DE2502258A1

DE2502258A1 - Verfahren zur herstellung von formylierten digitoxin-, digoxin- oder gitoxinderivaten

Verfahren zur herstellung von formylierten digitoxin-, digoxin- oder gitoxinderivaten

Info

Publication number: DE2502258A1
Authority: DE; Germany
Prior art keywords: gitoxin; digoxin; digitoxin; formylated; derivatives
Prior art date: 1974-01-23
Legal status : Pending

Application number

DE19752502258

Other languages

German (de)

English (en)

Inventor

Ivica Horvat

Rado Kocjan

Borut Zule

Current Assignee

Lek Pharmaceuticals dd

Original Assignee

Lek Pharmaceuticals and Chemical Co dd

Priority date

1974-01-23

Filing date

1975-01-21

Publication date

1975-07-24

1975-01-21 Application filed by Lek Pharmaceuticals and Chemical Co dd filed Critical Lek Pharmaceuticals and Chemical Co dd

1975-07-24 Publication of DE2502258A1 publication Critical patent/DE2502258A1/de

Status Pending legal-status Critical Current

Links

LKRDZKPBAOKJBT-CNPIRKNPSA-N gitoxin Chemical class 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 title claims description 9
238000000034 method Methods 0.000 title claims description 9
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 title claims description 8
229960005156 digoxin Drugs 0.000 title claims description 8
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 title claims description 8
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 title claims description 8
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 title claims description 7
229960000648 digitoxin Drugs 0.000 title claims description 7
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 title claims description 7
238000004519 manufacturing process Methods 0.000 title description 4
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 15
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 7
235000019253 formic acid Nutrition 0.000 claims description 7
ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 claims description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 6
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
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 5
229950000974 gitoxin Drugs 0.000 claims description 5
YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 4
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 claims description 4
230000022244 formylation Effects 0.000 claims description 4
238000006170 formylation reaction Methods 0.000 claims description 4
238000011065 in-situ storage Methods 0.000 claims description 4
239000011541 reaction mixture Substances 0.000 claims description 4
239000012320 chlorinating reagent Substances 0.000 claims description 3
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 3
238000002360 preparation method Methods 0.000 claims description 2
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 2
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 7
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
229940097217 cardiac glycoside Drugs 0.000 description 3
239000002368 cardiac glycoside Substances 0.000 description 3
238000006243 chemical reaction Methods 0.000 description 3
239000003795 chemical substances by application Substances 0.000 description 3
239000000203 mixture Substances 0.000 description 3
239000002244 precipitate Substances 0.000 description 3
239000000047 product Substances 0.000 description 3
229930002534 steroid glycoside Natural products 0.000 description 3
150000008143 steroidal glycosides Chemical class 0.000 description 3
238000003756 stirring Methods 0.000 description 3
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
239000007795 chemical reaction product Substances 0.000 description 2
210000001035 gastrointestinal tract Anatomy 0.000 description 2
229930182470 glycoside Natural products 0.000 description 2
150000002338 glycosides Chemical class 0.000 description 2
125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
239000003208 petroleum Substances 0.000 description 2
239000002904 solvent Substances 0.000 description 2
238000001228 spectrum Methods 0.000 description 2
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
101000639763 Homo sapiens Regulator of telomere elongation helicase 1 Proteins 0.000 description 1
102100034469 Regulator of telomere elongation helicase 1 Human genes 0.000 description 1
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
DOMHWKQEPDYUQX-LJAQBGIBSA-N [(2r,3r,4s,6r)-3-[(2s,4s,5r,6r)-5-[(2s,4s,5r,6r)-4,5-diformyloxy-6-methyloxan-2-yl]oxy-4-formyloxy-6-methyloxan-2-yl]oxy-6-[[(3s,5r,8r,9s,10s,13r,14s,16s,17r)-16-formyloxy-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 Chemical compound C1[C@H](OC=O)[C@H](OC=O)[C@@H](C)O[C@H]1O[C@H]1[C@@H](OC=O)C[C@H](O[C@H]2[C@H](C[C@@H](O[C@@H]2C)O[C@@H]2C[C@@H]3[C@]([C@@H]4[C@H]([C@]5(C[C@@H]([C@@H]([C@@]5(C)CC4)C=4COC(=O)C=4)OC=O)O)CC3)(C)CC2)OC=O)O[C@@H]1C DOMHWKQEPDYUQX-LJAQBGIBSA-N 0.000 description 1
XXQKBYWZPGTSQA-DHHAOGPWSA-N [(2r,3r,4s,6r)-3-[(2s,4s,5s,6r)-5-[(2s,4s,5r,6r)-4,5-diformyloxy-6-methyloxan-2-yl]oxy-6-formyloxy-4-methyloxan-2-yl]oxy-6-[[(3s,5r,8r,9s,10s,12r,13s,14s,17r)-12-formyloxy-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 Chemical compound C1([C@@H]2[C@@]3(C)[C@H](OC=O)C[C@H]4[C@H]([C@]3(CC2)O)CC[C@H]2[C@]4(C)CC[C@@H](C2)O[C@@H]2O[C@H](C)[C@H]([C@H](C2)OC=O)O[C@@H]2C[C@@H]([C@@H]([C@@H](OC=O)O2)O[C@@H]2O[C@H](C)[C@@H](OC=O)[C@@H](OC=O)C2)C)=CC(=O)OC1 XXQKBYWZPGTSQA-DHHAOGPWSA-N 0.000 description 1
FWRCXZPLTUEYGS-UHFFFAOYSA-N [3-[5-(4,5-diformyloxy-6-methyloxan-2-yl)oxy-4-formyloxy-6-methyloxan-2-yl]oxy-6-[[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-3-yl]oxy]-2-methyloxan-4-yl] formate Chemical compound C1C(OC=O)C(OC=O)C(C)OC1OC1C(OC=O)CC(OC2C(CC(OC2C)OC2CC3C(C4C(C5(CCC(C5(C)CC4)C=4COC(=O)C=4)O)CC3)(C)CC2)OC=O)OC1C FWRCXZPLTUEYGS-UHFFFAOYSA-N 0.000 description 1
238000010521 absorption reaction Methods 0.000 description 1
150000008064 anhydrides Chemical class 0.000 description 1
PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 description 1
238000004440 column chromatography Methods 0.000 description 1
150000001875 compounds Chemical class 0.000 description 1
238000001816 cooling Methods 0.000 description 1
239000012043 crude product Substances 0.000 description 1
YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
239000003480 eluent Substances 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
NHGVZTMBVDFPHJ-UHFFFAOYSA-N formyl fluoride Chemical compound FC=O NHGVZTMBVDFPHJ-UHFFFAOYSA-N 0.000 description 1
229960001486 gitoformate Drugs 0.000 description 1
229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
229910052943 magnesium sulfate Inorganic materials 0.000 description 1
235000019341 magnesium sulphate Nutrition 0.000 description 1
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
238000001556 precipitation Methods 0.000 description 1
230000035484 reaction time Effects 0.000 description 1
229920006395 saturated elastomer Polymers 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 0.000 description 1
238000004809 thin layer chromatography Methods 0.000 description 1
YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
238000005406 washing Methods 0.000 description 1