird der Rückstand abfiltriert, mit Wasser gewaschen und das Rohprodukt an 105 g Kieselgel mit e'inem Methylenchlorid-Aceton-Gradienten (0-20 % Aceton) gereinigt. Man isoliert 938 ml 17^-Butyryloxy-D) A suspension of 3.0 g £ 9o ~ bromo-i7 iX "-butyryloxy-11beta, 21-dihydroxy-6cx -methyl-1,4-pregnadien-3,20-dione in 60 ml of hexamethylphosphoric triamide with 3.0 g of lithium chloride for 1 h at 80 0 C. bath temperature. JMach of ice water precipitation, the residue is filtered off, washed with water and the crude product chromatographed on 105 g silica gel with e'inem methylene chloride-acetone gradient (0-20% acetone). One isolated 938 ml of 17-butyrolactone
62 998 18 - 6 -62 998 18 - 6 -
-11 ß, 21-dihydroxy-6 oc-methyl-1,4,8-pregnatsiien-3,20-dion als Schaum. ££v/q = -53,8 (Chloroform)·-11β, 21-dihydroxy-6 oc-methyl-1,4,8-pregnatsien-3,20-dione as a foam. ££ v / q = -53.8 (chloroform) ·
A) Analog Beispiel 1B) werden 17,4 g 9<36-Brom-i1ß, 17<* j 21-trihydroxy-6-x-methyl-1,4-pre»gnadien-3,20-dion mit 42,0 ml Ortliobenzoesäuretriethylester umgesetzt und aufgearbeitet· Man isoliert 9^-BrOm-17^ , 21-(1-ethoxyben2;ylidendioxy)-1 1ß-hydroxy-6ος-methyl-1,4-pregnadien-3,20-dion als ül.A) Analogously to Example 1B) are 17.4 g of 9 <36-bromo-i1ß, 17 <* 21-trihydroxy-6-x-methyl-1,4-pragnadiene-3,20-dione with 42.0 triethyl ester of aminovinylbenzoate is reacted and worked up. 9-Bromo-17-, 21- (1-ethoxybenzylidene-dioxy) -1,1β-hydroxy-6α-methyl-1,4-pregnadiene-3,20-dione are isolated as an aliquot.
B) Das rohe 9c^-Brom-17^,21-(i-ethoxybenzylidendioxy)~11ßhydroxy-6;3C-methyl-1,4-pregnadien-3,20-dion wird unter den Bedingungen des Beispiels 1C) hydrolysiert und aufgearbeitet. Das Rohprodukt wird an 1 kg Kieselgel mit einem Hexan-Acetön-Gradienten (0.50 & Aceton) gereinigt. Ausbeute 12,47 g 17oi.-Benzoyloxy-9^C-brom-11 ß,21 -dihydroxy- 6c£ -methyl-Λ ,4-pregnadien-3,20-dion· Schmp. 159 0C.B) The crude 9c-bromo-17 ^, 21- (i-ethoxybenzylidenedioxy) ~ 11β-hydroxy-6; 3C-methyl-1,4-pregnadiene-3,20-dione is hydrolyzed and worked up under the conditions of Example 1C) , The crude product is purified on 1 kg silica gel with a hexane-acetone gradient (0.50 & acetone). Yield 12.47 g 17oi.-benzoyloxy-9 ^ C-bromo-11 beta, 21-dihydroxy 6c £ Λ methyl-, 4-pregnadiene-3,20-dione mp. 159 0 C.
C) Eine Lösung von 2,0 g 17«^ -Benzoyloxy-9oc-brom-11ß,21 dihydroxy-6oo-methyl-1,4-pregnadien-3,20-dion wird mit 2,0 g Lithiumchlorid analog Beispiel 1D) umgesetzt und aufgearbeitet. Das Rohprodukt wird an 105 g Kieselgel mit einem MethylenChlorid Aceton-Gradienten (0-20 % Aceton) gereinigt· Ausbeute .1,2 g 17^-Benzoyloxy-Hß,21· dihydroxy-6 t*-me thyl-1 ^,S-pregnatyien^, 20-dion· Schmp. 206 - 208 0C,C) A solution of 2.0 g of 17'-benzoyloxy-9oc-bromo-11β, 21-dihydroxy-6oo-methyl-1,4-pregnadiene-3,20-dione is mixed with 2.0 g of lithium chloride analogously to Example 1D). implemented and worked up. The crude product is purified on 105 g of silica gel with a methylene chloride acetone gradient (0-20 % acetone). Yield. 1.2 g of 17-benzoyloxy-H 2 O, 21-dihydroxy-6-t-methyl-1, S -pregnatyls, 20-dione · m.p. 206-208 0 C,
A) 3,0 g 17v/i/-Benzoyloxy-9.«c-brom-11 ß,21 -dihydroxy-6<&- methyl-1,4-pregnadien-3,20-dion werden in 30 ml PyridinA) 3.0 g of 17v / i / benzoyloxy-9. "C-bromo-11β, 21 -dihydroxy-6 <& -methyl-1,4-pregnadiene-3,20-dione are dissolved in 30 ml of pyridine
62 998 1862 998 18
mit 15 ml Acetanhydrid 3 h bei Raumtemperatur gerührt. Wach der üblichen Aufarbeitung erhält man 3»2 g 21-Acetoxy-i7v£-benzoyloxy~9ov-brom-11ß-hydroxy-6Qt methyl-1,4-pregnadien-3,20-dion· ochmp. 172 - 173 0G.stirred with 15 ml of acetic anhydride for 3 h at room temperature. Wake up the usual work-up to obtain 3 »2 g of 21-acetoxy-7a-benzoyloxy ~ 9 ov -bromo-11β-hydroxy-6Q t -methyl-1,4-pregnadiene-3,20-dion.mpmp. 172 - 173 0 G.
B) 3,3 g 21-Acetoxy-17o£-benzoyloxy~9^-brom-11ßhydroxy-6^ty-methyl-1,4-pregnadien-3,20-dion werden analog Beispiel 1D) mit 3»3 g Lithiumchlorid umgesetzt und aufgearbeitet· Das Rohprodukt wird an 200 g Kieselgel mit einem Methylenchlorid-Aceton-Gradienten (0 - 15 % Aceton) gereinigt. Ausbeute 1,78 g 21-Acetoxy-17 A/-benzoyloxy-11ß-hydroxy-6 oC-methyl-1, 4,8-pregnatrien-3,20-dion. Schmp. 229 - 230 0C.B) 3.3 g of 21-acetoxy-17o-benzoyloxy-9-bromo-11β-hydroxy-6-yl-methyl-1,4-pregnadiene-3,20-dione are analogous to Example 1D) with 3 g of lithium chloride reacted and worked up. The crude product is purified on 200 g of silica gel with a methylene chloride-acetone gradient (0-15 % acetone). Yield 1.78 g of 21-acetoxy-17A / -benzoyloxy-11β-hydroxy-6 oC-methyl-1,4,8-pregnatriene-3,20-dione. Mp 229 -. 230 0 C.
A) Analog Beispiel 3A) werden 3,0 g 17 <sC--Benzoyloxy-9oobrom-11ß,21-dihydroxy-6 °* -methyl-1,4-pregnadien-3,20-dion mit Propionsäureanhydrid umgesetzt und aufgearbeitet. Man erhält 3,1 g 17·> -Benzoyloxy^^-brom-Hßhydroxy-6 o*- -methyl-21 -propionyloxy-1,4-pregnadien-3,20-dion. Schmp. 155 - 15b 0G.A) Analogously to Example 3A) 3.0 g of 17 <sC - benzoyloxy-9oobrom-11ß, 21-dihydroxy-6 ° * -methyl-1,4-pregnadiene-3,20-dione reacted with propionic anhydride and worked up. This gives 3.1 g of 17 ·> -Benzoyloxy ^^ - bromo-Hßhydroxy-6 o * - methyl-21-propionyloxy-1,4-pregnadiene-3,20-dione. M.p. 155 - 15b 0 G.
B) 3,2 g i7c*>-Benzoyloxy-9^-brom-11ß~hydroxy-6oomethyl-21-propionyloxy 1,4-pregnadien-3,20-dion werden unter den Bedingungen des Beispiels 1D) mit Lithiumchiorid umgesetzt, aufgearbeitet und gepeinigt. Man iso-Iiert 1,96 g 17 ^ -Benzoyloxy-1 Tß-hydroxy-6 vjc -methyl-21-propionyloxy-1,4,8-pregnatrien-3,20-dion. Schmp. 225 - 226 0C.B) 3.2 g of i7c *> - benzoyloxy-9 ^ -bromo-11β-hydroxy-6o-ethyl-21-propionyloxy-1,4-pregnadiene-3,20-dione are reacted under the conditions of Example 1D) with lithium chloride, worked up and tormented. Iso-Iiert 1.96 g of 17 ^ -Benzoyloxy-1 Tβ-hydroxy-6 vjc-methyl-21-propionyloxy-1,4,8-pregnatriene-3,20-dione. Mp 225 -. 226 0 C.
Claims (5)
aus einem Kortikoid der allgemeinen i'ormel IIIHp is a hydrogen atom, a 1-oxoalkyl radical having 2 to 6 carbon atoms or a benzoyl radical, characterized in that in a manner known per se
from a corticosteroid of the general i'ormel III
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823248435 DE3248435A1 (en) | 1982-12-23 | 1982-12-23 | NEW 6 (ALPHA) METHYLPREDNISOLONE DERIVATIVES THEIR PRODUCTION AND USE |
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| Publication Number | Publication Date |
|---|---|
| DD210694A5 true DD210694A5 (en) | 1984-06-20 |
Family
ID=6182025
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DD83258236A DD210694A5 (en) | 1982-12-23 | 1983-12-20 | PROCESS FOR THE PREPARATION OF 6ALPHA-METHYL PREDNISOLONE DERIVATIVES |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP0112467B1 (en) |
| JP (1) | JPS59130300A (en) |
| AT (1) | ATE28878T1 (en) |
| AU (1) | AU2220283A (en) |
| CA (1) | CA1250571A (en) |
| CS (1) | CS236900B2 (en) |
| DD (1) | DD210694A5 (en) |
| DE (2) | DE3248435A1 (en) |
| DK (1) | DK159118C (en) |
| ES (1) | ES528323A0 (en) |
| GB (1) | GB2132620B (en) |
| GR (1) | GR79453B (en) |
| HU (1) | HU187939B (en) |
| IE (1) | IE56400B1 (en) |
| IL (1) | IL70452A (en) |
| NO (1) | NO156410C (en) |
| PL (1) | PL141513B1 (en) |
| PT (1) | PT77880B (en) |
| RO (1) | RO88666A (en) |
| SU (1) | SU1299514A3 (en) |
| ZA (1) | ZA839573B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6141820A (en) * | 1996-10-28 | 2000-11-07 | Firma Carl Freudenberg | Floor-cloth-type covering |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1026160A (en) * | 1964-04-29 | 1966-04-14 | American Cyanamid Co | Pregnatrienes |
| DE2645104C2 (en) * | 1976-10-04 | 1986-04-24 | Schering AG, 1000 Berlin und 4709 Bergkamen | 11β-Hydroxy-1,4,8-pregnatriene-3,20-dione derivatives and processes for their preparation |
-
1982
- 1982-12-23 DE DE19823248435 patent/DE3248435A1/en not_active Withdrawn
-
1983
- 1983-11-03 EP EP83110948A patent/EP0112467B1/en not_active Expired
- 1983-11-03 DE DE8383110948T patent/DE3372970D1/en not_active Expired
- 1983-11-03 AT AT83110948T patent/ATE28878T1/en active
- 1983-11-16 CA CA000441287A patent/CA1250571A/en not_active Expired
- 1983-12-08 AU AU22202/83A patent/AU2220283A/en not_active Abandoned
- 1983-12-14 IE IE2944/83A patent/IE56400B1/en not_active IP Right Cessation
- 1983-12-15 IL IL70452A patent/IL70452A/en not_active IP Right Cessation
- 1983-12-16 SU SU833673977A patent/SU1299514A3/en active
- 1983-12-19 GB GB08333741A patent/GB2132620B/en not_active Expired
- 1983-12-20 DD DD83258236A patent/DD210694A5/en unknown
- 1983-12-20 RO RO83112962A patent/RO88666A/en unknown
- 1983-12-21 GR GR73318A patent/GR79453B/el unknown
- 1983-12-21 PL PL1983245246A patent/PL141513B1/en unknown
- 1983-12-21 HU HU834382A patent/HU187939B/en not_active IP Right Cessation
- 1983-12-22 PT PT77880A patent/PT77880B/en unknown
- 1983-12-22 NO NO834759A patent/NO156410C/en unknown
- 1983-12-22 ES ES528323A patent/ES528323A0/en active Granted
- 1983-12-22 ZA ZA839573A patent/ZA839573B/en unknown
- 1983-12-23 DK DK597783A patent/DK159118C/en not_active IP Right Cessation
- 1983-12-23 JP JP58242345A patent/JPS59130300A/en active Granted
- 1983-12-23 CS CS839879A patent/CS236900B2/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6141820A (en) * | 1996-10-28 | 2000-11-07 | Firma Carl Freudenberg | Floor-cloth-type covering |
Also Published As
| Publication number | Publication date |
|---|---|
| DE3248435A1 (en) | 1984-06-28 |
| DK597783D0 (en) | 1983-12-23 |
| PL245246A1 (en) | 1984-10-22 |
| AU2220283A (en) | 1984-06-28 |
| PT77880A (en) | 1984-01-01 |
| DE3372970D1 (en) | 1987-09-17 |
| IE56400B1 (en) | 1991-07-17 |
| DK159118B (en) | 1990-09-03 |
| HU187939B (en) | 1986-03-28 |
| NO156410B (en) | 1987-06-09 |
| SU1299514A3 (en) | 1987-03-23 |
| CS236900B2 (en) | 1985-05-15 |
| ATE28878T1 (en) | 1987-08-15 |
| DK159118C (en) | 1991-02-11 |
| DK597783A (en) | 1984-06-24 |
| EP0112467B1 (en) | 1987-08-12 |
| IL70452A (en) | 1987-12-31 |
| JPH0415800B2 (en) | 1992-03-19 |
| NO834759L (en) | 1984-06-25 |
| NO156410C (en) | 1987-09-30 |
| IE832944L (en) | 1984-06-23 |
| JPS59130300A (en) | 1984-07-26 |
| RO88666A (en) | 1986-02-28 |
| PL141513B1 (en) | 1987-08-31 |
| GB2132620A (en) | 1984-07-11 |
| PT77880B (en) | 1986-04-09 |
| CA1250571A (en) | 1989-02-28 |
| ES8502128A1 (en) | 1985-01-01 |
| ES528323A0 (en) | 1985-01-01 |
| EP0112467A1 (en) | 1984-07-04 |
| GB2132620B (en) | 1986-06-04 |
| ZA839573B (en) | 1984-08-29 |
| GB8333741D0 (en) | 1984-01-25 |
| IL70452A0 (en) | 1984-03-30 |
| GR79453B (en) | 1984-10-30 |
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