DE927030C - Process for the preparation of allopregnan-17ª ‡, 21-diol-3, 11, 20-trione and its esters - Google Patents
Process for the preparation of allopregnan-17ª ‡, 21-diol-3, 11, 20-trione and its estersInfo
- Publication number
- DE927030C DE927030C DES28658A DES0028658A DE927030C DE 927030 C DE927030 C DE 927030C DE S28658 A DES28658 A DE S28658A DE S0028658 A DES0028658 A DE S0028658A DE 927030 C DE927030 C DE 927030C
- Authority
- DE
- Germany
- Prior art keywords
- allopregnan
- dione
- trione
- diol
- solution
- 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.)
- Expired
Links
- 150000002148 esters Chemical class 0.000 title claims description 9
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title description 3
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 8
- 239000000194 fatty acid Substances 0.000 claims description 8
- 229930195729 fatty acid Natural products 0.000 claims description 8
- -1 fatty acid ester Chemical class 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 150000004665 fatty acids Chemical class 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims 3
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims 2
- 150000001242 acetic acid derivatives Chemical class 0.000 claims 1
- 235000011056 potassium acetate Nutrition 0.000 claims 1
- 235000009518 sodium iodide Nutrition 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 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 2
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 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 2
- 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 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 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
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229960004544 cortisone Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- ZIQRIAYNHAKDDU-UHFFFAOYSA-N sodium;hydroiodide Chemical compound [Na].I ZIQRIAYNHAKDDU-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- VOYADQIFGGIKAT-UHFFFAOYSA-N 1,3-dibutyl-4-hydroxy-2,6-dioxopyrimidine-5-carboximidamide Chemical class CCCCn1c(O)c(C(N)=N)c(=O)n(CCCC)c1=O VOYADQIFGGIKAT-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SVYOXGBINYWSDQ-UHFFFAOYSA-N 1,4-dioxane;ethanol Chemical compound CCO.C1COCCO1 SVYOXGBINYWSDQ-UHFFFAOYSA-N 0.000 description 1
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 1
- GLVYLTSKTCWWJR-UHFFFAOYSA-N 2-carbonoperoxoylbenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1C(O)=O GLVYLTSKTCWWJR-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000000950 dibromo group Chemical group Br* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-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
- 238000007127 saponification reaction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
-
- 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)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
Description
Verfahren zur Herstellung von Allopregnan-17 a, 21-diol-3,11, 20-trion und seinen Estern Gegenstand der Erfindung ist ein Verfahren zur Herstellung von Allopregnan-i7a, 2i-diol-3, 11, 20-trion und seinen Estern.Process for the preparation of allopregnan-17 a, 21-diol-3,11, 20-trione and its esters. The invention relates to a process for the preparation of Allopregnan-i7a, 2i-diol-3, 11, 20-trione and its esters.
Es ist bekannt, Allopregnan-17a, 2i-diol-3, 11, 20-trion und besonders seine Ester in das therapeutisch wichtige d4-Pregnan-i7a, 2i-diol-3, ii, 2o-trion (Cortison) umzuwandeln, indem man diese zum 2, q.-Dibromderivat bromiert, die Dibromderivate in der Wärme mit Jodalkali umsetzt und die so erhaltenen 2-Jod-4 4-derivate mit einem Reduktionsmittel behandelt. Die vorliegende Erfindung beschreibt ein neues Verfahren zur Herstellung eines wertvollen Cortison-Zwischenproduktes.It is known to allopregnan-17a, 2i-diol-3, 11, 20-trione and especially its esters into the therapeutically important d4-pregnan-i7a, 2i-diol-3, ii, 2o-trione (Cortisone) by brominating them to the 2, q.-dibromo derivative, the dibromo derivatives reacts in the heat with iodine alkali and the 2-iodine-4 4-derivatives thus obtained with treated with a reducing agent. The present invention describes a new one Process for the production of a valuable intermediate cortisone product.
Ein Teil des neuen Verfahrens wird durch folgende Formeln wiedergegeben R bedeutet den Rest einer niedermolekularen Fettsäure, wie Essigsäure oder Propionsäure, oder auch den einer aromatischen Säure, z. B. Benzoesäure. Die erhaltenen Ester des Allopregnan-ri, 2o-dion-3 ß-ols lassen sich in Allopregnan-17a, 2i-diol-3, 1i, 20-trion und seine Ester nach den folgenden Formeln umwandeln Zur Ausführung dieser Verfahren wird d 4-Pregnen-3, 11, 2o-trion (ii-Ketoprogesteron) in einem organischen Lösungsmittel, z. B. in Äthylacetat, gelöst und in einer Wasserstoffatmosphäre mit einem vorher reduzierten io°/oigen Palladium-Holzkohle-Katalysator geschüttelt. Nach etwa 2 Stunden wird die Lösung filtriert, eingedampft und das rohe Allopregnan-3, 11, 2o-trion aus Aceton umkristallisiert. Zur Reduktion der 3-ständigen Ketogruppe dieses Trions wird dessen Lösung in einem Lösungsmittel, wie Äthanol-Dioxan oder Alkohol, gelöst und etwa 3 bis 6 Stunden in einer Wasserstoffatmosphäre in Gegenwart eines Raneynickelkatalysators geschüttelt. Nach dem Filtrieren und Reinigen, z. B. mit Girards Reagens, und Umkristallisieren erhält man Allopregnan-3ß-o1-11, 20-dion, das dann in üblicher Weise zum 3-Acetat acetyliert wird. Die Reaktionslösung kann jedoch nach dem Abdampfen zur Trockne auch direkt acetyliert werden. Nach der Reinigung erhält man ebenfalls das 3-Acetat des Allopregnan-3ß-01-ii, 2o-dions.Part of the new method is represented by the following formulas R denotes the residue of a low molecular weight fatty acid, such as acetic acid or propionic acid, or that of an aromatic acid, e.g. B. benzoic acid. The resulting esters of allopregnan-ri, 2o-dione-3β-ol can be converted into allopregnan-17a, 2i-diol-3, 1i, 20-trione and its esters according to the following formulas To carry out this process, d 4-pregnen-3, 11, 2o-trione (ii-ketoprogesterone) is added in an organic solvent, e.g. B. in ethyl acetate, dissolved and shaken in a hydrogen atmosphere with a previously reduced io% palladium-charcoal catalyst. After about 2 hours, the solution is filtered, evaporated and the crude allopregnan-3, 11, 2o-trione is recrystallized from acetone. To reduce the 3-position keto group of this trione, its solution is dissolved in a solvent such as ethanol-dioxane or alcohol and shaken for about 3 to 6 hours in a hydrogen atmosphere in the presence of a Raney nickel catalyst. After filtering and cleaning, e.g. B. with Girard's reagent, and recrystallization gives allopregnan-3ß-o1-11, 20-dione, which is then acetylated in the usual way to 3-acetate. However, the reaction solution can also be acetylated directly after evaporation to dryness. After purification, the 3-acetate of allopregnan-3ß-01-ii, 2o-dione is also obtained.
Das Allopregnan-3ß-01-ii, 2o-dionacetat oder ein anderer auf diese Weise dargestellter Ester einer niedermolekularen Fettsäure läBt sich dann mit Essigsäureanhydrid oder dem Anhydrid einer anderen Fettsäure in Gegenwart einer aromatischen Sulfonsäure in das Enol eines niedermolekularen Fettsäurediacylats, z. B. des Diacetats, umwandeln, welches nach Behandlung mit einer aromatischen Persäure, z. B. Perbenzoesäure oder Perphtalsäure, und nachfolgender Verseifung, z. B. mit einem Alkalihydroxyd in Alkohol, das Allopregnan-3ß, i7a-diol-ii, 2o-dion liefert. Mischt man das Dion mit i Mol Brom und löst z. B. in Chloroform, so erhält man durch selektive Bromierung die 2i-Bromverbindung, die dann durch Umsetzung mit Jodnatrium und Kaliumacetat in das 2i-Monoacetat des Allopregnan-3 ß, 17a, 2i-triolii, 2o-dions (2i-Monoacetat von Reichsteins Verbindung D) übergeführt werden kann. Selektive Oxydation der letztgenannten Verbindung mit N-Bromacetamid in Gegenwart einer organischen Base, wie Pyridin, liefert das Allopregnan-17a, 21-diol-3, 11, 20-trion-21-acetat (Dihydroallocortison).The allopregnan-3ß-01-ii, 2o-dione acetate or another on this The esters of a low molecular weight fatty acid prepared in this way can then be mixed with acetic anhydride or the anhydride of another fatty acid in the presence of an aromatic sulfonic acid into the enol of a low molecular weight fatty acid diacylate, e.g. B. the diacetate, convert, which after treatment with an aromatic peracid, e.g. B. perbenzoic acid or Perphthalic acid, and subsequent saponification, e.g. B. with an alkali hydroxide in alcohol, which gives allopregnan-3ß, i7a-diol-ii, 2o-dione. If you mix the dione with i mole Bromine and dissolves z. B. in chloroform, the selective bromination is obtained 2i-bromine compound, which is then converted into the 2i-monoacetate of allopregnan-3 ß, 17a, 2i-triolii, 2o-dione (2i-monoacetate of Reichstein's connection D) can be transferred. Selective oxidation of the latter Compound with N-bromoacetamide in the presence of an organic base such as pyridine, supplies the allopregnan-17a, 21-diol-3, 11, 20-trione-21-acetate (dihydroallocortisone).
Für die Herstellung des Ausgangsstoffes, Allopregnan-3, ix, 2o-trion, wird Schutz nicht begehrt. Beispiel a) Eine Lösung aus i g d 4-Pregnen-3, ii, 2o-trion, F. = 172 bis 174°, [a] ö = 2q.0° (Aceton) in 40 ccm Äthylacetat wurde 2 Stunden in einer Wasserstoffatmosphäre mit 18o mg eines io°/oigen Palladium-Holzkohle-Katalysators, der vorher reduziert worden war, geschüttelt. Nach dem Abfiltrieren des Katalysators wurde die Lösung zur Trockne eingedampft und das rohe Allopregnan-3, =i, 2o-trion aus Äthylacetat umkristallisiert; F. = 216 bis 218°.For the production of the starting material, allopregnan-3, ix, 2o-trione, protection is not desired. Example a) A solution of i g d 4-pregnen-3, ii, 2o-trione, F. = 172 to 174 °, [a] ö = 2q.0 ° (acetone) in 40 ccm Ethyl acetate was 2 hours in a hydrogen atmosphere with 180 mg of a 10% palladium-charcoal catalyst, which had previously been reduced, shaken. After filtering off the catalyst the solution was evaporated to dryness and the crude allopregnan-3, = i, 2o-trione recrystallized from ethyl acetate; F. = 216 to 218 °.
b) Das erhaltene Allopregnan-3, =i, 2o-trion -wurde in 50 ccm eines Gemisches aus gleichen Teilen Äthanol und Dioxan gelöst, die Lösung 6 Stunden in einer Wasserstoffatmosphäre mit i g Raneynickel geschüttelt und die Lösung im Vakuum zur Trockne eingedampft. Aus dem Rückstand wurde durch Reinigen das Allopregnan-3ß-ol-ii, 2o-dion gewonnen oder der Rückstand durch Acetylieren, z. B. durch Lösen in =o ccm Pyridin und =o ccm Essigsäureanhydridund istündiges Erhitzen auf dem Dampfbad, Eingießen in Wasser, Extraktion mit Äther, Neutralwaschen, Trocknen über Natriumsulfat und Eindampfen zur Trockne, verestert. Der zweimal aus Aceton-Hexan umkristallisierte Rückstand lieferte das Allopregnan-3ß-o1-11, 2o-dion-3-acetat, F. = 142 bis 144°, [a] ä = 85° (Chloroform). Die Veresterung mit Propionsäure- bzw. Benzoesäureanhydrid ergab das 3-Propionat bzw. 3-Benzoat.b) The allopregnan-3, = i, 2o-trione obtained was dissolved in 50 ccm of a mixture of equal parts of ethanol and dioxane, the solution was shaken for 6 hours in a hydrogen atmosphere with ig Raney nickel and the solution was evaporated to dryness in vacuo. The allopregnan-3ß-ol-ii, 2o-dione was obtained from the residue by purification or the residue was obtained by acetylation, e.g. B. by dissolving in = o cc of pyridine and = o cc of acetic anhydride and heating for one hour on the steam bath, pouring into water, extraction with ether, neutral washing, drying over sodium sulfate and evaporation to dryness, esterified. The residue, which was recrystallized twice from acetone-hexane, gave the allopregnan-3β-o1-11,2o-dione-3-acetate, mp = 142 to 144 °, [a] ä = 85 ° (chloroform). Esterification with propionic anhydride or benzoic anhydride gave the 3-propionate or 3-benzoate.
Man kann das Allopregnan-3, =i, 2o-trion auch in alkoholischer Lösung bei gewöhnlicher Temperatur und unter Atmosphärendruck durch 150 Minuten andauerndes Schütteln mit Raneynickel in einer Wasserstoffatmosphäre selektiv hydrieren, nach dem Abfiltrieren des Katalysators die Lösung zur Trockne eindampfen und den Rückstand in üblicher Weise mit Girards Reagens behandeln. Es wurde nur ein unbedeutender, nicht ketonischerAnteil (2o-Hydroxylverbindung), der während der Reaktion entstanden war, erhalten. Der ketonische Anteil ergab nach dem Umkristallisieren aus Aceton-Hexan das Allopregnan-3ß-ol-i=, 2o-dion vom F. = igo bis i93°. Das in der üblichen Weise hergestellte Acetat hatte den F. = 141 bis 143° und war in jeder Weise identisch mit der vorstehend erhaltenen Verbindung.Allopregnan-3, = i, 2o-trione can also be used in alcoholic solution at ordinary temperature and under atmospheric pressure for 150 minutes Selectively hydrogenate shaking with Raney nickel in a hydrogen atmosphere, after After filtering off the catalyst, evaporate the solution to dryness and the residue treat as usual with Girard's reagent. It just turned out to be an insignificant non-ketonic part (2o-hydroxyl compound) formed during the reaction was received. The ketonic portion resulted after recrystallization from acetone-hexane the allopregnan-3ß-ol-i =, 2o-dione from F. = igo to 193 °. That in the usual way The acetate produced had a m.p. = 141 to 143 ° and was identical in every way with the compound obtained above.
c) Die Lösung aus =g,9 g Allopregnan-3ß-o1-11, 20-dion-3-acetat (F. = 142 bis 1q4°) in 1,71 Essigsäureanhydrid und =o,2 g Paratoluolsulfosäure wurde innerhalb 5 Stunden langsam auf Zoo ccm eingeengt und dann in Eiswasser gegossen, dem 30 ccm Pyridin zugesetzt waren. Das Reaktionsprodukt wurde mit Äther extrahiert und die ätherische Lösung mit 2°/oiger Natronlauge und Wasser neutral gewaschen. Nach dem Verdampfen des Lösungsmittels wurde der Rückstand in Hexan gelöst, zur Entfernung von Verunreinigungen durch eine Tonschicht filtriert und zur Trockne eingedampft. Der ölige Rückstand von 23,1 g d il, i7 Allopregnadien-3ß-1i, 2o-trioltriacetat wurde in Zoo ccm Chloroform gelöst und mit 157 ccm einer Chloroformlösung, die 63 mg Perbenzoesäure j e Kubikzentimeter enthielt, versetzt. Nach 40stündigem Stehen bei gewöhnlicher Temperatur wurde die Lösung mit Chloroform verdünnt, mit jodnatriumlösung, Natriumthiosulfat, Natriumcarbonat und Wasser gewaschen, auf ein geringes Volumen eingeengt, mit 11 i%iger methanolischer Natronlauge bei gewöhnlicher Temperatur versetzt, nach 3 Minuten mit Essigsäure neutralisiert, die Lösung im Vakuum auf 300 ccm eingeengt, mit Wasser bis zur vollständigen Ausfällung verdünnt und der Niederschlag aus Äther unter Zusatz von etwas Hexan umkristallisiert, wobei 14,2 g Allopregnan-3ß, i7a-diol-ii, 2o-dion vom F. = 27o bis 272° erhalten wurden.c) The solution of = g, 9 g of allopregnan-3ß-o1-11, 20-dione-3-acetate (F. = 142 to 1q4 °) in 1.71 acetic anhydride and = 0.2 g of paratoluene sulfonic acid was within 5 hours slowly concentrated to zoo cc and then poured into ice water to which 30 cc of pyridine had been added. The reaction product was extracted with ether and the ethereal solution was washed neutral with 2% sodium hydroxide solution and water. After evaporation of the solvent, the residue was dissolved in hexane, filtered through a layer of clay to remove impurities and evaporated to dryness. The oily residue of 23.1 gdil, 17 allopregnadiene-3β-1i, 2o-triol triacetate was dissolved in zoo cc of chloroform and treated with 157 cc of a chloroform solution containing 63 mg perbenzoic acid per cubic centimeter. After standing for 40 hours at normal temperature, the solution was diluted with chloroform, washed with sodium iodine solution, sodium thiosulfate, sodium carbonate and water, concentrated to a small volume, treated with 11% strength methanolic sodium hydroxide solution at normal temperature, and after 3 minutes neutralized with acetic acid, the solution concentrated in vacuo to 300 cc, diluted with water until complete precipitation and the precipitate recrystallized from ether with the addition of a little hexane, with 14.2 g of allopregnan-3ß, i7a-diol-ii, 2o-dione from F. = 27o to 272 ° were obtained.
d) Eine Lösung aus 7,1 g Brom in 7o ccm Chloroform wurde während 30 Minuten (ohne Zusatz von Bromwasserstoffsäure) in eine Lösung aus 15,3 g des nach c) erhaltenen Dions in =5o ccm Chloroform eingetropft, die Lösung mit Chloroform verdünnt, gut mit Wasser gewaschen, über Natriumsulfat getrocknet und unterhalb 4o° im Vakuum eingeengt. Der aus Chloroform-Äther umkristallisierte Rückstand bestand aus 16,3 g 2i-Bromallopregnan-3ß-17a-diol-ii, 2o-dion vom F. = 242 bis 244° unter Zersetzung.d) A solution of 7.1 g of bromine in 70 cc of chloroform was added dropwise over 30 minutes (without addition of hydrobromic acid) to a solution of 15.3 g of the dione obtained in c) in 50 cc of chloroform, and the solution was diluted with chloroform , washed well with water, dried over sodium sulfate and concentrated below 40 ° in vacuo. The residue recrystallized from chloroform-ether consisted of 16.3 g of 2i-bromoallopregnan-3β-17a-diol-ii, 2o-dione with a temperature of 242 to 244 ° with decomposition.
e) Die erhaltene Bromverbindung wurde ohne vorherige Reinigung in 400 ccm Aceton gelöst und =o Minuten mit einer Lösung aus =o g Jodnatrium in ioo ccm Aceton am Rückflußkühler erhitzt. Das während der Reaktion ausgefallene Bromnatrium wurde abfiltriert, das Filtrat mit Aceton auf 8oo ccm aufgefüllt, ein Gemisch aus 75 g Kaliumbicarbonat und 46 ccm Essigsäure zugesetzt und die Mischung =o Stunden am Rückflußkühler erhitzt. Die Lösung wurde dann auf Zoo ccm eingeengt, mit Wasser verdünnt, der Niederschlag gewaschen und getrocknet. Nach dem Umkristallisieren aus Hexan-Aceton wurdenii,7gAllopregnan-3ß,-i7a, 2i-triol-ii, 2o-dion-2i-acetat vom F. = 235 bis 23g°, [a] = 8o,6° D (Aceton) erhalten.e) The bromine compound obtained was without prior purification in 400 ccm of acetone dissolved and = o minutes with a solution of = o g of sodium iodine in ioo ccm of acetone heated on the reflux condenser. The sodium bromide precipitated during the reaction was filtered off, the filtrate made up to 8oo ccm with acetone, a mixture of 75 g of potassium bicarbonate and 46 cc of acetic acid were added and the mixture = o hours heated on the reflux condenser. The solution was then concentrated to zoo cc with water diluted, the precipitate washed and dried. After recrystallization from hexane-acetone became ii, 7g allopregnan-3ß, -i7a, 2i-triol-ii, 2o-dione-2i-acetate obtained from m.p. = 235 to 23 °, [a] = 8o.6 ° D (acetone).
f) 9,6 g N-Bromacetamid wurden einer Lösung aus 11,7 g der nach e) erhaltenen Verbindung in 25o ccm Pyridin zugesetzt. Nach 4ostündigem Stehen bei gewöhnlicher Temperatur wurde mit 31 i°/oiger Salzsäure verdünnt, der Niederschlag filtriert, gewaschen, getrocknet und aus Äthylacetat umkristallisiert. Die Ausbeute betrug 10,3 g Allopregnan-i7a, 2i-diol-3, 11, 2o-trion-2i-acetat vom F. = 235 bis 237°, . = 78 bzw. 89° (Acetön bzw. Chloroform). f) 9.6 g of N-bromoacetamide were added to a solution of 11.7 g of the compound obtained according to e) in 250 cc of pyridine. After standing for 4 hours at ordinary temperature, the mixture was diluted with 31% hydrochloric acid, and the precipitate was filtered, washed, dried and recrystallized from ethyl acetate. The yield was 10.3 g of allopregnan-i7a, 2i-diol-3, 11, 2o-trione-2i-acetate with a melting point of 235 ° to 237 °. = 78 or 89 ° (acetone or chloroform).
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MX927030X | 1951-05-25 |
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| Publication Number | Publication Date |
|---|---|
| DE927030C true DE927030C (en) | 1955-04-28 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DES28658A Expired DE927030C (en) | 1951-05-25 | 1952-05-24 | Process for the preparation of allopregnan-17ª ‡, 21-diol-3, 11, 20-trione and its esters |
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| Country | Link |
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| DE (1) | DE927030C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| USRE35517E (en) * | 1987-08-25 | 1997-05-20 | University Of Southern California | Method, compositions, and compounds for modulating brain excitability |
-
1952
- 1952-05-24 DE DES28658A patent/DE927030C/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| USRE35517E (en) * | 1987-08-25 | 1997-05-20 | University Of Southern California | Method, compositions, and compounds for modulating brain excitability |
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