BE553345A

BE553345A -

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Publication number: BE553345A
Authority: BE; Belgium
Prior art keywords: lithium; lithium carbonate; couple; hydroxy; dibromo
Prior art date

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English (en)

French (fr)

Publication of BE553345A publication Critical patent/BE553345A/fr

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ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 78
238000000034 method Methods 0.000 claims description 39
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical group [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 28
229910052808 lithium carbonate Inorganic materials 0.000 claims description 24
XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 21
239000000203 mixture Substances 0.000 claims description 14
MAZMPHFJWNZKEQ-UHFFFAOYSA-L dilithium hydrogen carbonate bromide Chemical compound C([O-])(O)=O.[Li+].[Br-].[Li+] MAZMPHFJWNZKEQ-UHFFFAOYSA-L 0.000 claims description 13
KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Inorganic materials [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 13
XMRPGKVKISIQBV-UHFFFAOYSA-N (+-)-5- Pregnane-3,20-dione Natural products C1CC2CC(=O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2 XMRPGKVKISIQBV-UHFFFAOYSA-N 0.000 claims description 11
238000002360 preparation method Methods 0.000 claims description 11
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 9
238000006243 chemical reaction Methods 0.000 claims description 9
238000001556 precipitation Methods 0.000 claims description 9
229910052744 lithium Inorganic materials 0.000 claims description 7
-1 lithium halide Chemical class 0.000 claims description 7
238000010992 reflux Methods 0.000 claims description 5
229910052736 halogen Inorganic materials 0.000 claims description 4
150000002367 halogens Chemical class 0.000 claims description 4
RAJWOBJTTGJROA-UHFFFAOYSA-N (5alpha)-androstane-3,17-dione Natural products C1C(=O)CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC21 RAJWOBJTTGJROA-UHFFFAOYSA-N 0.000 claims description 3
YZZVVLUNOZJXCM-DADBAOPHSA-N (8s,9s,10r,13s,14s,17s)-17-acetyl-10,13-dimethyl-7,8,9,12,14,15,16,17-octahydro-6h-cyclopenta[a]phenanthrene-3,11-dione Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2=O YZZVVLUNOZJXCM-DADBAOPHSA-N 0.000 claims description 3
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
239000011541 reaction mixture Substances 0.000 claims description 3
239000002904 solvent Substances 0.000 claims description 3
150000001408 amides Chemical class 0.000 claims description 2
IRGYNZPMSCRQNC-UHFFFAOYSA-L dilithium hydrogen carbonate chloride Chemical compound C([O-])(O)=O.[Li+].[Cl-].[Li+] IRGYNZPMSCRQNC-UHFFFAOYSA-L 0.000 claims description 2
150000004820 halides Chemical class 0.000 claims description 2
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
230000008878 coupling Effects 0.000 claims 1
238000010168 coupling process Methods 0.000 claims 1
238000005859 coupling reaction Methods 0.000 claims 1
235000014113 dietary fatty acids Nutrition 0.000 claims 1
229930195729 fatty acid Natural products 0.000 claims 1
239000000194 fatty acid Substances 0.000 claims 1
150000004665 fatty acids Chemical class 0.000 claims 1
XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims 1
HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Inorganic materials [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims 1
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 42
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 36
239000000047 product Substances 0.000 description 26
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
229910052757 nitrogen Inorganic materials 0.000 description 21
238000003756 stirring Methods 0.000 description 19
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
150000001993 dienes Chemical class 0.000 description 14
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
238000004458 analytical method Methods 0.000 description 6
150000001875 compounds Chemical class 0.000 description 6
238000001953 recrystallisation Methods 0.000 description 6
MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 6
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
241001342522 Vampyrum spectrum Species 0.000 description 5
125000000950 dibromo group Chemical group Br* 0.000 description 5
229960004618 prednisone Drugs 0.000 description 5
JWMFYGXQPXQEEM-GCOKGBOCSA-N 5α-pregnane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](CC)[C@@]2(C)CC1 JWMFYGXQPXQEEM-GCOKGBOCSA-N 0.000 description 4
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
230000015572 biosynthetic process Effects 0.000 description 4
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
229910052794 bromium Inorganic materials 0.000 description 4
230000005587 bubbling Effects 0.000 description 4
230000018044 dehydration Effects 0.000 description 4
238000006297 dehydration reaction Methods 0.000 description 4
238000006704 dehydrohalogenation reaction Methods 0.000 description 4
238000010586 diagram Methods 0.000 description 4
238000001035 drying Methods 0.000 description 4
239000005457 ice water Substances 0.000 description 4
XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 4
238000000746 purification Methods 0.000 description 4
LKQVYBSBDWEBEM-VMXHOPILSA-N (8s,9s,10r,13s,14s)-10,13-dimethyl-6,7,8,9,11,12,14,15,16,17-decahydro-3h-cyclopenta[a]phenanthrene Chemical compound C1CC2=CCC=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 LKQVYBSBDWEBEM-VMXHOPILSA-N 0.000 description 3
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
238000010521 absorption reaction Methods 0.000 description 3
238000005360 mashing Methods 0.000 description 3
150000003124 pregnadienes Chemical class 0.000 description 3
150000003128 pregnanes Chemical class 0.000 description 3
238000001228 spectrum Methods 0.000 description 3
238000002211 ultraviolet spectrum Methods 0.000 description 3
238000005406 washing Methods 0.000 description 3
AHRWWYGWQKBKBF-PCHYHQBZSA-N (5r,8s,9s,10s,13s,14s,17s)-17-acetyl-10,13-dimethyl-2,4,5,6,7,8,9,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthrene-3,11-dione Chemical compound C([C@H]1CC2)C(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1=O AHRWWYGWQKBKBF-PCHYHQBZSA-N 0.000 description 2
GIRZGILISCUEPM-MWJYAYKCSA-N (9R,10S,13R,17S)-17-acetyl-10,13-dimethyl-1,2,3,4,5,6,9,11,12,17-decahydrocyclopenta[a]phenanthren-16-one Chemical class CC([C@H]1C(C=C2C3=CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C)=O)=O GIRZGILISCUEPM-MWJYAYKCSA-N 0.000 description 2
VOYADQIFGGIKAT-UHFFFAOYSA-N 1,3-dibutyl-4-hydroxy-2,6-dioxopyrimidine-5-carboximidamide Chemical compound CCCCn1c(O)c(C(N)=N)c(=O)n(CCCC)c1=O VOYADQIFGGIKAT-UHFFFAOYSA-N 0.000 description 2
WHBHBVVOGNECLV-OBQKJFGGSA-N 11-deoxycortisol Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 WHBHBVVOGNECLV-OBQKJFGGSA-N 0.000 description 2
XMRPGKVKISIQBV-BJMCWZGWSA-N 5alpha-pregnane-3,20-dione Chemical compound C([C@@H]1CC2)C(=O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 XMRPGKVKISIQBV-BJMCWZGWSA-N 0.000 description 2
QZLYKIGBANMMBK-DYKIIFRCSA-N 5β-androstane Chemical compound C([C@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 QZLYKIGBANMMBK-DYKIIFRCSA-N 0.000 description 2
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
238000013019 agitation Methods 0.000 description 2
HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
230000031709 bromination Effects 0.000 description 2
238000005893 bromination reaction Methods 0.000 description 2
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
238000000354 decomposition reaction Methods 0.000 description 2
OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 2
239000007789 gas Substances 0.000 description 2
238000002844 melting Methods 0.000 description 2
230000008018 melting Effects 0.000 description 2
150000007659 semicarbazones Chemical class 0.000 description 2
239000000725 suspension Substances 0.000 description 2
CBMYJHIOYJEBSB-UHFFFAOYSA-N (10S)-3t.17t-Dihydroxy-10r.13c-dimethyl-(5cH.8cH.9tH.14tH)-hexadecahydro-1H-cyclopenta[a]phenanthren Natural products C1C(O)CCC2(C)C3CCC(C)(C(CC4)O)C4C3CCC21 CBMYJHIOYJEBSB-UHFFFAOYSA-N 0.000 description 1
NYGWTZLABYSHOP-FCYODTKKSA-N (8R,9S,10S,13R)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12-decahydro-1H-cyclopenta[a]phenanthrene Chemical compound C([C@H]12)CC3CCCC[C@]3(C)[C@H]1CC[C@@]1(C)C2=CC=C1 NYGWTZLABYSHOP-FCYODTKKSA-N 0.000 description 1
OIGNJSKKLXVSLS-UHFFFAOYSA-N 11,17,21-Trihydroxypregna-1,4-diene-3,20-dione Chemical compound O=C1C=CC2(C)C3C(O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 OIGNJSKKLXVSLS-UHFFFAOYSA-N 0.000 description 1
FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 1
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
QZLYKIGBANMMBK-UGCZWRCOSA-N 5α-Androstane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CCC[C@@]2(C)CC1 QZLYKIGBANMMBK-UGCZWRCOSA-N 0.000 description 1
YEXBXGXBJIUZBA-POMAFESVSA-N BrC1CC([C@@H]2CC[C@@H]3[C@H](CC[C@@]4(CCC[C@H]43)C)[C@]2(C1)C)Br Chemical compound BrC1CC([C@@H]2CC[C@@H]3[C@H](CC[C@@]4(CCC[C@H]43)C)[C@]2(C1)C)Br YEXBXGXBJIUZBA-POMAFESVSA-N 0.000 description 1
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
101100439236 Caenorhabditis elegans cfi-1 gene Proteins 0.000 description 1
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
101000767160 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Intracellular protein transport protein USO1 Proteins 0.000 description 1
DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
125000004423 acyloxy group Chemical group 0.000 description 1
HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
235000019445 benzyl alcohol Nutrition 0.000 description 1
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
229910052799 carbon Inorganic materials 0.000 description 1
239000007795 chemical reaction product Substances 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
238000004587 chromatography analysis Methods 0.000 description 1
238000003776 cleavage reaction Methods 0.000 description 1
UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
230000000052 comparative effect Effects 0.000 description 1
238000001816 cooling Methods 0.000 description 1
229960004544 cortisone Drugs 0.000 description 1
239000012043 crude product Substances 0.000 description 1
239000012153 distilled water Substances 0.000 description 1
230000000694 effects Effects 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
229940011871 estrogen Drugs 0.000 description 1
239000000262 estrogen Substances 0.000 description 1
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
238000001914 filtration Methods 0.000 description 1
229960003336 fluorocortisol acetate Drugs 0.000 description 1
238000001640 fractional crystallisation Methods 0.000 description 1
KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
239000013067 intermediate product Substances 0.000 description 1
238000004519 manufacturing process Methods 0.000 description 1
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
238000013048 microbiological method Methods 0.000 description 1
244000005700 microbiome Species 0.000 description 1
230000005012 migration Effects 0.000 description 1
238000013508 migration Methods 0.000 description 1
239000012299 nitrogen atmosphere Substances 0.000 description 1
230000003647 oxidation Effects 0.000 description 1
238000007254 oxidation reaction Methods 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
229960005205 prednisolone Drugs 0.000 description 1
OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
150000003126 pregnane derivatives Chemical class 0.000 description 1
239000012429 reaction media Substances 0.000 description 1
230000035484 reaction time Effects 0.000 description 1
239000011347 resin Substances 0.000 description 1
229920005989 resin Polymers 0.000 description 1
238000007127 saponification reaction Methods 0.000 description 1
230000007017 scission Effects 0.000 description 1
235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
238000009987 spinning Methods 0.000 description 1
239000007858 starting material Substances 0.000 description 1
239000003270 steroid hormone Substances 0.000 description 1
125000001424 substituent group Chemical group 0.000 description 1
GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
238000003786 synthesis reaction Methods 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1