DE2010422A1

DE2010422A1 - Acetylated cardiotonic glucosides

Acetylated cardiotonic glucosides

Info

Publication number: DE2010422A1
Authority: DE; Germany
Prior art keywords: acetylated; glucosides; transesterification; acetyl; partial hydrolysis
Prior art date: 1970-03-05
Legal status : Withdrawn

Application number

DE19702010422

Other languages

German (de)

English (en)

Other versions

DE2010422B (enrdf_load_stackoverflow

DE2010422C (enrdf_load_stackoverflow

Inventor

Walter Dr.; Merz Herbert Dr.; 6507 Ingelheim. P Lösel

Current Assignee

CH Boehringer Sohn AG and Co KG

Original Assignee

CH Boehringer Sohn AG and Co KG

Priority date

1970-03-05

Filing date

1970-03-05

Publication date

1971-09-30

1970-03-05 Application filed by CH Boehringer Sohn AG and Co KG filed Critical CH Boehringer Sohn AG and Co KG

1970-03-05 Priority to DE19702010422 priority Critical patent/DE2010422A1/de

1971-02-03 Priority to RO65791A priority patent/RO60624A/ro

1971-02-18 Priority to US00116646A priority patent/US3803123A/en

1971-02-22 Priority to SU1626532A priority patent/SU430549A3/ru

1971-02-25 Priority to PH12224*UA priority patent/PH9522A/en

1971-03-02 Priority to CS155071A priority patent/CS153574B2/cs

1971-03-02 Priority to JP1091571A priority patent/JPS5521040B1/ja

1971-03-02 Priority to SE02662/71A priority patent/SE366035B/xx

1971-03-03 Priority to IL36330A priority patent/IL36330A/en

1971-03-03 Priority to BG016962A priority patent/BG20346A3/xx

1971-03-03 Priority to CH306971A priority patent/CH554327A/xx

1971-03-03 Priority to YU527/71A priority patent/YU34142B/xx

1971-03-04 Priority to BE763817A priority patent/BE763817A/xx

1971-03-04 Priority to DK101971AA priority patent/DK126425B/da

1971-03-04 Priority to ES388871A priority patent/ES388871A1/es

1971-03-04 Priority to AT186571A priority patent/AT323901B/de

1971-03-04 Priority to FI710637A priority patent/FI50532C/fi

1971-03-04 Priority to PL1971146662A priority patent/PL81544B1/pl

1971-03-04 Priority to NO821/71A priority patent/NO136099C/no

1971-03-04 Priority to ZA711428A priority patent/ZA711428B/xx

1971-03-05 Priority to FR7107668A priority patent/FR2104737B1/fr

1971-03-05 Priority to IE275/71A priority patent/IE34982B1/xx

1971-03-05 Priority to NLAANVRAGE7102947,A priority patent/NL170738C/xx

1971-04-19 Priority to GB2316271*A priority patent/GB1339057A/en

1971-09-30 Publication of DE2010422A1 publication Critical patent/DE2010422A1/de

1972-09-21 Application granted granted Critical

1972-09-21 Publication of DE2010422C publication Critical patent/DE2010422C/de

Status Withdrawn legal-status Critical Current

Links

229930182478 glucoside Natural products 0.000 title abstract 4
150000008131 glucosides Chemical class 0.000 title abstract 4
230000003177 cardiotonic effect Effects 0.000 title abstract 2
238000000034 method Methods 0.000 claims abstract description 10
229960000648 digitoxin Drugs 0.000 claims abstract description 4
229960005156 digoxin Drugs 0.000 claims abstract description 4
239000011260 aqueous acid Substances 0.000 claims description 6
229940082657 digitalis glycosides Drugs 0.000 claims description 6
229930182470 glycoside Natural products 0.000 claims description 6
238000005809 transesterification reaction Methods 0.000 claims description 6
150000002338 glycosides Chemical class 0.000 claims description 5
230000007062 hydrolysis Effects 0.000 claims description 5
238000006460 hydrolysis reaction Methods 0.000 claims description 5
230000002378 acidificating effect Effects 0.000 claims description 4
239000012442 inert solvent Substances 0.000 claims description 4
239000011541 reaction mixture Substances 0.000 claims description 4
WDJUZGPOPHTGOT-OAXVISGBSA-N Digitoxin Natural products O([C@H]1[C@@H](C)O[C@@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@@](C)([C@H](C6=CC(=O)OC6)CC5)CC4)CC3)CC2)C[C@H]1O)[C@H]1O[C@@H](C)[C@H](O[C@H]2O[C@@H](C)[C@@H](O)[C@@H](O)C2)[C@@H](O)C1 WDJUZGPOPHTGOT-OAXVISGBSA-N 0.000 claims description 3
LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 claims description 3
OCEDEAQHBIGPTE-UHFFFAOYSA-N Gitoxin Natural products CC1OC(CC(O)C1O)OC2C(O)CC(OC3C(O)CC(OC4CCC5(C)C(CCC6C5CCC7(C)C(C(O)CC67O)C8=CCOC8=O)C4)OC3C)OC2C OCEDEAQHBIGPTE-UHFFFAOYSA-N 0.000 claims description 3
239000003054 catalyst Substances 0.000 claims description 3
WDJUZGPOPHTGOT-XUDUSOBPSA-N digitoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O WDJUZGPOPHTGOT-XUDUSOBPSA-N 0.000 claims description 3
LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 claims description 3
LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 claims description 3
229950000974 gitoxin Drugs 0.000 claims description 3
LKRDZKPBAOKJBT-CNPIRKNPSA-N gitoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(C[C@H](O)[C@@H]([C@@]6(C)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LKRDZKPBAOKJBT-CNPIRKNPSA-N 0.000 claims description 3
-1 acyclic orthoacetic acid ester Chemical class 0.000 claims description 2
239000007864 aqueous solution Substances 0.000 claims description 2
238000002360 preparation method Methods 0.000 claims description 2
238000002955 isolation Methods 0.000 claims 2
238000009835 boiling Methods 0.000 claims 1
239000013067 intermediate product Substances 0.000 claims 1
125000004122 cyclic group Chemical group 0.000 abstract description 3
238000007127 saponification reaction Methods 0.000 abstract description 2
206010019280 Heart failures Diseases 0.000 abstract 1
125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
125000000217 alkyl group Chemical group 0.000 abstract 1
229960003584 proscillaridin Drugs 0.000 abstract 1
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 description 3
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
239000002253 acid Substances 0.000 description 3
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
HPMZBILYSWLILX-UMDUKNJSSA-N 3'''-O-acetyldigitoxin Chemical compound C1[C@H](OC(C)=O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O HPMZBILYSWLILX-UMDUKNJSSA-N 0.000 description 2
HPMZBILYSWLILX-UHFFFAOYSA-N Acetyl-digitoxine Natural products C1C(OC(C)=O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O HPMZBILYSWLILX-UHFFFAOYSA-N 0.000 description 2
KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
SZHBGTRKQDNXNC-RIYHBKJUSA-N [(3s,5r,8r,9s,10s,13r,16r,17r)-3-[(2s,4s,5r,6r)-4,5-bis[[(2r,4s,5s,6r)-4,5-dihydroxy-6-methyloxan-2-yl]oxy]-6-methyloxan-2-yl]oxy-14-hydroxy-10,13-dimethyl-17-(5-oxo-2h-furan-3-yl)-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-16 Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@@H]1O[C@@H]1[C@H](O[C@H]2O[C@H](C)[C@@H](O)[C@@H](O)C2)[C@@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@]([C@@H]4[C@H](C5(C[C@H]([C@@H]([C@@]5(C)CC4)C=4COC(=O)C=4)OC(C)=O)O)CC3)(C)CC2)C1 SZHBGTRKQDNXNC-RIYHBKJUSA-N 0.000 description 2
229960003635 acetyldigitoxin Drugs 0.000 description 2
238000006243 chemical reaction Methods 0.000 description 2
230000008018 melting Effects 0.000 description 2
238000002844 melting Methods 0.000 description 2
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical class CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
239000007832 Na2SO4 Substances 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
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
230000021736 acetylation Effects 0.000 description 1
238000006640 acetylation reaction Methods 0.000 description 1
HWKJSYYYURVNQU-DXJNJSHLSA-N acetyldigoxin Chemical compound C1[C@H](OC(C)=O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O HWKJSYYYURVNQU-DXJNJSHLSA-N 0.000 description 1
150000007513 acids Chemical class 0.000 description 1
MGVYFNHJWXJYBE-UHFFFAOYSA-N alpha-Acetyl-digoxin Natural products CC1OC(CC(O)C1O)OC2C(O)CC(OC3C(C)OC(CC3OC(=O)C)OC4CCC5(C)C(CCC6C5CCC7(C)C(C(O)CC67O)C8=CC(=O)OC8)C4)OC2C MGVYFNHJWXJYBE-UHFFFAOYSA-N 0.000 description 1
229920001429 chelating resin Polymers 0.000 description 1
239000007795 chemical reaction product Substances 0.000 description 1
238000004440 column chromatography Methods 0.000 description 1
229910000365 copper sulfate Inorganic materials 0.000 description 1
ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
230000007812 deficiency Effects 0.000 description 1
238000001035 drying Methods 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
230000008020 evaporation Effects 0.000 description 1
238000001704 evaporation Methods 0.000 description 1
230000002349 favourable effect Effects 0.000 description 1
238000001640 fractional crystallisation Methods 0.000 description 1
150000002500 ions Chemical class 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
229910000343 potassium bisulfate Inorganic materials 0.000 description 1
239000000843 powder Substances 0.000 description 1
239000000047 product Substances 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
238000010992 reflux Methods 0.000 description 1
150000003839 salts Chemical class 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
239000002904 solvent Substances 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical class OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
238000010626 work up procedure Methods 0.000 description 1
235000005074 zinc chloride Nutrition 0.000 description 1
239000011592 zinc chloride Substances 0.000 description 1