DE1618605B2 - Process for the preparation of scillarenin - Google Patents
Process for the preparation of scillareninInfo
- Publication number
- DE1618605B2 DE1618605B2 DE19671618605 DE1618605A DE1618605B2 DE 1618605 B2 DE1618605 B2 DE 1618605B2 DE 19671618605 DE19671618605 DE 19671618605 DE 1618605 A DE1618605 A DE 1618605A DE 1618605 B2 DE1618605 B2 DE 1618605B2
- Authority
- DE
- Germany
- Prior art keywords
- scillarenin
- proscillaridin
- preparation
- tetrahydrofuran
- 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 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 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
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 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
- 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
- 230000035484 reaction time Effects 0.000 description 2
- 229940082658 scilla glycosides used in cardiac therapy Drugs 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 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
- 241001609170 Urginea Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001652 bufadienolides Chemical class 0.000 description 1
- 150000001738 cardenolides Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 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
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 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
- 239000000284 extract Substances 0.000 description 1
- 239000007789 gas Substances 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
Landscapes
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Saccharide Compounds (AREA)
Description
Scillarenin wurde erstmals durch enzymatische Spaltung von Scilla-Glykosiden hergestellt [A. Stoll et al. HeIv. Chim. Acta 34, 2301 (1951)]. Später gelang den gleichen Autoren auch die Herstellung von Scillarenön, das aus Scilla-Glykosiden durch fermentative Spaltung erhältlich ist [HeIv. Chim. Acta 35, 1934 (1952)]. Schließlich wurde noch die Isolierung geringer Mengen von Scillarenin aus Extrakten der Pflanze Urginea Burkei beschrieben (P. Zoller, Ch. Tamm, HeIv. Chim. Acta 36, 1744 (1953)].Scillarenin was first produced by enzymatic cleavage of Scilla glycosides [A. Stoll et al. HeIv. Chim. Acta 34, 2301 (1951)]. Later the same authors also succeeded in making Scillarenön, obtainable from Scilla glycosides by fermentative cleavage [HeIv. Chim. Acta 35, 1934 (1952)]. Finally, small amounts of scillarenin were isolated from extracts of the Urginea plant Burkei (P. Zoller, Ch. Tamm, HeIv. Chim. Acta 36, 1744 (1953)].
Eine Darstellung des Scillarenins durch Säurehydrolyse der Glykoside, wie sie bei Cardenoliden oder Bufadienoliden bekannt ist, gelingt nach den Literaturangeben nicht. Versuche zur Darstellung von Scillarenin durch Hydrolyse von Glykosiden mit 1 %iger Schwefelsäure in methanolischer Lösung bei ca. 700C führten zu dem wasserärmeren Scillaridin [A. Stoll et al. HeIv. Chim. Acta 16, 703 (1933)].A representation of scillarenin by acid hydrolysis of the glycosides, as it is known for cardenolides or bufadienolides, does not succeed according to the literature. Attempts to prepare scillarenin by hydrolysis of glycosides with 1% sulfuric acid in methanol solution at about 70 0 C led to the lower water content Scillaridin [A. Stoll et al. HeIv. Chim. Acta 16, 703 (1933)].
Enzymatischen Abbaureaktionen ist gemeinsam, daß sie in größeren Ansätzen aufwendig und technisch nur schwierig zu bewältigen sind. Es war daher wünschenswert ein einfacheres Verfahren zur Darstellung von Scillarenin zu finden, welches als Zwischenprodukt für herzwirksame Arzneimittel interessant ist.Enzymatic degradation reactions have in common that they are complex and technical in larger batches difficult to manage. It was therefore desirable to have a simpler method of illustration of scillarenin, which is interesting as an intermediate for cardiac drugs.
Überraschenderweise wurde gefunden, daß die Herstellung von Scillarenin auf einfachem Wege gelingt, wenn man Proscillaridin-Lösungen bei normaler oder mäßig erhöhter Temperatur der sauren Hydrolyse mit 0,05 bis 2n Lösungen von Chlorwasserstoff in Tetrahydrofuran, Aceton oder Dioxan unterwirft.Surprisingly, it has been found that scillarenin can be produced in a simple way, when using proscillaridin solutions at normal or moderately elevated temperature of acid hydrolysis 0.05 to 2N solutions of hydrogen chloride in tetrahydrofuran, acetone or dioxane.
Bei Verwendung dieser Lösungsmittel erfolgt die Aufarbeitung des Reaktionsgemisches sehr schonend und außerdem treten keine unerwünschten Nebenreaktionen auf.When these solvents are used, the reaction mixture is worked up very gently and in addition, there are no undesirable side reactions.
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 Reaktionsdauer 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 ίο neutralisiert. Das entstandene Aglucon 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 aglucon formed is extracted then in a manner known per se. The reaction product can be purified by chromatography will.
100 g Proscillaridin werden in 1 1 In HCl-Tetrahydrofuran (hergestellt durch Einleiten von Chlorwasserstoffgas in easserfreiem Tetrahydrofuran) gelöst und 50 Minuten bei 400C hydrolysiert. Zur Aufarbeitung gießt man die Reaktionslösung in ein Gemisch von 1 1 In 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 wäschtProscillaridin 100 g are dissolved in 1 1 (prepared in tetrahydrofuran easserfreiem by introducing hydrogen chloride gas) were dissolved in tetrahydrofuran-HCl and hydrolyzed for 50 minutes at 40 0 C. For working up, the reaction solution is poured into a mixture of 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 l of ethyl acetate each time and washed
die vereinigten Athylacetatlösungen zweimal mit je 2/21 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.the combined Athylacetatlösungen twice with 2/2 1 water. After drying over sodium sulfate and distilling off the solvent, the residue is chromatographed on silica gel. Scillarenin is obtained in a yield of over 80%. Unreacted proscillaridin is completely recovered.
100 g Proscillaridin werden in 1 1 In HCl-Tetrahydrofuran gelöst, 100 Minuten bei 200C hydrolysiert und anschließend wie in Beispiel 1 beschrieben aufgearbeitet. Ausbeute 84%.100 g of proscillaridin are dissolved in 1 liter of HCl-tetrahydrofuran, hydrolyzed for 100 minutes at 20 ° C. and then worked up as described in Example 1. Yield 84%.
100 g Proscillaridin werden in 2 1 0,6n HCl-Aceton gelöst, 12 Stunden bei Raumtemperatur hydrolysiert und anschließend in ein Gemisch von 2 1 0,6n NaOH in 3 1 Eiswasser gegossen. Danach wird wie in Beispiel 1 beschrieben aufgearbeitet. Ausbeute 79,5 %.100 g of proscillaridin are dissolved in 2 liters of 0.6N HCl acetone and hydrolyzed for 12 hours at room temperature and then poured into a mixture of 2 1 0.6N NaOH in 3 1 ice water. Then as in example 1 described worked up. Yield 79.5%.
Beispiel 1 wird wiederholt, jedoch wird an Stelle von Tetrahydrofuran Dioxan verwendet. Man erhält Scillarenin in einer Ausbeute von 81,5%.Example 1 is repeated, except that dioxane is used instead of tetrahydrofuran. Scillarenin is obtained in a yield of 81.5%.
Claims (1)
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 DE1618605A1 (en) | 1971-04-01 |
| DE1618605B2 true 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 |
| DE1618605A1 (en) | 1971-04-01 |
| GB1154680A (en) | 1969-06-11 |
| FR1560934A (en) | 1969-03-21 |
| ES353954A1 (en) | 1969-10-16 |
| BE713921A (en) | 1968-10-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE2626783C2 (en) | Process for the preparation of daunomycin and its analogues modified in ring D. | |
| DE2504108C2 (en) | Process for the extraction and purification of pullulan | |
| EP0045076B1 (en) | Process for the preparation of 1,4:3,6-dianhydro-d-glucite-5-nitrate (isosobide-5-nitrate) | |
| DE1618605C3 (en) | Process for the preparation of scillarenin | |
| DE2740950A1 (en) | METHOD OF MANUFACTURING FLAVONS | |
| DE1618605B2 (en) | Process for the preparation of scillarenin | |
| AT275756B (en) | Process for the production of scillarenin | |
| DE2731306C3 (en) | 9-deacetyl- and 9-deacetyl-9-epi-daunorubicin, process for their preparation and their use | |
| Zderic et al. | Steroids. CXXX. 1 Synthesis of 12β-Hydroxyprednisolone 11β, 12β-Acetonide 21-Acetate | |
| DE2004280A1 (en) | Method of crystallizing vitamin D deep 3 | |
| DE936592C (en) | Process for the production of a blood and urine sugar lowering preparation from trioxyflavone glucoside-containing parts of plants | |
| CH518272A (en) | Process for the manufacture of 4-halogeno-1 2alpha 6 | |
| DE2501958C2 (en) | Process for the production of bicyclomycin | |
| DE1568924C (en) | Proscillaridine ketals and process for their preparation | |
| AT270882B (en) | Process for the production of new, easily absorbable proscillaridin ketals | |
| DE951444C (en) | Process for the preparation of 4-pregnen-8, 17ª ‡, 21-triol-3, 20-dione | |
| AT226383B (en) | Process for the production of new steroid compounds | |
| DE1958016C3 (en) | Inosine-3 'to 5'-monophosphate-2'-O-ester | |
| CH498822A (en) | Process for b-scillarenin | |
| DE1024948B (en) | Process for the preparation of 2-amino-2-deoxy-aldohexoses and their salts | |
| DE1187237B (en) | Process for the production of 4-hydroxy-3-keto-delta-steroids of the androstane or de9-nor-androstane series | |
| DE1028573B (en) | Process for the preparation of 16-alkyl-1, 3, 5 (10) -oestratriene-3, 16, 17-triols and their ethers and esters | |
| DE1944000A1 (en) | Iso-adenosine -3'-$'-monophosphoric acid - and its salts | |
| DE1107663B (en) | Process for the preparation of 16, 17-methylene-20-keto steroids | |
| DE2016783B2 (en) | METHOD OF CONVERTING A 17 BETA HYDROXY STEROID INTO THE CORRESPONDING 17 ALPHA HYDROXY COMPOUND |
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 |