DE1060396B - Process for the production of prednisolone acetate - Google Patents
Process for the production of prednisolone acetateInfo
- Publication number
- DE1060396B DE1060396B DEF23804A DEF0023804A DE1060396B DE 1060396 B DE1060396 B DE 1060396B DE F23804 A DEF23804 A DE F23804A DE F0023804 A DEF0023804 A DE F0023804A DE 1060396 B DE1060396 B DE 1060396B
- Authority
- DE
- Germany
- Prior art keywords
- acetate
- thallium
- iii
- prednisolone acetate
- prednisolone
- 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
- LRJOMUJRLNCICJ-JZYPGELDSA-N Prednisolone acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O LRJOMUJRLNCICJ-JZYPGELDSA-N 0.000 title claims description 22
- 229960002800 prednisolone acetate Drugs 0.000 title claims description 22
- 238000000034 method Methods 0.000 title claims description 20
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 229910052716 thallium Inorganic materials 0.000 claims description 8
- BKVIYDNLLOSFOA-UHFFFAOYSA-N thallium Chemical compound [Tl] BKVIYDNLLOSFOA-UHFFFAOYSA-N 0.000 claims description 8
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 7
- 229930195729 fatty acid Natural products 0.000 claims description 7
- 239000000194 fatty acid Substances 0.000 claims description 7
- 150000004665 fatty acids Chemical class 0.000 claims description 7
- 239000007791 liquid phase Substances 0.000 claims description 7
- -1 thallium (III) compound Chemical class 0.000 claims description 7
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 2
- XWVKTOHUMPLABF-UHFFFAOYSA-N thallium(3+) Chemical class [Tl+3] XWVKTOHUMPLABF-UHFFFAOYSA-N 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims 1
- 150000001298 alcohols Chemical class 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- 150000002430 hydrocarbons Chemical class 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000018044 dehydration Effects 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- 230000002906 microbiologic effect Effects 0.000 description 4
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- GBECUEIQVRDUKB-UHFFFAOYSA-M thallium monochloride Chemical compound [Tl]Cl GBECUEIQVRDUKB-UHFFFAOYSA-M 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- SMRRYUGQTFYZGD-UHFFFAOYSA-K diacetyloxythallanyl acetate Chemical compound [Tl+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SMRRYUGQTFYZGD-UHFFFAOYSA-K 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000004816 paper chromatography Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 239000011669 selenium Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- KTZHUTMWYRHVJB-UHFFFAOYSA-K thallium(3+);trichloride Chemical compound Cl[Tl](Cl)Cl KTZHUTMWYRHVJB-UHFFFAOYSA-K 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HJFFLJUEFIYEPI-JYSOYWRPSA-N (8R,9S,10R,13S,14S,17R)-2,4-dibromo-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-1,2,3,4,5,6,7,8,9,11,12,14,15,17-tetradecahydrocyclopenta[a]phenanthren-16-one Chemical compound BrC1CC(C2CC[C@H]3[C@@H]4CC([C@@H]([C@]4(CC[C@@H]3[C@]2(C1)C)C)[C@H](C)CCCC(C)C)=O)Br HJFFLJUEFIYEPI-JYSOYWRPSA-N 0.000 description 1
- VPGRYOFKCNULNK-ACXQXYJUSA-N Deoxycorticosterone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)COC(=O)C)[C@@]1(C)CC2 VPGRYOFKCNULNK-ACXQXYJUSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- 239000012531 culture fluid Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 229960004486 desoxycorticosterone acetate Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 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 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
- 239000012535 impurity Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- ZHZOIVSXSKARMO-UHFFFAOYSA-N tert-butyl chlorate Chemical compound CC(C)(C)OCl(=O)=O ZHZOIVSXSKARMO-UHFFFAOYSA-N 0.000 description 1
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 1
- 150000003475 thallium Chemical class 0.000 description 1
- 150000003476 thallium compounds Chemical class 0.000 description 1
- FHYUCVWDMABHHH-UHFFFAOYSA-N toluene;1,2-xylene Chemical group CC1=CC=CC=C1.CC1=CC=CC=C1C FHYUCVWDMABHHH-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
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 Prednisolon-acetat Das zur Klasse der J1,4-3-Ketosteroide gehörende dl-4-Pregnadien-11ß,17a, 21-triol-3,20-dion-acetat-(21), im folgenden mit Prednisolon-acetat bezeichnet, ist bekanntlich die wirksame Substanz zahlreicher pharmazeutischer Zubereitungen. Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Herstellung von Prednisolon-acetat.Process for the preparation of Prednisolone Acetate That belongs to the class of Dl-4-pregnadiene-11ß, 17a, 21-triol-3,20-dione-acetate- (21), belonging to J1,4-3-ketosteroids, hereinafter referred to as prednisolone acetate, is known to be the active substance numerous pharmaceutical preparations. Subject of the present invention is a process for the production of Prednisolone Acetate.
Es ist bekannt, daß man 41.4-3-Ketosteroide auf mikrobiologischem Wege, ausgehend von J4-3-Ketosteroiden oder 3-Ketosteroiden, herstellen kann (z. B. USA.-Patentschriften 2 756 179 und 2 776 927, belgische Patentschriften 544 631, 546 636 und 544993).It is known that 41.4-3-ketosteroids can be used on a microbiological basis Ways starting from J4-3-keto steroids or 3-keto steroids (e.g. B. USA patents 2,756,179 and 2,776,927, Belgian patents 544,631, 546 636 and 544993).
Die mikrobiologischen Verfahren erfordern alle große Flüssigkeitsmengen, sogenannte Kulturflüssigkeiten, und vor allem ein steriles Arbeiten; ein chemisches Verfahren wäre daher von technischem Interesse.The microbiological processes all require large amounts of fluids, so-called culture fluids, and above all sterile work; a chemical Process would therefore be of technical interest.
Es ist nun bekannt, daß man z_91.4-3-Ketosteroide auch auf chemischem Wege erhalten kann. So ergibt z.B. die Behandlung von 2,4-Dibromcholestanon mit Kollidin .91,4-Cholestadienon-(3) (B u t e n a n d t und Mitarbeiter, Bericht der dtsch. chem. Ges., Bd. 72, 1939, S. 1617; I n h o f f e n und Mitarbeiter, Bericht der dtsch. chem. Ges., Bd. 73, 1940, S. 451) ; 2-Jod-d4-Ketosteroide kann man mittels Raneynickel zu 41,4-Ketosteroiden umwandeln (britische Patentschrift 761351). It is now known that z_91.4-3-ketosteroids can also be obtained chemically. For example, the treatment of 2,4-dibromocholestanone with collidine gives .91,4-cholestadienone- (3) (Butenandt and coworkers, report of the German chem. Ges., Vol. 72, 1939, p. 1617; I nhoffen and coworkers, report of the German chem. Ges., Vol. 73, 1940, p. 451); 2-iodine-d4-keto steroids can be converted to 41,4-keto steroids using Raney nickel (British patent specification 761351).
Ausgangsprodukte für die Synthese von Prednisolon-acetat sind vor allem das 44-Pregnen-11,B,17a, 21-triol-3,20-dion, die entsprechende 11-Ketoverbindung und die entsprechenden 21-Acetate. Daher benötigt man bei den obgenannten chemischen Verfahren mindestens zwei Stufen. Es ist weiter bekannt, daß man im Einstufenverfahren bei der Behandlung von 44-Pregnen-21-ol-3,20-dion-acetat (Desoxycorticosteronacetat) mit Bleitetraaceatat 41,4-Pregnadien-21-ol-3,20-dion-acetat in geringer Menge (6,5 °/o) erhält.Starting products for the synthesis of prednisolone acetate are available especially the 44-pregnen-11, B, 17a, 21-triol-3,20-dione, the corresponding 11-keto compound and the corresponding 21-acetates. Therefore one needs chemical in the case of the above Procedure at least two stages. It is also known that one-step process in the treatment of 44-pregnen-21-ol-3,20-dione acetate (deoxycorticosterone acetate) with lead tetraaceatate 41,4-pregnadien-21-ol-3,20-dione-acetate in a small amount (6.5 ° / o).
Schließlich kann man A4-Pregnen-11ß,17a,21-triol-3,20,dion-21-acetat (Kendall's Compound F, im folgenden mit »F-Acetat« bezeichnet) mittels Selendioxyd mit guten Ausbeuten zum Prednisolon-acetat dehydrieren (belgische Patentschrift 548 288). Es ist jedoch ebenfalls bekannt, daß das nach diesem Verfahren hergestellte Prednisolon-acetat selenhaltig ist. Die Abtrennung des selenhaltigen Körpers bereitet große Schwierigkeiten und bringt eine erheblicheAusbeuteverminderung an Prednisolon-acetat mit sich (z. B. F 1 o r e y , R e s t i v o, J. Org. Chem., 22, 1957, S.406).Finally, A4-Pregnen-11ß, 17a, 21-triol-3,20, dione-21-acetate (Kendall's Compound F, hereinafter referred to as "F-acetate") using selenium dioxide dehydrate to prednisolone acetate with good yields (Belgian patent 548 288). However, it is also known that the manufactured by this method Prednisolone Acetate contains selenium. The separation of the selenium-containing body prepares great difficulties and brings a considerable decrease in the yield of prednisolone acetate with itself (e.g. F 1 o r e y, R e s t i v o, J. Org. Chem., 22, 1957, p. 406).
Es wurde nun ein Einstufenverfahren zur Herstellung von Prednisolon-acetat aus dem F-Acetat gefunden, das dadurch gekennzeichnet ist, daß man F-Acetat mit Verbindungen des dreiwertigen Thalliums in flüssiger Phase dehydriert. Als flüssige Phase verwendnet man vorzugsweise niedere Fettsäuren, mit Ausnahme von Ameisensäure, z. B. Essigsäure, Propionsäure oder Buttersäure. Man kann aber auch tert. Butylalkohol oder ein Gemisch von tert. Butylalkohol mit den genannten Fettsäuren oder auch ein Gemisch dieser Fettsäuren mit indifferenten Lösungsmitteln, wie Benzol, Toluol oder Xylol, verwenden.A one-step process for the manufacture of prednisolone acetate has now been established found from the F-acetate, which is characterized in that one F-acetate with Compounds of trivalent thallium are dehydrated in the liquid phase. As a liquid Phase is preferably used lower fatty acids, with the exception of formic acid, z. B. acetic acid, propionic acid or butyric acid. But you can also tert. Butyl alcohol or a mixture of tert. Butyl alcohol with the fatty acids mentioned or a Mixture of these fatty acids with inert solvents such as benzene, or toluene Xylene.
Die Temperatur ist von Einfluß auf die Ausbeute. Bei höheren Temperaturen, z. B. 95° C, erhält man z. B. in Eisessig nach 3 Stunden ein Gemisch, das 20 % Prednisolon-acetat und 34 % F-Acetat enthält. Bei 40° C erhält man z. B. in Eisessig nach 500 Stun, den ein Gemisch, das 33 % Prednisolon-acetat und 32 % F-Acetat enthält.- Längere Einwirkung der Thallium(III)-verbindung verschiebt jeweils das Ausbeuteverhältnis zugunsten von Prednisolon-acetat, vermindert jedoch die Ausbeute an Prednisolonacetat, bezogen auf das verbrauchteAusgangsmaterial. Durch Zugabe von tert. Butanol oder aromatischen Kohlenwasserstoffeh kann man die Reaktion bei höheren Temperaturen, z. B. 80 bis 100° C, ablaufen lassen, ohne einen schnellen Abbau wie bei Verwendung der reinen Fettsäuren zu erhalten. Das nach dem Verfahren gemäß der Erfindung eingesetzte Thallium wird in Form des Thallium(I)-chlorids in praktisch quantitativer Ausbeute wiedergewonnen und kann in bekannter Weise wieder zu der gewünschten Thallium(III)-verbindung regeneriert werden.The temperature has an influence on the yield. At higher temperatures, z. B. 95 ° C, you get z. B. in glacial acetic acid after 3 hours a mixture containing 20% prednisolone acetate and contains 34% F-acetate. At 40 ° C z. B. in glacial acetic acid after 500 hours, den a mixture that contains 33% prednisolone acetate and 32% F-acetate - longer The action of the thallium (III) compound shifts the yield ratio in each case in favor of prednisolone acetate, but reduces the yield of prednisolone acetate, based on the raw material consumed. By adding tert. Butanol or aromatic hydrocarbons can be the reaction at higher temperatures, z. B. 80 to 100 ° C, drain without a rapid degradation as when using of pure fatty acids. That used according to the method according to the invention Thallium is obtained in the form of thallium (I) chloride in practically quantitative yield recovered and can in a known manner back to the desired thallium (III) compound be regenerated.
Die erfindungsgemäße Reaktion- ist für den Fachmann überraschend. Es ist noch kein Fall einer Oxydation oder Dehydrierung mit Hilfe von Thallium(III)-verbindungen bekannt. Vor allem aber sind bei komplizierten Molekülen wie den 44-3-Ketosteroiden sehr viele Möglichkeiten für eine Oxydation oder Dehydrierung gegeben, die im allgemeinen wahrscheinlicher sind als die A1-Dehydrierung. Man weiß z. B. von den mikrobiologischen Verfahren her, daß nicht nur eine Dehydrierung von 44-3-Ketosteroiden in 1-Stellung, sondern z. B. ebenso eine Oxydation an den Kohlenstoffatomen 11 oder 14 erfolgen kann (vgl. z. B. belgische Patentschrift 549 221) ; mit Chloranil entstehen 414#s- oder J4,6-3-Ketosteroide, jedoch nicht JI,4-3-Ketosteroide (A g n e l l o , Laubach, T. Amer. Chem. Soc., Bd. 79, 1957, S. 1258) ; mit Kupferacetat und Sauerstoff wird die 21 ständige Hydroxy lgruppe oxydiert (deutsche Auslegeschrift 1002756), mit Chormsäure-tert.butylester in Pyridin die l lständige Hydroxylgruppe.The reaction according to the invention is surprising to the person skilled in the art. There is still no known case of oxidation or dehydrogenation with the aid of thallium (III) compounds. Above all, there are many possibilities for oxidation or dehydration in the case of complicated molecules such as the 44-3 ketosteroids, which are generally more likely than A1 dehydration. One knows z. B. from the microbiological process that not only a dehydration of 44-3-ketosteroids in the 1-position, but z. B. can also be carried out an oxidation at the carbon atoms 11 or 14 (cf. z. B. Belgian patent 549 221); with chloranil 414 # s- or J4,6-3-ketosteroids are formed, but not JI, 4-3-ketosteroids (Ag nello, Laubach, T. Amer. Chem. Soc., Vol. 79, 1957, p. 1258 ); The hydroxyl group in the 21 position is oxidized with copper acetate and oxygen (German Auslegeschrift 1002756), with the chloric acid tert-butyl ester in pyridine the essential hydroxyl group.
Man führt die Reaktion gemäß der Erfindung vorzugsweise so aus, daß man FAcetat und die Thallium (III)-v erbindung in flüssiger Phase entsprechende Zeit bei Temperaturen zwischen 20 und 110° C, vorzugsweise 40 und 80° C, hält, die flüssige Phase entfernt und den Rückstand mit einem geeigneten Lösungsmittel, z. B. 1Iethylenchlorid, und Wasser behandelt. Natriumbisulfit und ein lösliches Chlorid, z. B. Kochsalz, zur Reduktion nicht umgesetzter Thallium(III)-verbindung bzw. zur Fällung des Thallium(I)-chlorids zugibt. Man trennt die Methylenchloridlösung ab, trocknet z. B. mit Natriumsulfat und zieht das Lösungsmittel ab.The reaction according to the invention is preferably carried out in such a way that one FAcetat and the thallium (III) compound in the liquid phase corresponding Time at temperatures between 20 and 110 ° C, preferably 40 and 80 ° C, holds the liquid phase removed and the residue with a suitable solvent, e.g. B. 1Iethylene chloride, and treated water. Sodium bisulfite and a soluble chloride, z. B. table salt, for the reduction of unreacted thallium (III) compound or for Precipitation of thallium (I) chloride adds. The methylene chloride solution is separated off, dries z. B. with sodium sulfate and removes the solvent.
Der Rückstand, der neben Prednisolon-acetat noch Zersetzungsprodukte und eventuell F-Acetat enthält, wird in an sich bekannter Weise aufgearbeitet. So kann man ihn z. B. mit wenig Essigester verreiben. Dabei bleiben lediglich Prednisolon-acetat und eventuell vorhandenes F-Acetat ungelöst. Die Trennung von Prednisolon-acetat und F-Acetat kann in an sich bekannter Weise erfolgen, z. B. durch Gegenstromverteilung zwischen z. B. Propylenglykol und Toluol oder durch Chromatographie an Papier.The residue, in addition to prednisolone acetate, also decomposition products and possibly contains F-acetate, is worked up in a manner known per se. So can you z. B. rub with a little ethyl acetate. All that remains is prednisolone acetate and any F-acetate present undissolved. Separation of Prednisolone Acetate and F-acetate can be made in a manner known per se, e.g. B. by countercurrent distribution between z. B. propylene glycol and toluene or by chromatography on paper.
Als Thallium(III)-verbindung werden vorzugsweise das Thalliumoxyhydrat T 100H oder die Thalliumsalze niederer Fettsäuren, mitAusnahme derAmeisensäure, verwendet. Man kann aber auch z. B. Thallium(III)-chlorid verwenden und den bei der Reaktion entstehenden Chlorwasserstoff durch Zugabe von Puffersubstanzen, z. B. Natriumacetat, abfangen. Man verwendet die Thalliumv erbindung vorzugsweise im Überschuß, wobei ein solcher von mindestens 75 °/o vorteilhaft ist.The preferred thallium (III) compound is thallium oxyhydrate T 100H or the thallium salts of lower fatty acids, with the exception of formic acid, used. But you can also z. B. use thallium (III) chloride and the two the reaction resulting from hydrogen chloride by adding buffer substances, e.g. B. sodium acetate. The thallium compound is preferably used in the Excess, an excess of at least 75% being advantageous.
Das Verfahren gemäß der Erfindung ermöglicht es, in einem chemischen Einstufenverfahren vom F-Acetat zu Prednisolon-acetat zu gelangen. Gegenüber den mikrobiologischen Verfahren hat es vor allem den Vorteil, daß man das Arbeiten unter sterilen Bedingungen vermeiden kann.The method according to the invention makes it possible in a chemical One-step process to get from F-acetate to prednisolone acetate. Compared to the The main advantage of microbiological processes is that you can work under avoid sterile conditions.
Die Ausbeuten bei dem erfindungsgemäßen Verfahren sind gegenüber dem obengenannten Verfahren mit Bleitetraacetat wesentlich erhöht. Im Vergleich zur Dehydrierung mit Selendioxyd hat das neue Verfahren den bedeutenden Vorzug, daß bereits das entstehende Rohprodukt frei von anorganischen Verunreinigungen ist.The yields in the process according to the invention are compared to the Above-mentioned process with lead tetraacetate increased significantly. In comparison to Dehydration with selenium dioxide, the new process has the significant advantage that the resulting crude product is already free of inorganic impurities.
Beispiel 1 400 mg F-Acetat und 600 mg Thallium(III) -acetat werden in 90m1 Eisessig gelöst. Die Lösung hält man 6 Tage auf 50° C, gibt nochmals 600 mg Thallium(III)-acetat zu und läßt weitere 6 Tage bei 50° C stehen. Dann wird der Eisessig bei 50° C im Vakuum abgezogen, der Rückstand mit 100m1 Methylenchlorid und 10 ml gesättigter Kochsalzlösung, der eine Spatelspitze Natriumbisulfit zugesetzt ist, geschüttelt. Dabei bilden sich zwei Schichten, die braune Farbe des dreiwertigen Thalliums verschwindet, und es scheidet sich an der Trennfläche der beiden Flüssigkeitsphasen Thallium(I)-chlorid ab, das durch Filtration gesammelt wird. Dann trennt man die Methylenchloridphase ab, trocknet mit Natriumsulfat und verdampft das Lösungsmittel. Es hinterbleiben 390 mg einer Substanz mit einem papierchromatographisch ermittelten Gehalt von 32 % Prednisolon-acetat sowie von 36 °/o F-Acetat (Bestimmung nach Z a f f a r o n i und Mitarbeiter, J. biol. Chemistry, Bd. 188, 1951, S. 763).Example 1 400 mg of F acetate and 600 mg of thallium (III) acetate are used dissolved in 90m1 glacial acetic acid. The solution is kept at 50 ° C. for 6 days, and another 600 is added mg of thallium (III) acetate and allowed to stand at 50 ° C. for a further 6 days. Then the Glacial acetic acid is stripped off in vacuo at 50 ° C., and the residue is treated with 100 ml of methylene chloride and 10 ml of saturated saline solution, to which a spatula tip of sodium bisulfite is added is shaken. Two layers are formed, the brown color of the trivalent Thallium disappears and it separates at the interface between the two liquid phases Thallium (I) chloride, which is collected by filtration. Then you separate them Methylene chloride phase, dried with sodium sulfate and evaporated the solvent. 390 mg of a substance remain behind with a paper chromatography determined Content of 32% prednisolone acetate and 36% F-acetate (determination according to Z a f f a r o n i and coworkers, J. biol. Chemistry, Vol. 188, 1951, p. 763).
Das Rohprodukt wird mit wenig Essigester angerieben und kalt abgesaugt. Das verbleibende Produkt hat einen Gehalt von 45 a/o Predisolon-acetat und 50 a/o F-Acetat. Bei der präparativen absteigenden Papierchromatographie mit Hilfe von Schleicher-&-Schüll-Papier 2043 b Mgl mit Propylenglykol als stationärer und Toluol als mobiler Phase erhält man mit über 50 cm langem Papier zwei scharf getrennte Fraktionen, deren erste das nicht umgesetzte F-Acetat, deren zweite Prednisolon-acetat enthält. Nach dem Abdampfen des Lösungsmittels und Verreiben mit wenig Essigester zur Entfernung des Propylenglykols erhält man reines Prednisolon-acetat.The crude product is rubbed with a little ethyl acetate and filtered off with suction while cold. The remaining product has a content of 45 a / o predisolone acetate and 50 a / o F acetate. In preparative descending paper chromatography using Schleicher - & - Schüll-Papier 2043 b Mgl with propylene glycol as stationary and Toluene as the mobile phase is obtained with paper over 50 cm long, two sharply separated Fractions, the first of which is the unreacted F-acetate, the second of which is prednisolone acetate contains. After evaporation of the solvent and trituration with a little ethyl acetate pure prednisolone acetate is obtained to remove the propylene glycol.
Eine Probe ergibt nach einmaligem Umkristallisieren aus Methanol ein Produkt, das alle für diese Substanz typischen Infrarotbanden zeigt (bei 6,02; 6,20; 6,26; 7,62; 8,55; 10,66; 12,16 l,) und in dem alle für das F-Acetat typischen Banden (bei 6,12; 6,88; 10,16; 11,36; 13,41 [) fehlen. Beispiel 2 Man erhitzt ein Gemisch von 400 mg F -Acetat und von 400 mg Thalliumoxyhydrat mit 90 ml Eisessig 3 Stunden auf dem Dampfbad und arbeitet auf, wie unter Beispiel 1 angegeben. Das so erhaltene Rohprodukt hat einen Gehalt von 20%. Prednisolon-acetat und von 34 °/a F-Acetat.A sample gives a single recrystallization from methanol Product showing all infrared bands typical for this substance (at 6.02; 6.20; 6.26; 7.62; 8.55; 10.66; 12, 16 l,) and in which all the bands typical of F-acetate (at 6.12; 6.88; 10.16; 11.36; 13.41 [) are missing. Example 2 A mixture is heated of 400 mg of F acetate and of 400 mg of thallium oxyhydrate with 90 ml of glacial acetic acid for 3 hours on the steam bath and works on as indicated under Example 1. The thus obtained Raw product has a content of 20%. Prednisolone Acetate and 34% F acetate.
Das hier verwendeteThalliumoxyhydrat wird durch Fällen aus Thallium(III)-chloridlösung mit Natronlauge, Waschen mit Wasser und Methanol und Trocknen im Exsikkator über Phosphorpentoxyd hergestellt.The thallium oxyhydrate used here is obtained by precipitation from thallium (III) chloride solution with caustic soda, washing with water and methanol and drying in a desiccator over Phosphorus pentoxide produced.
Claims (4)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEF23804A DE1060396B (en) | 1957-08-21 | 1957-08-21 | Process for the production of prednisolone acetate |
| CH6307058A CH370074A (en) | 1957-08-21 | 1958-08-19 | Process for the production of prednisolone 21 acetate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEF23804A DE1060396B (en) | 1957-08-21 | 1957-08-21 | Process for the production of prednisolone acetate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1060396B true DE1060396B (en) | 1959-07-02 |
Family
ID=7090996
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEF23804A Pending DE1060396B (en) | 1957-08-21 | 1957-08-21 | Process for the production of prednisolone acetate |
Country Status (2)
| Country | Link |
|---|---|
| CH (1) | CH370074A (en) |
| DE (1) | DE1060396B (en) |
-
1957
- 1957-08-21 DE DEF23804A patent/DE1060396B/en active Pending
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1958
- 1958-08-19 CH CH6307058A patent/CH370074A/en unknown
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| Publication number | Publication date |
|---|---|
| CH370074A (en) | 1963-06-30 |
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