DE1618605A1 - Process for the production of scillarenin - Google Patents
Process for the production of scillareninInfo
- Publication number
- DE1618605A1 DE1618605A1 DE19671618605 DE1618605A DE1618605A1 DE 1618605 A1 DE1618605 A1 DE 1618605A1 DE 19671618605 DE19671618605 DE 19671618605 DE 1618605 A DE1618605 A DE 1618605A DE 1618605 A1 DE1618605 A1 DE 1618605A1
- Authority
- DE
- Germany
- Prior art keywords
- scillarenin
- proscillaridin
- reaction
- production
- solutions
- 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.)
- Granted
Links
- OVUOVMIMOCJILI-KFZANIOBSA-N scillarenin Chemical compound C=1([C@H]2CC[C@]3(O)[C@H]4[C@@H]([C@]5(CC[C@H](O)C=C5CC4)C)CC[C@@]32C)C=CC(=O)OC=1 OVUOVMIMOCJILI-KFZANIOBSA-N 0.000 title claims description 20
- OVUOVMIMOCJILI-UHFFFAOYSA-N 3alpha-Scillarenin Natural products CC12CCC(C3(CCC(O)C=C3CC3)C)C3C1(O)CCC2C=1C=CC(=O)OC=1 OVUOVMIMOCJILI-UHFFFAOYSA-N 0.000 title claims description 10
- 238000000034 method Methods 0.000 title claims description 6
- 238000004519 manufacturing process Methods 0.000 title description 2
- MYEJFUXQJGHEQK-ALRJYLEOSA-N Proscillaridin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C=C2CC[C@H]3[C@@]4(O)CC[C@H](C5=COC(=O)C=C5)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1 MYEJFUXQJGHEQK-ALRJYLEOSA-N 0.000 claims description 6
- 229930190098 proscillaridin Natural products 0.000 claims description 6
- 229960003584 proscillaridin Drugs 0.000 claims description 6
- MYEJFUXQJGHEQK-UHFFFAOYSA-N proscillaridin A Natural products OC1C(O)C(O)C(C)OC1OC1C=C2CCC3C4(O)CCC(C5=COC(=O)C=C5)C4(C)CCC3C2(C)CC1 MYEJFUXQJGHEQK-UHFFFAOYSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 150000002338 glycosides Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- SMPAPEKFGLKOIC-UHFFFAOYSA-N oxolane;hydrochloride Chemical compound Cl.C1CCOC1 SMPAPEKFGLKOIC-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XJJBIDDTIZKCAO-FIJLXMTKSA-N 5-[(8r,9s,10r,13r,14s,17r)-14-hydroxy-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,15,16,17-decahydro-1h-cyclopenta[a]phenanthren-17-yl]pyran-2-one Chemical compound C=1([C@H]2CC[C@]3(O)[C@H]4[C@@H]([C@]5(CCC(=O)C=C5CC4)C)CC[C@@]32C)C=CC(=O)OC=1 XJJBIDDTIZKCAO-FIJLXMTKSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 241001285170 Drimia sanguinea Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000001652 bufadienolides Chemical class 0.000 description 1
- 150000001738 cardenolides Chemical class 0.000 description 1
- 239000002371 cardiac agent Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- -1 for example Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229930190071 lycoside Natural products 0.000 description 1
- HPOKESDSMZRZLC-UHFFFAOYSA-N propan-2-one;hydrochloride Chemical compound Cl.CC(C)=O HPOKESDSMZRZLC-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Saccharide Compounds (AREA)
Description
CHEMISCHE FABRIKENCHEMICAL FACTORY
Patent- u. Lizenz-Abteilung Ludwigshafen/Ehein,Patent and License Department Ludwigshafen / Ehein,
Dr.W./2954 den 16. Mai 1967Dr.W./2954 on May 16, 1967
Verfahren zur Herstellung von ScillareninProcess for the production of scillarenin
Scillarenin wurde erstmals durch enzymatische Spaltung von Scilla-G-lykosiden hergestellt £Ä.. Stoll et al. HeIv. Chim. Aeta, J4;, 2301 (1951Ϊ7· Später gelang den gleichen Autoren auch die' Herstellung von Scillarenon, das.aus Seilla-Glykosiden durch fermentative Spaltung erhältlich ist /SeIv. Ghim. Acta, J5£, 1934 (1952J7· Schließlich wurde noch die Isolierung geringer Mengen von Scillarenin aus Extrakten der Pflanze Urginea Burkei beschrieben /P. Zoller, Ch. Tamm, HeIv. Chim. Acta, %&, 1744- (195327·Scillarenin was first produced by enzymatic cleavage of Scilla G lycosides . . Stoll et al. HeIv. Chim. Aeta, J4 ;, 2301 (1951Ϊ7 · Later, the same authors succeeded in the 'preparation of Scillarenon, das.aus Seilla glycosides by fermentative cleavage is available / SeIv. Ghim. Acta, J5 £ 1934 (1952J7 · Finally it has been the Isolation of small amounts of scillarenin from extracts of the Urginea Burkei plant described / P. Zoller, Ch. Tamm, HeIv. Chim. Acta, % &, 1744- (195327
Eine Darstellung des Scillarenins durch Säurehydrolyse der fflykoside, wie sie bei Cardenoliden oder Bufadienoliden bekannt ist, gelingt nach den Literaturangaben nicht. Versuche zur Darstellung von Scillarenin durch Hydrolyse von Glykosiden mit .1 foiger Schwefelsäure in methanolischer Lösung bei cirka 700C führten zu dem wasserärmeren Scillaridin £k. Stoll et al. HeIv. Chim. Acta, 16, 703 (1933)7-A representation of scillarenin by acid hydrolysis of the fflykoside, as it is known with cardenolides or bufadienolides, does not succeed according to the literature. Attempts to prepare scillarenin by hydrolysis of glycosides with .1 foiger sulfuric acid in methanolic solution at approximately 70 0 C k supplied to the lower water content Scillaridin £. Stoll et al. HeIv. Chim. Acta, 16, 703 (1933) 7-
Enzymati0chen Abbaureaktionen ist gemeinsam, daß sie in größeren Ansätzen aufwendig und technisch nur schwierig zu bewältigen sind. Es war daher wünschenswert ein einfacheres Verfahren zur DarstellungEnzymatic degradation reactions have in common that they occur in larger Approaches are complex and technically difficult to master. It was therefore desirable to have a simpler method of illustration
SAD ORIGINALSAD ORIGINAL
H-H-
Ί 6Ί 6
KMOLL A. G.KMOLL A. G.
CHEMISCHE FABRIKENCHEMICAL FACTORY
von Scillarenin zu finden, welches als Zwischenprodukt für herzwirksame Arzneimittel interessant ist.of Scillarenin to find which as an intermediate for cardiac drug is interesting.
Überraschenderweise wurde gefunden, daß die Herstellung von Scillarenin auf einfachem Wege gelingt, wenn man Proscillaridin-Lösungen bei normaler oder mäßig erhöhter Temperatur der sauren P Hydrolyse unterwirft.Surprisingly, it has been found that scillarenin can be produced in a simple manner if proscillaridin solutions are used Subjected to acidic hydrolysis at normal or moderately elevated temperatures.
Fach dem erfindungsgemäßen Verfahren sind zur Hydrolyse 0,05 - 2 η Lösungen von Chlorwasserstoff "besonders geeignet. Anstelle von Chlorwasserstofflösungen kann man auch Perchlorsäure, p-Toluolsulfonsäure oder Schwefelsäure verwenden.In the process according to the invention, 0.05-2 η solutions of hydrogen chloride "are particularly suitable for the hydrolysis. Instead of hydrogen chloride solutions, perchloric acid, p-toluenesulfonic acid or sulfuric acid can also be used.
Die Reaktion kann praktisch in allen üblichen Lösungsmitteln durchgeführt werden, wie Kohlenwasserstoffe, Äther, Ester oder Ketone, wie zum Beispiel Cyclohexan, Benzol, Tetrahydrofuran, Essigsäureäthylester und Methyläthy!keton. Tetrahydrofuran, Aceton oder Dioxan sind besonders geeignet, da bei Verwendung dieser Lösungsmittel die Aufarbeitung des Reaktionsgemisches sehr schonend erfolgt und außerdem keine unerwünschten Nebenreaktionen auftreten.The reaction can be carried out practically in all common solvents, such as hydrocarbons, ethers, esters or Ketones, such as, for example, cyclohexane, benzene, tetrahydrofuran, ethyl acetate and methyl ethyl ketone. Tetrahydrofuran, Acetone or dioxane are particularly suitable because when these solvents are used, the reaction mixture is worked up takes place very gently and, moreover, no undesirable side reactions appear.
ORIGINAL INSPECTEDORIGINAL INSPECTED
- 3 109814/215 1 - 3 109814/215 1
K IST O L L AG.K IST O L L AG.
CHEMISCHE FABRIKENCHEMICAL FACTORY
Die Verseifung gelingt bereits bei 200C und ein- bis zweistündiger Reaktionsdauer in hohen Ausbeuten. Sie ist jedoch auch bei mäßig erhöhter Temperatur durchführbar. Erhöht man hingegen Re akt ions dauer und/oder Reaktionstemperatur wesentlich, so entsteht wie in der Literatur beschrieben Scillaridin.The saponification is already successful at 20 ° C. and a reaction time of one to two hours in high yields. However, it can also be carried out at a moderately elevated temperature. If, on the other hand, the reaction time and / or reaction temperature is increased significantly, then scillaridin is formed, as described in the literature.
Nach Beendigung der Reaktion wird die Lösung neutralisiert. Das entstandene Aglueon extrahiert man anschließend in an sich bekannter Weise. Das Reaktionsprodukt kann durch Chromatographie gereinigt werden.After the reaction has ended, the solution is neutralized. The resulting agglueon is then extracted in an known way. The reaction product can be determined by chromatography getting cleaned.
109814/2151109814/2151
ORiGaNAL INSPECTEDORiGaNAL INSPECTED
161"^05161 "^ 05
CHEMISCHE FABRIKENCHEMICAL FACTORY
100 g Proscillaridin werden in 1 1 1 η HCl-Tetrahydrofuran (hergestellt durch Einleiten von Chlorwasserstoffgas in wasserfreiem Tetrahydrofuran) gelöst und 50 Minuten bei 4-00C hydrolysiert. Zur Aufarbeitung gießt man die Reaktionslösung in ein Gemisch von 1 1 1 η NaOH in 1,5 1 Eiswasser. Die Lösung wird erforderlichenfalls durch Zugabe geringer Mengen Säure oder Base genau auf pH = 7 eingestellt. Man extrahiert zweimal mit je 1 1 Äthylacetat und wäscht die vereinigten Äthylacetatlösungen zweimal mit je 1/2 1 Wasser. Nach Trocknen über Natriumsulfat und Abdestillieren des Lösungsmittels wird der Rückstand an Kieselgel chromatographiert. Man erhält in über 80 $iger Ausbeute Scillarenin. Nicht umgesetztes Proscillaridin wird vollständig zurückgewonnen.100 g proscillaridin be in η 1 1 1 HCl-tetrahydrofuran (prepared by passing hydrogen chloride gas in anhydrous tetrahydrofuran) and hydrolyzed for 50 minutes at 4-0 0 C. For work-up, the reaction solution is poured into a mixture of 1 1 1 NaOH in 1.5 1 ice water. If necessary, the solution is adjusted to exactly pH = 7 by adding small amounts of acid or base. It is extracted twice with 1 liter of ethyl acetate each time and the combined ethyl acetate solutions are washed twice with 1/2 liter of water each time. After drying over sodium sulfate and distilling off the solvent, the residue is chromatographed on silica gel. Scillarenin is obtained in over 80% yield. Unreacted proscillaridin is completely recovered.
100 g Proscillaridin werden in 1 1 1 η HCl-Tetrahydrofuran gelöst, 100 Minuten bei 200C hydrolysiert und anschließend wie in Beispiel 1 beschrieben aufgearbeitet. Ausbeute 84- i< >. 100 g proscillaridin are dissolved in 1 1 1 η HCl-tetrahydrofuran, hydrolyzed at 20 ° C. for 100 minutes and then worked up as described in Example 1. Yield 84- i <>.
100 g Proscillaridin werden in 2 1 0,6 η HCl-Aceton gelöst,100 g proscillaridin are dissolved in 2 1 0.6 η HCl acetone,
IQ 9 8 TIQ 9 8 T
ORlQfNAL INSPECTEDORlQfNAL INSPECTED
5151
161 π R ο161 π R ο
CHEMISCHE FABRIKENCHEMICAL FACTORY
12 Stunden "bei Raumtemperatur hydrolysiert und anschließend in ein Gemisch von 2 1 0,6 η NaOH in 3 1 Eiswasser gegossen. Danach wird wie in Beispiel 1 "beschrieben aufgearbeitet. · Ausbeute 79,5 1°- 12 hours "hydrolyzed at room temperature and then poured into a mixture of 2 1 0.6 η NaOH in 3 1 ice-water. Then, as described in Example 1" is worked up. Yield 79.5 1 ° -
ORIGINAL INSPECTEDORIGINAL INSPECTED
1098U/21511098U / 2151
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEK0062316 | 1967-05-18 | ||
| DEK0062316 | 1967-05-18 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DE1618605A1 true DE1618605A1 (en) | 1971-04-01 |
| DE1618605B2 DE1618605B2 (en) | 1975-06-12 |
| DE1618605C3 DE1618605C3 (en) | 1976-01-22 |
Family
ID=
Also Published As
| Publication number | Publication date |
|---|---|
| IL29852A0 (en) | 1968-06-20 |
| JPS5034033B1 (en) | 1975-11-05 |
| CH487139A (en) | 1970-03-15 |
| NL6806382A (en) | 1968-11-19 |
| GB1154680A (en) | 1969-06-11 |
| FR1560934A (en) | 1969-03-21 |
| DE1618605B2 (en) | 1975-06-12 |
| ES353954A1 (en) | 1969-10-16 |
| BE713921A (en) | 1968-10-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C3 | Grant after two publication steps (3rd publication) | ||
| E77 | Valid patent as to the heymanns-index 1977 | ||
| EHJ | Ceased/non-payment of the annual fee |