DE1812945C - Cardiac 4beta, 5beta 14beta, 15beta Dioxidobufadienohde - Google Patents
Cardiac 4beta, 5beta 14beta, 15beta DioxidobufadienohdeInfo
- Publication number
- DE1812945C DE1812945C DE19681812945 DE1812945A DE1812945C DE 1812945 C DE1812945 C DE 1812945C DE 19681812945 DE19681812945 DE 19681812945 DE 1812945 A DE1812945 A DE 1812945A DE 1812945 C DE1812945 C DE 1812945C
- Authority
- DE
- Germany
- Prior art keywords
- cardiac
- dioxidobufadienohde
- 15beta
- 14beta
- 4beta
- 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
- 230000000747 cardiac effect Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 3
- 125000004432 carbon atoms Chemical group C* 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000004593 Epoxy Substances 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N Perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- -1 aromatic sulfonic acids Chemical class 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 229960000583 Acetic Acid Drugs 0.000 description 3
- JMSRBKPMLUGHCR-UHFFFAOYSA-N Bromohydrin Chemical compound BrC[C]1CO1 JMSRBKPMLUGHCR-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000003700 epoxy group Chemical group 0.000 description 3
- 238000005755 formation reaction Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000002211 ultraviolet spectrum Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N al2o3 Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- HCDSTARONIHDMB-UHFFFAOYSA-N aluminum;lithium;hydride;2-methylpropan-2-olate Chemical compound [H-].[Li+].CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C HCDSTARONIHDMB-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000001264 neutralization Effects 0.000 description 2
- 150000004965 peroxy acids Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-Diazabicyclo(4.3.0)non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-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
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- STABAPSYCQFWOK-UHFFFAOYSA-N 4-chlorobenzenecarboperoxoic acid Chemical compound OOC(=O)C1=CC=C(Cl)C=C1 STABAPSYCQFWOK-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- PTEWBCBLYXHSHI-UHFFFAOYSA-N BrNS(=O)=O Chemical class BrNS(=O)=O PTEWBCBLYXHSHI-UHFFFAOYSA-N 0.000 description 1
- NKRJRPDCNYYXEZ-UHFFFAOYSA-N CC(C)(C)O[AlH2] Chemical compound CC(C)(C)O[AlH2] NKRJRPDCNYYXEZ-UHFFFAOYSA-N 0.000 description 1
- 206010007554 Cardiac failure Diseases 0.000 description 1
- 206010011416 Croup infectious Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failure Diseases 0.000 description 1
- CUILPNURFADTPE-UHFFFAOYSA-N Hypobromous acid Chemical compound BrO CUILPNURFADTPE-UHFFFAOYSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- VBTQNRFWXBXZQR-UHFFFAOYSA-N N-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 description 1
- XCRBXWCUXJNEFX-UHFFFAOYSA-N Peroxybenzoic acid Chemical compound OOC(=O)C1=CC=CC=C1 XCRBXWCUXJNEFX-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 229940116362 Tragacanth Drugs 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 238000006359 acetalization reaction Methods 0.000 description 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 230000001458 anti-acid Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 201000010549 croup Diseases 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N ethoxyethane;trifluoroborane Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000000297 inotrophic Effects 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- NZTNZPDOBQDOSO-UHFFFAOYSA-N lithium;boron(1-) Chemical compound [Li+].[B-] NZTNZPDOBQDOSO-UHFFFAOYSA-N 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- NRZWQKGABZFFKE-UHFFFAOYSA-N trimethylsulfonium Chemical compound C[S+](C)C NRZWQKGABZFFKE-UHFFFAOYSA-N 0.000 description 1
Description
a j 14 - Anhydro - scillarenon [3 - Oxo - bui'a - 4.! 4. 20(21),22(23)-tetraenolid] zu 14-Anhydro-scillaie· nin reduziert, dieses in 3-Stellung acyliert. die μ erhaltenen 3,-i-Acyloxy verbindungen mit N-Bron: säureamiden zu 3//-Acyloxy-4/i',14i>'-dihydro.v.-5-i,15«-dibrom-bufadienoliden umsetz;, diese rvni HBr-abspaltenden Mitteln behandelt und .:. wünschtenfalls in den erhaltenen Verbindungen die 3/i-Acylgruppe abspaltet, odera j 14 - anhydro - scillarenon [3 - oxo - bui'a - 4th! 4th 20 (21), 22 (23) -tetraenolide] to 14-Anhydro-scillaie reduced nin, this acylated in the 3-position. the μ obtained 3, -i-acyloxy compounds with N-Bron: acid amides to 3 // - acyloxy-4 / i ', 14i>' - dihydro.v.-5-i, 15 "-dibromo-bufadienolides implement ;, this rvni HBr-releasing agents treated and.:. if desired in the compounds obtained splits off the 3 / i-acyl group, or
b) 3{i - Hydroxy - 14,15/* - epoxy - bufa - 4.20(2 ί ι. 22(23)-trie.iolid mit Persäuren behandelt und da·- Produkt gewiinschtenfalls anschließend in 3-Stellung acyliert.b) 3 {i - Hydroxy - 14,15 / * - epoxy - bufa - 4.20 (2 ι. 22 (23) -trie.iolide treated with peracids and then, if desired, the product is acylated in the 3-position.
Die einzelnen Teilschritte des Verfahrens sind in dem folgenden Fonr.,!schema wiedergegeben:
OThe individual sub-steps of the process are shown in the following form:
O
IIII
HOBrHOBr
IVIV
Ilia) R = H
I lib) R =AcyIIlia) R = H
I lib) R = AcyI
Die einzelnen Verfahrensschritte werden in an sich vorzugsweise Natriumborhydrid, Lilhiumborhydrid bekannter Weise durchgeführt. Zur Reduktion der oder Lithium-tri-(tert.-butoxy)-aluminiumhydrid. Die 3-K.etogruppe in II verwendet man Metallhydride, Umsetzung von III b) zum Bromhydrin IV kann z. B.The individual process steps are per se preferably sodium borohydride, lithium borohydride carried out in a known manner. For the reduction of or lithium tri- (tert-butoxy) aluminum hydride. the 3-K.eto group in II is used metal hydrides, conversion of III b) to the bromohydrin IV can, for. B.
durch Behandeln mit N-Broniacetamid in Dioxan in Gegenwart von Perchlorsäure oder durch Umsetzung mit N-Bromsulfonamiden, vorzugsweise aromatischen Sulfonsäuren, ζ. B. Ν,Ν-Dibrom-benzolsulfonamid in schwach saurer Lösung, z. B. in Essigsäure, durchgeführt werden. Das Bromhydrin IV bedarf keiner weiteren Reinigung, sondern kann unmittelbar zum Epoxyd I umgesetzt werden. Diese Umsetzung wird in üblicher Weise mit HBr-abspaltenden Mitteln, z. B. mit organischen Basen wie Pyridin, Triäthylamin, 1.5-Diazabicyclo-[4,3,0]-5-nonen oder mittels Aluminiumoxyd, Kieselgel, Natfiumacetat oder Natriumcarbonat durchgeführt.by treatment with N-broniacetamide in dioxane in the presence of perchloric acid or by reaction with N-bromosulfonamides, preferably aromatic sulfonic acids, ζ. B. Ν, Ν-dibromobenzenesulfonamide in weakly acidic solution, e.g. B. in acetic acid. The bromohydrin IV does not need any further cleaning, but can be converted directly to epoxy I. This implementation will in the usual way with HBr-releasing agents, e.g. B. with organic bases such as pyridine, triethylamine, 1,5-diazabicyclo- [4,3,0] -5-nonene or by means of aluminum oxide, silica gel, sodium acetate or sodium carbonate accomplished.
Bei der Darstellung von I aus V mittels Persäuren gemäß b) werden vorzugsweise Monoperphthalsäure, Perbenzoesäure oder Monochlorperbenzoesäure verwendet. In the representation of I from V by means of peracids according to b) monoperphthalic acid, Perbenzoic acid or monochloroperbenzoic acid is used.
Die Verbindung II läßt sich, ausgehend von dem literaturbekannten 1 Sn-Hydroxycorticosteron. durch aufeinanderfolgende Oxydation der 21-Hydroxylgruppe, Acetalisierung der gebildeten 21-Aldehydgruppe, losylierung der Hydroxylgruppe in 15-a-Stellung. Bildung der l-14-Doppelbindung durch Abspaltung von Toluolsuifonsäure mittels Lithiumcarbonat. Schutz der 3-Ketogruppe durch Enolesterbildung mit Orthoameisensaureester. Bildung des 20,22-Epoxyds mit TrimethylsulfoniumjodidN'aH. gleichzeitige Abspaltung der' Acetal- und Enolester-Kruppen und Aufspaltung des Epoxydrinees mit HBr. Regenerierung des 20.22-Epoxydringes aus dem entstandenen Bromhydrin mit Triäthylamin. selektive Kondensation der 21-Aldchydgruppe mit Carbomethoxymethyl-diäthylphosphonat zur 21-Carbomethoxymetinlenvcrbindung unter Erhaltung der 3-Ketogruppe, isomerisierung des 20.22-Epoxydrinsies zum 22-Aldehyd mit Bortrifluoridäthera! und Rmgschluß zu II mit wäßrig-methanolisclier HCl nach dem Verfahren der deutschen Offenlegungsschriften I 668 009 und 1 768 226 herstellen.The compound II can be, starting from the literature known 1 Sn-hydroxycorticosterone. through successive oxidation of the 21-hydroxyl group, acetalization of the 21-aldehyde group formed, losylation of the hydroxyl group in the 15-a-position. Formation of the l-14 double bond by cleavage of toluenesulfonic acid using lithium carbonate. Protection of the 3-keto group through enol ester formation with ortho ant acid ester. Formation of the 20,22-epoxide with trimethylsulfonium iodideN'aH. simultaneous splitting off of the acetal and enol ester croups and splitting of the epoxydrine with HBr. Regeneration of the 20.22 epoxy ring from the resulting Bromohydrin with triethylamine. selective condensation of the 21-aldehyde group with carbomethoxymethyl diethylphosphonate to the 21-carbomethoxymetine linkage with retention of the 3-keto group, isomerization of the 20.22-epoxydrinsies to 22-aldehyde with boron trifluoride ether! and closing of II with aqueous methanolic HCl according to the process of German Offenlegungsschrift I 668 009 and 1 768 226.
V laßt sich aus II in an sich bekannter Weise durch Umsetzung mit N-Bromacetamid, Perchlorsäure zum 14,15-Bromhydnn. Abspaltung von HBr und Bildung des Epoxyringes durch Behandlung mit einer Base und Reduktion der Ketogruppe in 3-Stellung zur Hydroxygruppe mit Lithium-tri-(tert.-butoxy)-aluminiumhydrid erhalten.V can be obtained from II in a manner known per se by reaction with N-bromoacetamide, perchloric acid to form 14,15-bromohydron. Breakaway from HBr and education of the epoxy ring by treatment with a base and reduction of the keto group in the 3-position to Hydroxyl group obtained with lithium tri- (tert-butoxy) aluminum hydride.
Die erfindungsgemäß erhaltenen Produkte sind neu Und zeichnen sich durch eine starke positiv inotrope Wirkung und eine dadurch bedingte stark ausgeprägte Herzwirksamkeit aus. Sie eignen sich daher zur medikamentösen Behandlung von Herzschäden, insbesondere bei Herzinsuffizienz und Tachykardie. Sie weiden vorzugsweise oral in Form von Tabletten oder Dragees verabreicht, die außer den Wirkstoffen übliche Hilfs- und Trägerstoffe enthalten, wie z. B. Miichlucker. Stärke, Traganth u. a.The products obtained according to the invention are new and are characterized by a strong positive inotropic Effect and a resulting strongly pronounced cardiac effectiveness. They are therefore suitable for medicinal use Treatment of heart damage, especially heart failure and tachycardia. They graze preferably administered orally in the form of tablets or dragees, which are customary in addition to the active ingredients Contain auxiliaries and carriers, such as. B. Miichlucker. Starch, tragacanth and others
Die Verfahrensprodukte können auch als Zwischenprodukte zur Herstellung von Arzneimitteln verwendet weiden.The products of the process can also be used as intermediate products in the manufacture of pharmaceuticals graze.
3/i-Acetoxy-4,5ff: 14,15/J-bis-oxido-bufa-20(21),22(23)-dienolid 3 / i-acetoxy-4,5ff: 14,15 / J-bis-oxido-bufa-20 (21), 22 (23) -dienolide
a) 3//-Hydroxy-bufa-4.14.20(2l).22(23)-tetraenolid
(IIIa) (Anhydro-scillarenin)a) 3 // - Hydroxy-bufa-4.14.20 (2l) .22 (23) -tetraenolide
(IIIa) (anhydro-scillarenin)
Zu einer Lösung von 518 mg 3-Oxo-bufa-4,14.20(21). 22(23)-tetraenolid in 52 ml absolutem Tetrahydrofuran gibt man bei -10 bis -5CC unter Rühren eine Lösung von 3,75 g Lithium-iri-(tert.-butoxy)-aluminiumhydrid in 16,0 ml absolutem Tetrahydrofuran tropfenweise hinzu. Man läßt 2'/4 Stunden bei —3 bisTo a solution of 518 mg 3-Oxo-bufa-4,14.20 (21). 22 (23) -tetraenolid in 52 ml of absolute tetrahydrofuran are added at -10 to -5 C C with stirring, a solution of 3.75 g of lithium-IRI (tert-butoxy) aluminum hydride in 16.0 ml of absolute tetrahydrofuran was added dropwise added. It is allowed to 2 '/ 4 hours at -3 to
5 O'C weiterrühren und dann unter intensiver Kühlung langsam 20 ml einer 5%igen wäßrigen Essigsäure zutropfen, rührt noch 30 Minuten nach, versetzt das Reaktionsgemisch mit Wasser und extrahiert es mit Methylenchlorid. Danach destilliert man das Methylenchlorid ab, wobei ein kristalliner Rückstand erhalten wird, der aus Methylenchlorid/Äther unter Zusatz von 2 Tropfen Pyridin umkristallisiert wird. Man erhält 377 mg HIa (14-Anhydro-scillarenin) vom Schmelzpunkt 198 bis 2000C (Koflerbank).Stir 5 o'clock further and then slowly add dropwise 20 ml of a 5% aqueous acetic acid with intensive cooling, stir for a further 30 minutes, the reaction mixture is mixed with water and extracted with methylene chloride. The methylene chloride is then distilled off, a crystalline residue being obtained which is recrystallized from methylene chloride / ether with the addition of 2 drops of pyridine. This gives 377 mg HIa (14-anhydro-scillarenin) of melting point 198-200 0 C (Kofler bank).
Charakter: IR-Banden: 3480, 1735 und 1715Character: IR bands: 3480, 1735 and 1715
(Schulter), 1700, 1625, 1530 cm "x;
UV-Spektrum: lmax = 299 bis 300 πΐμ. r = 5450.(Shoulder), 1700, 1625, 1530 cm "x;
UV spectrum: l max = 299 to 300 πΐμ. r = 5450.
b) 3,-i-Acetoxy-bufa-4.14,20(21).22(23Metra-b) 3, -i-acetoxy-bufa-4.14.20 (21) .22 (23Metra-
enolid (IUh)enolid (IUh)
250mg 3(-i-Hydroxy-bufa-4.14,20(2l).22(23)-tetraenolid werden in einer Mischung aus 4 ml Pyridin +2 ml Acetanhydrid 17 Stunden lang bei 20= C stehengelassen. Dann wird das Reaktionsgemisch in etwa 50 ml Wasser eingegossen und nach 17 Stunden Stehen das ausgefallene öl durch Dekantieren abgetrennt. Es wird in Methylenchlorid gelöst, die Lösung wird mit Wasser neutral gewaschen, und das Methylenchlorid wird abdestiliiert. Man erhält das 3|>'-Acetoxybufa-4,14.20(21j.22(23)-tetraenolid als rohen amorphen Schaum, der ohne Reinigung weiter umgesetzt wird.3 250mg (-i-Hydroxy-bufa-4.14,20 (2l) .22 (23) are allowed to stand in a mixture of 4 ml of pyridine +2 ml of acetic anhydride for 17 hours at 20 = C -tetraenolid. Then the reaction mixture is approximately Pour 50 ml of water and after 17 hours of standing the oil which has precipitated is separated off by decanting. It is dissolved in methylene chloride, the solution is washed neutral with water, and the methylene chloride is distilled off. The 3 |>'- acetoxybufa-4,14.20 ( 21j.22 (23) -tetraenolide as crude amorphous foam, which is further converted without purification.
Charakteristische IR-Banden: 1715 bis 1745,1630. ■v" 1530. 1230 cm"1, keine Hydroxylbande:Characteristic IR bands: 1715 to 1745, 1630. ■ v "1530. 1230 cm" 1 , no hydroxyl band:
UV-Spektrum: ).max 298 bis 209 ηΐμ. >■ = 5050.UV spectrum:) . max 298 to 209 ηΐμ. > ■ = 5050.
O 3J;-Acetoxy-4,5/i:14,LV-bis-oxido-bufa-20f21),
22(23)-dienolid (I)O 3 J ; -Acetoxy-4,5 / i: 14, LV-bis-oxido-bufa-20f21),
22 (23) -dienolide (I)
Eine Lösung von 3//-Acetoxy-bufa-4,14.20(21), 22(23)-tetraenolid (JIIb) in 9 ml Dioxan wird mit 0,32 ml Eisessig, 2,7 ml Wasser und 210 mg RN-Dibiombenzolsulfonamid versetzt und das Ganze 3 Stunden beiO bis 200C im Dunklen stehengelassen. Danach gießt man das Reaktionsgemisch in 100 ml Wasser,A solution of 3 // - acetoxy-bufa-4,14.20 (21), 22 (23) -tetraenolide (JIIb) in 9 ml of dioxane is mixed with 0.32 ml of glacial acetic acid, 2.7 ml of water and 210 mg of RN-dibiombenzenesulfonamide added and the whole thing left to stand for 3 hours at 0 to 20 0 C in the dark. The reaction mixture is then poured into 100 ml of water,
so extrahiert mehrmals mit Methylenchlorid, wäscht die Extrakte mit Wasser und destilliert die Lösungsmittel im Vakuum bei maximal 4O0C ab. Das hinterbleibende rohe 3/> -Acetoxy-4^,14ji-dihydroxy-5α, 15α-dibrombufa-20(21),22(23t-dienolid (IV) wird ohne weiteres in wenig Methylenchlorid/Benzol 2: 1 gelöst und auf eine Säule von Aluminiiimoxyd Woelm neutral, Aktivitätsstufe II (Höhe 10 cm; 0 = 2 cm), aufgetragen. Nachdem man die Säule 20 Minuten sich selbst überlassen hat, eluicrt man mit Methylenchlorid,so extracted several times with methylene chloride, the extracts are washed with water and the solvent is distilled off in vacuo at 4O 0 C maximum. The remaining crude 3 /> -Acetoxy-4 ^, 1 4ji- dihydroxy-5α, 15α-dibrombufa-20 (21), 22 (23t-dienolide (IV) is easily dissolved in a little methylene chloride / benzene 2: 1 and dissolved a column of aluminum oxide Woelm neutral, activity level II (height 10 cm; 0 = 2 cm), applied. After the column has been left to stand for 20 minutes, it is eluted with methylene chloride,
no Benzol 2:1. Man fangt insgesamt 300 ml Elutionsmittel auf und erhält nach dom Abdestillieren des Lösungsmittels 175 mg (1). das nach dem Umkristallisieren aus Methylenchlorid/Äther bei 210 bis 211 "C schmilzt.no benzene 2: 1. Collect a total of 300 ml of eluent and receives 175 mg (1) after the solvent has been distilled off. that after recrystallization from methylene chloride / ether at 210 to 211 "C melts.
Charakter: IR-Banden: 1715 bis 1740, 1625. 1530,Character: IR bands: 1715 to 1740, 1625, 1530,
1235 cm ', keine Hydroxylbande;
UV-Spektrum: ).max = 298 bis 299 m,x. ,· = 5770.1235 cm ', no hydroxyl band;
UV spectrum:) . max = 298 to 299 m, x. , · = 5770.
5 7 6 5 7 6
Beispiel 2 mit Natriumbicarbonatlösupg und Wasser gewaschen,Example 2 washed with sodium bicarbonate solution and water,
3^-Acetoxy-4,5/?:14,15/?-bis-oxido-bu!'a-20(21) Über Natriumsulfat getrocknet und im Vakuum zur3 ^ -Acetoxy-4,5 / ?: 14,15 /? - bis-oxido-bu! 'A-20 (21) dried over sodium sulfate and in a vacuum for
22(23)-dienolid ' Trockne eingedampft. Das erhaltene Rohprodukt22 (23) -dienolide 'evaporated to dryness. The crude product obtained
ρ;- _ τ =_„_ Ofin , . ,, , _ . j wird ώ 5 ml Pyridin selös:, die Lösung mit 2 ml Lssig-ρ; - _ τ = _ "_ Ofin,. ,,, _. j is dissolved ώ 5 ml of pyridine :, the solution with 2 ml of liquid
hlkg16ViΓκΎ^Γ ^f^^cillanniin; 5 Säureanhydrid verseht und 18 Stunden bei Raumtenthlk g 16 V i ΓκΎ ^ Γ ^ f ^^ cillanniin; 5 acid anhydride supplies and 18 hours with Raumtent
i S Tn^bis 165 Cm 30 ml Methylenchlorid peratur stehengelassen. Die weitere Aufarbeitung*i S Tn ^ to 165 cm 30 ml of methylene chloride allowed to stand at temperature. The further processing *
r^Zf Ζ00 H ? ^8 Monoperphthal- erfolgt wie im Beispiel 1 c). Der Rückstand wird aus r ^ Zf Ζ 00 H? ^ 8 Monoperphthal- takes place as in Example 1 c). The residue will be off
temoeratufiheZf "n 5J3T^ ^ **** Methylenchlorid/Atherumkristallisien.SchmelzpunkttemoeratufiheZf "n 5 J 3 T ^ ^ **** Meth ylenchlorid / Atherumkristallisien. Melting point
temperatur stehengelassen. Die Reaktionslosung wird 210 bis 21Γ C (Koflerbank).temperature left to stand. The reaction solution is 210 to 21Γ C (Koflerbank).
Claims (1)
4&5/Ϊ-1 Aß, 15/S-Dioxido-bufadienoIide der Formel'Claim:
4 & 5 / Ϊ-1 Aß, 15 / S-Dioxido-bufadienoIide of the formula
Priority Applications (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19681812945 DE1812945C (en) | 1968-12-05 | Cardiac 4beta, 5beta 14beta, 15beta Dioxidobufadienohde | |
| NL6917924A NL6917924A (en) | 1968-12-05 | 1969-11-28 | |
| IL33466A IL33466A (en) | 1968-12-05 | 1969-12-01 | Cardio-active oxido-bufadienolides and process for their manufacture |
| US881581A US3681344A (en) | 1968-12-05 | 1969-12-02 | Certain cardioactive oxido-bufadienolides |
| DK643169AA DK123935B (en) | 1968-12-05 | 1969-12-04 | Analogous process for the preparation of 4,5β: 14,15β-bis-oxido-bufa-20,22-dienolides. |
| ES374234A ES374234A1 (en) | 1968-12-05 | 1969-12-04 | Certain cardioactive oxido-bufadienolides |
| AT1136169A AT293639B (en) | 1968-12-05 | 1969-12-05 | Process for the production of new oxydobufadienolides |
| BE742719D BE742719A (en) | 1968-12-05 | 1969-12-05 | |
| GB5961769A GB1288060A (en) | 1968-12-05 | 1969-12-05 | |
| FR696942080A FR2025439B1 (en) | 1968-12-05 | 1969-12-05 | |
| AT1089270A AT301057B (en) | 1968-12-05 | 1969-12-05 | Process for the production of new oxydobufadienolides |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19681812945 DE1812945C (en) | 1968-12-05 | Cardiac 4beta, 5beta 14beta, 15beta Dioxidobufadienohde |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE1812945A1 DE1812945A1 (en) | 1970-06-18 |
| DE1812945C true DE1812945C (en) | 1973-04-19 |
Family
ID=
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