WO2004087731A1 - Process for the preparation of steroidal carbothioic acid derivatives and intermediates - Google Patents
Process for the preparation of steroidal carbothioic acid derivatives and intermediates Download PDFInfo
- Publication number
- WO2004087731A1 WO2004087731A1 PCT/DK2004/000242 DK2004000242W WO2004087731A1 WO 2004087731 A1 WO2004087731 A1 WO 2004087731A1 DK 2004000242 W DK2004000242 W DK 2004000242W WO 2004087731 A1 WO2004087731 A1 WO 2004087731A1
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- WIPO (PCT)
- Prior art keywords
- group
- formula
- represent
- optionally substituted
- steroidal
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 73
- 230000003637 steroidlike Effects 0.000 title claims abstract description 42
- 239000002253 acid Substances 0.000 title claims abstract description 29
- 239000000543 intermediate Substances 0.000 title claims description 20
- 238000002360 preparation method Methods 0.000 title description 8
- 230000008569 process Effects 0.000 title description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 229960000289 fluticasone propionate Drugs 0.000 claims abstract description 16
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 claims abstract description 16
- 150000002148 esters Chemical class 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 78
- -1 heteroaliphatic Chemical group 0.000 claims description 55
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 42
- 239000003795 chemical substances by application Substances 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 239000003623 enhancer Substances 0.000 claims description 32
- 229910052717 sulfur Inorganic materials 0.000 claims description 29
- 230000008878 coupling Effects 0.000 claims description 28
- 239000007822 coupling agent Substances 0.000 claims description 28
- 238000010168 coupling process Methods 0.000 claims description 28
- 238000005859 coupling reaction Methods 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- 230000000269 nucleophilic effect Effects 0.000 claims description 21
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 17
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 125000001931 aliphatic group Chemical group 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- 239000011734 sodium Substances 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 229910052708 sodium Inorganic materials 0.000 claims description 13
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- LHMHCLYDBQOYTO-UHFFFAOYSA-N bromofluoromethane Chemical compound FCBr LHMHCLYDBQOYTO-UHFFFAOYSA-N 0.000 claims description 12
- 238000011065 in-situ storage Methods 0.000 claims description 12
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 239000011541 reaction mixture Substances 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 125000004434 sulfur atom Chemical group 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- ZNKXTIAQRUWLRL-UHFFFAOYSA-M sodium;sulfane;hydroxide Chemical compound O.[Na+].[SH-] ZNKXTIAQRUWLRL-UHFFFAOYSA-M 0.000 claims description 9
- 150000003431 steroids Chemical class 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 150000004763 sulfides Chemical class 0.000 claims description 8
- 229910052727 yttrium Inorganic materials 0.000 claims description 8
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 7
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 7
- 150000001718 carbodiimides Chemical class 0.000 claims description 7
- 229910052744 lithium Inorganic materials 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 238000005580 one pot reaction Methods 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- 239000011593 sulfur Substances 0.000 claims description 7
- PBXJGQQGODZSQR-CWQDBKDDSA-N (8r,9s,10s,13s,14s,17s)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthrene-17-carboxylic acid Chemical compound C1CCC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)C(O)=O)[C@@H]4[C@@H]3CCC21 PBXJGQQGODZSQR-CWQDBKDDSA-N 0.000 claims description 6
- XWCDCDSDNJVCLO-UHFFFAOYSA-N Chlorofluoromethane Chemical compound FCCl XWCDCDSDNJVCLO-UHFFFAOYSA-N 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- JPOXNPPZZKNXOV-UHFFFAOYSA-N bromochloromethane Chemical compound ClCBr JPOXNPPZZKNXOV-UHFFFAOYSA-N 0.000 claims description 6
- 150000001721 carbon Chemical group 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 6
- XGDRLCRGKUCBQL-UHFFFAOYSA-N 1h-imidazole-4,5-dicarbonitrile Chemical compound N#CC=1N=CNC=1C#N XGDRLCRGKUCBQL-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 5
- 238000002955 isolation Methods 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- RPENMORRBUTCPR-UHFFFAOYSA-M sodium;1-hydroxy-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].ON1C(=O)CC(S([O-])(=O)=O)C1=O RPENMORRBUTCPR-UHFFFAOYSA-M 0.000 claims description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims description 5
- 229910052721 tungsten Inorganic materials 0.000 claims description 5
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 4
- 125000002837 carbocyclic group Chemical group 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 230000008859 change Effects 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 claims description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 2
- 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 claims description 2
- 235000013877 carbamide Nutrition 0.000 claims description 2
- BNEIONMRSYCOPM-UHFFFAOYSA-N carbamimidoyl(oxido)azanium Chemical class NC(=N)[NH2+][O-] BNEIONMRSYCOPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 238000011437 continuous method Methods 0.000 claims description 2
- 125000003700 epoxy group Chemical group 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- 229910021645 metal ion Inorganic materials 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000003880 polar aprotic solvent Substances 0.000 claims description 2
- 229910052705 radium Inorganic materials 0.000 claims description 2
- 229910052701 rubidium Inorganic materials 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 150000003672 ureas Chemical class 0.000 claims description 2
- 125000005500 uronium group Chemical group 0.000 claims description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims 2
- GVJXGCIPWAVXJP-UHFFFAOYSA-N 2,5-dioxo-1-oxoniopyrrolidine-3-sulfonate Chemical compound ON1C(=O)CC(S(O)(=O)=O)C1=O GVJXGCIPWAVXJP-UHFFFAOYSA-N 0.000 claims 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims 1
- 229960002317 succinimide Drugs 0.000 claims 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 229910052736 halogen Inorganic materials 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 125000003118 aryl group Chemical group 0.000 description 10
- 150000002367 halogens Chemical class 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 description 5
- 229960003469 flumetasone Drugs 0.000 description 5
- WXURHACBFYSXBI-GQKYHHCASA-N flumethasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-GQKYHHCASA-N 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 125000005997 bromomethyl group Chemical group 0.000 description 3
- 125000002843 carboxylic acid group Chemical group 0.000 description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 125000000468 ketone group Chemical group 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 125000006574 non-aromatic ring group Chemical group 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical group C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical group C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 2
- 0 C*(C)C(Nc1cccc*1O)=*(C)C Chemical compound C*(C)C(Nc1cccc*1O)=*(C)C 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical group C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical group N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[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 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 125000006413 ring segment Chemical group 0.000 description 2
- 229940001593 sodium carbonate Drugs 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 2
- NBMKJKDGKREAPL-CXSFZGCWSA-N (8s,9r,10s,11s,13s,14s,16r,17r)-9-chloro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-3-one Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-CXSFZGCWSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- PGDCCHKYWADOGD-UHFFFAOYSA-N 3-oxooxolane-2-carboxamide Chemical compound NC(=O)C1OCCC1=O PGDCCHKYWADOGD-UHFFFAOYSA-N 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004487 4-tetrahydropyranyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- FAYOCELKCDKZCA-UHFFFAOYSA-N 5-hydroxy-2,4-dimethylthiophen-3-one Chemical compound CC1SC(O)=C(C)C1=O FAYOCELKCDKZCA-UHFFFAOYSA-N 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical class CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000005103 alkyl silyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 150000001441 androstanes Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229940092705 beclomethasone Drugs 0.000 description 1
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 1
- BVCRERJDOOBZOH-UHFFFAOYSA-N bicyclo[2.2.1]heptanyl Chemical group C1C[C+]2CC[C-]1C2 BVCRERJDOOBZOH-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229960003662 desonide Drugs 0.000 description 1
- WBGKWQHBNHJJPZ-LECWWXJVSA-N desonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O WBGKWQHBNHJJPZ-LECWWXJVSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229960004154 diflorasone Drugs 0.000 description 1
- WXURHACBFYSXBI-XHIJKXOTSA-N diflorasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-XHIJKXOTSA-N 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- AAXVEMMRQDVLJB-BULBTXNYSA-N fludrocortisone Chemical compound O=C1CC[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 AAXVEMMRQDVLJB-BULBTXNYSA-N 0.000 description 1
- 229960002011 fludrocortisone Drugs 0.000 description 1
- 229960001347 fluocinolone acetonide Drugs 0.000 description 1
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000004404 heteroalkyl group Chemical group 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Chemical group CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Chemical group C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 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
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000012048 reactive intermediate Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000012421 spiking Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- 229930192474 thiophene Chemical group 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
- C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
Definitions
- the present invention relates to a novel process for the conversion of steroidal carboxylic acids to 5 carbothioate derivatives such as fluticasone propionate via novel intermediates.
- the problem to be solved by the present invention is to provide a new method for the preparation 30 of steroidal carbothioic acid and derivatives thereof such as fluticasone propionate, especially a method in which a number of the relevant method steps may be performed as a continuous one-pot synthesis. This denotes a method where relevant synthetic steps may be performed in situ without change of solvent or isolation of the individual intermediates.
- the present invention provides a method which comprises A) reacting a steroidal carboxylic acid or a salt thereof with a coupling agent alone or in conjunction with a coupling enhancer; and B) reacting the product of step A) with a nucleophilic agent comprising a sulfur atom.
- the solution is based on the identification by the present inventors that by employing novel in situ generated esters, such as 17 ⁇ -carboxy- imidazolyl-, succinimidyl- or triazolyl esters of formula (III), as intermediates, an increased threshold against competing hydrolysis reactions was achieved. The reduced level of hydrolysis further raises the efficiency regarding the formation of the end steroidal carbothioate product and removes the need to work under strictly anhydrous conditions.
- the preferred steroidal carbothioate end products are defined by formula (I) herein. When Rio of formula (I) is a fluoromethyl group this represents fluticasone propionate.
- the intermediate (such as an ester of formula (III)) is very suitable for use in a method for the conversion of a steroidal carboxylic acid to a steroidal carbothioic acid or a carbothioate.
- an advantage of the method described herein relates to the possibility of performing relevant method steps in situ.
- the increased stability of the intermediates (such as compounds of formula (III)) against competing hydrolysis reactions removes the need to work under anhydrous conditions. This makes it possible to avoid the use of hydrogensulfide gas, allowing instead the use of hydrosulfide salts, either as solids with crystal water or as solutions of the desired sulfide salt in water. Further it sets the stage for an in situ process where relevant steps may be performed in one-pot.
- the present invention also discloses a novel process for the preparation of e.g. fluticasone propionate. By employing the method described herein, three out of five steps may be performed in one-pot, thus yielding fluticasone propionate in an overall yield of 89% (see example 3 herein).
- Coupling agents and enhancers have primarily been used in peptide chemistry where the need to activate carboxylic acids in order to facilitate peptide couplings has been recognized for decades (Handbook of Reagents for Organic Synthesis, Activating Agents and Protecting Groups, ed. A. J. Pearson and W.R. Roush, John Wiley & Sons, 1999).
- a novel oxo-tetra-hydrofuranoyl amide was prepared by activating the androstane 17 ⁇ -carboxylic acid with 1-hydroxybenzotriazole (HOBt) in conjunction with l-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride (EDC).
- HOBt 1-hydroxybenzotriazole
- EDC carbodiimide hydrochloride
- the substituents have the same meanings as in IUPAC Compendium of Chemical Terminology unless otherwise defined.
- the substituent definition comprises a range (e.g. C6 to C22 or C 1 to CIO)
- the range is understood to comprise all integers in that range, i.e. 1, 23, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 etc.
- substituted means that one or more (such as 1, 2, 3, 4, 5, or 6) hydrogen atoms are substituted with substituents independently selected from groups such as: halogen atoms, nitro groups, hydroxyl, mercapto, cyano, carbamoyl, optionally substituted amino, optionally substituted alkyl (e.g.
- perhalogenalkyl optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalk(en/yn)yl, optionally substituted aryl, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted (hetero)aryl, optionally substituted (hetero)aryloxy or acyl groups.
- Two hydrogen atoms on the same carbon atom can be substituted with a divalent substituent, such as optionally substituted C1-C6 alkylene, O, NH, S.
- halogen represents fluoro, chloro, bromo, or iodo.
- heteroatom or “hetero” includes atoms such as 0, S, or N.
- alkyl includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms. Preferably, the alkyl group has 1-10 carbon atoms, and most preferred 1, 2, 3, 4, 5, or 6 carbon atoms.
- the alkyl groups may be interrupted by one or more heteroatoms, and may be substituted, e.g. with groups as defined above, such as halogen, hydroxyl, aryl, cycloalkyl, aryloxy, or alkoxy.
- Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl.
- alkoxy stands for an -O-alkyl group.
- cycloalkyl includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more rings of preferably 3, 4, 5, 6, or 7 ring members, which can be fused or isolated.
- the rings may be substituted, e.g. with groups as defined above, such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or alkyl.
- Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- alkenyl includes straight or branched chain hydrocarbon groups having 2 to 15 carbon atoms (e.g. 2, 3, 4, 5, 6 or 10 carbon atoms) with at least one carbon-carbon double bond, the chain being optionally interrupted by one or more heteroatoms.
- the chain hydrogens may be substituted, e.g. with groups as defined above, such as halogen.
- Preferred straight or branched alkenyl groups include vinyl, allyl, 1-butenyl, 1-methyl propenyl and 4-pentenyl.
- alkynyl includes straight or branched chain hydrocarbon groups having 2 to 15 carbon atoms (e.g. 2, 3, 4, 5, 6 or 10 carbon atoms) with at least one carbon-carbon triple bond, the chain being optionally interrupted by one or more heteroatoms.
- the chain hydrogens may be substituted, e.g with groups as defined above, such as halogen.
- Preferred straight or branched alkynyl groups include ethynyl, propynyl, 1-butynyl, lmethyl propynyl and 4-pentynyl.
- cycloalkenyl includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more non-aromatic rings of preferably 3, 4, 5, 6, or 7 ring members containing a carbon-carbon double bond, which can be fused or isolated.
- the rings may be substituted, e.g. with groups as defined above, such as halogen, hydroxyl, alkoxy, or alkyl.
- Preferred cycloalkenyl groups include cyclopentenyl and cyclohexenyl.
- aryl refers to carbon-based rings which are aromatic.
- the rings may be isolated, such as phenyl, or fused, such as naphthyl.
- the ring hydrogens may be substituted, e.g. with groups as defined above, such as alkyl, halogen, free or functionalized hydroxy, trihalomethyl, etc.
- Preferred aryl groups include phenyl, 3(trifluoromethyl)phenyl, 3-chlorophenyl, and 4-fluorophenyl.
- heteroaryl refers to aromatic hydrocarbon rings (having such as 3, 4, 5, 6, or 7 ring members) which contain at least one (e.g. 1, 2, 3, 4, or 5) heteroatom(s) in the ring. Heteroaryl rings may be isolated, preferably with 5 to 6 ring atoms, or fused, preferably with 8, 9 or 10 ring atoms.
- the heteroaryl ring(s) hydrogens or heteroatoms with open valency may be substituted, e.g. with groups as defined above, such as alkyl or halogen.
- heteroaryl groups include imidazole, pyridine, indole, quinoline, furane, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, and dihydrobenzindole.
- aliphatic group comprises both saturated and unsaturated, straight chain (i.e., unbranched), branched, cyclic, or polycyclic aliphatic hydrocarbons, which are optionally substituted with one or more functional groups.
- the term includes, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties. It is presently preferred that alkyl or other aliphatic groups have 1-6 carbon atoms (which may be substituted or unsubstituted as specified).
- suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
- heteroaliphatic group refers to aliphatic moieties (cf. the term aliphatic as defined above), which contain one or more oxygen, sulfur, nitrogen, phosphorous or silicon atoms, e.g., in place of carbon atoms. Heteroaliphatic moieties may be substituted or unsubstituted, branched, unbranched, cyclic or acyclic, and include saturated and unsaturated heterocycles such as morpholino, pyrrolidinyl, etc
- carrier group/ring includes a mono or bicyclic carbocyclic ring (e.g., cycloalkyl or cycloalkenyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, and bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl, etc.); optionally containing 1-2 double bonds and optionally substituted by 1 to 3 suitable substituents as defined above.
- cycloalkyl or cycloalkenyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl
- heterocyclic group/ring includes both heteroaryl as above defined as well as non- aromatic ring systems having five to fourteen members, preferably five to ten, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S.
- heterocyclic rings examples include 3-lH-benzimidazol-2-one, (l-substituted)-2-oxo- benzimidazol-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3- tetrahydropyranyl, 4-tetrahydropyranyl, [l,3]-dioxalanyl, [l,3]-dithiolanyl, [l,3]-dioxanyl, 2- tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2- thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1 -pyrrolidinyl, 2-pyrrolidinyl, 3- pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-
- heterocyclyl or “heterocyclic”, as it is used herein, is a group in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic or non- aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring.
- heterocyclic whether saturated or partially unsaturated, also refers to rings that are optionally substituted with substituents as above defined.
- acyl groups are formyl, C1-C6 alk(en/yn)ylcarbonyl, arylcarbonyl, aryl-Cl-C6 alk(en/yn)ylcarbonyl, cycloalkylcarbonyl, or cycloalkyl-Cl-C6 alk(en/yn)ylcarbonyl group.
- hydroxy-protecting group is intended to mean any group used for the temporary protection of hydroxy functions, such as for example, alkoxycarbonyl, acyl, alkylsilyl or alkylarylsilyl groups (hereinafter referred to simply as “silyl” groups), and alkoxyalkyl groups.
- Alkoxycarbonyl protecting groups are alkyl-0 ⁇ CO ⁇ groupings such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert- butoxycarbonyl, benzyloxycarbonyl or allyloxycarbonyl.
- Alkoxyalkyl protecting groups are groups such as methoxymethyl, ethoxymethyl, methoxyethoxymethyl, or tetrahydrofuranyl and tetrahydropyranyl.
- Preferred silyl-protecting groups are trimethylsilyl, triethylsilyl, t- butyldimethylsilyl, dibutylmethylsilyl, diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t- butylsilyl and analogous alkylated silyl radicals.
- a "protected hydroxy” group is a hydroxy group derivatised or protected by any of the above groups commonly used for the temporary or permanent protection of hydroxy functions, e.g. the silyl, alkoxyalkyl, acyl or alkoxycarbonyl groups, as previously defined
- steroid as used herein is intended to mean compounds having a cyclopentanophenanthrene nucleus.
- the use of bold and dashed lines to denote particular conformation of groups again follows the IUPAC steroid-naming convention.
- the symbols “alpha” and “beta” indicate the specific stereochemical configuration of a substituent at an asymmetric carbon atom in a chemical structure as drawn.
- alpha denoted by a broken line
- “beta” denoted by a bold line indicates that the group at the position in question is above the general plane of the molecule as drawn.
- steroidal carbothioate steroidal carbothioic acid
- steroidal carboxylic acid steroidal carboxylic acid
- a carbothioate group, carbothioic acid group or carboxylic acid group, respectively is bound to the steroid nucleus, either directly or via linker, such as an optionally substituted C1-C6 alkylene group, in any position of the nucleus.
- linker such as an optionally substituted C1-C6 alkylene group
- steroidal compound where the carbothioate group, carbothioic acid group or carboxylic acid group is bound to the carbon atom in position 17, more preferably directly to the nucleus without an intervening linker, and most preferably in beta configuration.
- R represents a substituent selected from: an aliphatic group, an heteroaliphatic group, a carbocyclic group, a heterocyclic group, a heteroaiyl group, an aryl group, etc; all said groups are optionally substituted as above defined.
- Presently preferred R is substituted alkyl or substituted heterocyclyl.
- nucleophilic agent means a chemical compound capable of forming a covalent bond with an activated carboxylic acid group.
- electrophilic agent as used herein relates to a chemical compound capable of forming a covalent bond with a electron rich system such as e.g. a thioanion (-S " ).
- a thioanion a thioanion
- examples are compounds of the formula X-Y, where X is halogen and Y is aryl, a heterocyclic group or an aliphatic or heteroaliphatic group, said groups being optionally substituted.
- preferred agents are optionally substituted alkylhalogenides or optionally substituted heterocyclylhalides.
- solvate represents an aggregate that comprises one or more molecules of the compound of the invention, with one or more molecules of solvent.
- Solvents may be, by way of example, water, ethanol, acetone, THF, DMA, or DMF.
- a first aspect of the invention relates to a method for preparing a steroidal carbothioic acid or a salt thereof, said method comprises;
- a coupling agent such as a carbodiimide derivative
- a coupling enhancer such as a chemical entity comprising a saturated or unsaturated 5-6 membered heterocyclic ring in which the 5-6 membered heterocyclic ring contains one, two or three nitrogen atoms, said heterocyclic ring is optional
- step B) reacting the product of step A) with a nucleophilic agent comprising a sulfur atom [such as hydrogen sulfide or a corresponding salt, optionally a hydrated salt thereof and preferably sodium hydrosulfide hydrate].
- a nucleophilic agent comprising a sulfur atom [such as hydrogen sulfide or a corresponding salt, optionally a hydrated salt thereof and preferably sodium hydrosulfide hydrate].
- EDC l-ethyl-3-(3-dimethylaminopropyl) carbodiimide
- the coupling agent can also be selected from the group consisting of:
- the coupling enhancer is selected from the group consisting of: A) a heterocyclic ring containing one or two nitrogen atoms, said ring being optionally substituted [such as by a keto group, a hydroxy group, an aliphatic group, a heteroaliphatic group, a cyano group, a halogen atom]; such as a compound of formula (D) or formula (E),
- R ⁇ and R )2 can be the same or different, and each represent a hydrogen atom or a cyano group (CsN);
- R ⁇ 3 represent a hydrogen atom or an alkyl group (such as methyl);
- 6-chloro-hydroxybenzotriasole (6-Cl-HOBt), 7-aza-hydroxybenzotriasole (HOAt), or 3-hydroxy-4-oxo-3,4-dihydro-l ,2,3-benzotriazine (Dbht-OH).
- the nucleophilic agent comprising a sulfur atom is selected from the group comprising: compounds of formula [M] + [SH] " wherein M is a metal such as Li, Na or K; or [M] 2+ [S] 2" wherein M is a metal such as Ca or Mg, the said sulfide salts being optionally hydrated (such as sodium hydrosulfide hydrate); and an in situ generated sulfide salt or a hydrated sulfide salt.
- the nucleophilic agent can be added in the form of a solid salt or dissolved in a suitable solvent prior to addition to the reaction mixture, eg, as a solution of the salt in water and/or an organic solvent or a combination thereof.
- the invention relates to preparing a steroidal carbothioic acid of formula (IV) or a salt thereof;
- R 2 represents a hydrogen atom, a hydroxy group, an alkoxy group (such as optionally substituted C ⁇ -6 alkoxy) in the ⁇ -configuration, an alkyl group (such as optionally substituted C ⁇ . 6 alkyl) which may be in either the ⁇ - or ⁇ -configuration, an alkylene group (such as optionally substituted C ⁇ -6 alkylene having the two free valencies on the same carbon atom, preferably methylen) [the alkylene group is bound to the steroid nucleus via a double bond] or Ri and R 2 together represent
- R 7 and R 8 are the same or different and each represent a hydrogen atom or an alkyl group
- R 3 represent hydrogen, hydroxy or a protected hydroxy group in either the ⁇ - or ⁇ -configuration or an oxo group (in which case the bond between R 3 and the steroid nucleus is a double bond);
- Ri represents a hydrogen atom or a halogen atom or R and R 4 together represent a carbon-carbon bond or an epoxy group in the ⁇ -configuration;
- R 5 represents a hydrogen atom or a halogen atom in either the ⁇ - or ⁇ -configuration
- R 9 represents a hydrogen atom or R 9 represent a metal ion [eg. the moiety -S-R 9 represents a group of the formula [-S] " [M] + wherein M is Li, Na or K]; the method comprising;
- the sequence of addition of the coupling agent and the coupling enhancer is not considered to be very important, as the agent can be added before the enhancer, or vice versa. It is also possible to add a mixture of a steroidal carboxylic acid to a mixture of the agent and the enhancer or vice versa. Presently, it is preferred to add the agent and the enhancer, in succession, as solids to a steroidal carboxylic acid dissolved in a polar aprotic solvent, preferably DMF or DMA, optionally at a elevated temperature
- the carbothioic acid or a salt thereof can be used in a process for producing steroidal carbothioates, and therefore the invention in a second aspect relates to a method for preparing a steroidal carbothioate (i.e. the carbothioic ester of the steroid), or a salt thereof, the method comprising: reacting a steroidal carbothioic acid or a salt thereof, which is prepared as defined in the first aspect of the invention, with an electrophilic agent [such as a di-or trihaloalkane].
- an electrophilic agent such as a di-or trihaloalkane
- the electrophilic agent is selected from the group consisting of: C ⁇ -6 di- or trihaloalkanes, preferably a trihalo- or a dihalomethane , such as chlorobromomethane or bromofluoromethane.
- the invention relates to a method for preparing a steroidal carbothioate of formula (I)
- Rio represents a C ⁇ haloalkyl [such as a fluoro-, chloro-, bromomethyl group, a difluoromethyl or a trifluoromethyl group, or a 2 , -fluoroethyl group] or a optionally substituted heterocyclic ring [such as a tetrahydrofuranyl group, preferably a 2-oxo-tetrahydrofuran-3-yl], the method comprising:
- a coupling agent such as a carbodiimide
- a coupling enhancer such as a compound of formula (D) or formula (E)
- Rn and R ⁇ 2 independently represent a hydrogen atoms or a cyano group (C ⁇ N);
- Ri 3 represent a hydrogen atom or an alkyl group (such as methyl).
- step B) reacting the product from step B) with an electrophilic agent [such as a C ⁇ . 6 di- or trihaloalkane, preferably a trihalo- or a dihalomethane such as chlorofluoromethane or bromofluoromethane] or a compound of the following formula;
- an electrophilic agent such as a C ⁇ . 6 di- or trihaloalkane, preferably a trihalo- or a dihalomethane such as chlorofluoromethane or bromofluoromethane
- formula (D) is NMI (N-methylimidazole) or DCI (4,5- dicyanoimidazole), or formula (E) is NHS (N-hydroxysuccinimide) or sulfo-NHS (a N-hydroxysulfosuccinimide salt).
- the invention relates to the above method wherein at least one of Rn and R12 is a cyano group (C ⁇ N), and/or R ⁇ 3 is a hydrogen atom, and/or Rio is a fluoromethyl group.
- step C) constitutes the in situ reaction of the product from step B) with bromofluoromethane to form a compound of formula (I) wherein Rio is a fluoromethyl group, such as fluticasone propionate.
- the method is performed without unnecessary isolation of intermediates, and thus in a preferred embodiment, at least two subsequent steps of the method are performed in situ, i.e. without any change or removal of solvents, or isolation of the individual intermediates.
- the steps A), B) and C) are conducted as a one-pot synthesis without solvent changes and/or are performed at room or elevated temperature.
- the method can be conducted as a continuous method.
- the invention relates to a method, wherein an androstane 17 ⁇ - carboxylic acid is converted to an androstane 17 ⁇ -carbothioate.
- step B) provides an alkalimetal salt of the thioic acid, such as a compound of formula (rV), in which the moiety -S-R 9 represent a group of the formula [-S] " [M] + wherein M is Li, Na or K e.g. -S " Na + , and the other substituents have the same meaning as defined for formula (I).
- a third aspect of the invention relates to a method for producing a compound of the formula
- R c represents S, O, NH
- Rc represents O
- W represents H or a salt thereof with a coupling agent alone or in conjunction with a coupling enhancer, (the agent and enhacer defined in claim 1, step A); and reacting the resulting product with
- a fourth aspect of the invention relates to the novel products which can be obtained by the methods of the invention, or novel compounds which are intermediates in the methods.
- the invention relates to a compound of the formula (III) and salts and solvates thereof
- ⁇ in the 1,2-position represent a single or a carbon-carbon double bond, wherein R l5 R 2; R 3 ⁇ R 4 , and R 5 are defined as above; and Z represent the structural moiety resulting from the reaction between the steroidal carboxylic acid of formula (II) and a coupling agent (preferably EDC), followed by a coupling enhancer as defined above, such as a compound selected from the group consisting of the compounds of formulas (D); (E); (F); and (G):
- a coupling agent preferably EDC
- a coupling enhancer as defined above, such as a compound selected from the group consisting of the compounds of formulas (D); (E); (F); and (G):
- Rn and R ⁇ 2 represent a hydrogen atom or a cyano group
- R ⁇ 3 represent a hydrogen atom or a alkyl group (such as methyl)
- the compounds of the invention also comprises salts and solvates of the above formulas, and the skilled person will know that the compounds exsist in several polymorph forms, which also is an aspect of the present invention. Also, the above methods lead to compounds in the form of free bases, salts and polymorphs.
- Rn and R n are compounds wherein at least one of Rn and R n is a cyano group (C ⁇ N), and/or compounds, wherein R i3 is a hydrogen atom, and/or compounds obtained using a coupling enhancer selected from the group consisting of: NMI (N- methylimidazole); DCI (4,5-dicyanoimidazole); NHS (N-hydroxysuccinimide); and sulfo-NHS (N- hydroxysulfosuccinimide sodium salt) and/or a compound having the formula:
- the fifth aspect of the invention relates to a composition comprising a compound according to the invention, and, as a sixth aspect, the use of a compound of the invention as an intermediate in a method for preparing a steroidal carbothioate or a steroidal carbothioic acid.
- the invention relates to the use of a compound of the invention as an intermediate in a method for preparing fluticasone propionate, especially in a method which comprises reaction with a nucleophilic agent comprising a sulfur atom [such as sodium hydrosulfide hydrate] and/or comprises reaction with an electrophilic agent [such as a C ⁇ .6 di- or trihaloalkane, preferably a trihalo- or a dihalomethane such as chlorofluoromethane or
- the method as described herein relates in a presently preferred embodiment to the conversion of androstane 17 ⁇ -carboxylic acids to 17 ⁇ -carbothioates such as e.g. fluticasone propionate via novel in situ activated 17 ⁇ -carboxylic acid intermediates.
- the 25 17 ⁇ -carbothioic esters are prepared by reacting an acid of formula (II) with a coupling agent in conjunction with a coupling enhancer.
- the terms "coupling agent” and “coupling enhancer” are herein used to refer to chemical reagents that facilitate the formation of a reactive intermediate of formula (III) where Z represent a group with the structural formula (D) or formula (E).
- Such intermediates may be formed between androstane 17 ⁇ -carboxylic acids and a carbodiimide derivative such as l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (a preferred example of a coupling agent) in combination with suitable coupling enhancers.
- a carbodiimide derivative such as l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (a preferred example of a coupling agent) in combination with suitable coupling enhancers.
- EDC l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
- suitable coupling enhancers as used herein can for example be represented by the structures of formula (D) and formula (E) as described above.
- the coupling agent and the optional coupling enhancers are preferably water-soluble so the reactions could be effected in aqueous solutions if preferred.
- R 9 may represent optionally substituted C ⁇ -6 alkyl groups like e.g.
- R 9 represent a hydrogen atom or a salt.
- salts include alkali metal salts; e.g. Li, Na or K, alkaline earth metal salts; e.g. Ca or Mg, tertiary amine salts; e.g.
- the nucleophilic agent is a hydrogen sulfide or a salt thereof or more preferably a hydrated sulfide salt such as sodium hydrosulfide hydrate.
- the electrophilic agent is chlorofluoromethane or more preferably bromofluoromethane.
- compounds of formula (III) as defined hereinbefore may be prepared by treating a compound of formula (II) with EDC in combination with a compound of formula (E).
- EDC in combination with a compound of formula (E).
- the resulting 17 ⁇ -carboxy succinimidyl ester which may be isolated if required is treated with a nucleophilic agent that displaces the active ester group to form a compound of formula (IV) as defined hereinbefore.
- the androstane 17 ⁇ -carboxylic acid starting materials employed in the present invention may be readily prepared by any means known in the art.
- Compounds of formula (II) can be prepared by oxidation of a suitable 21-hydroxy-20-keto pregnane of formula (V) as taught in e.g. US3636010 (example 1).
- Compounds of formula (V) which are commercially available include e.g. budesonide, desonide, triamcinolone acetonide, fluocinolone acetonide, betamethasone, dexamethasone, prednisolone, flumethasone, beclomethasone, icomethasone, diflorasone, hydrocortisone and fludrocortisone.
- budesonide desonide, triamcinolone acetonide, fluocinolone acetonide, betamethasone, dexamethasone, prednisolone, flumethasone, beclomethasone, icomethasone, diflorasone, hydrocortisone and fludrocortisone.
- DMF N,N-dimethylforrnamide
- DMA N,N-dimethylacetamide
- THF tetrahydrofurane
- EDC l-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride
- NHS N-hydroxysuccinimide
- NMI N-methylimidazole
- Example 3 S-fluoromethyl 6 ⁇ ,9 ⁇ -difluoro- 11 ⁇ -hydroxy- 16 ⁇ -methyl-3 -oxo- 17 ⁇ -propionyloxyandrosta- 1 ,4- diene-17 ⁇ -carbothioate (fluticasone propionate)
- 6 ⁇ ,9 ⁇ -difluoro-l 1 ⁇ -hydroxy- 16 ⁇ -methyl-3 -oxo- 17 ⁇ -propiony loxy-androsta- l,4-diene-17 ⁇ -carboxylic acid (0.30 g, 0.66 mmol) in DMA (30 ml) at -50 °C was added EDC (3.0 eq., 0.38 g) and NHS (3.1 eq., 0.24 g) and left stirring until the reaction was complete, as monitored by HPLC analysis.
- the solid thus formed was filtered and a minimum amount of acetone following temperated water was added to a beginning crystallisation.
- the refrigerated suspension was filtered, washed with water (30 ml) until the filtrate was neutral to pH-paper and dried under reduced pressure.
- the title compound was obtained as a white amorphous solid (0.10 g, 32%) with a purity of 98% by HPLC.
- the mixture was left stirring at 50 °C for 3 hours.
- the flask was removed from the oil-bath and the reaction mixture was diluted by the addition of DMF (5 ml).
- Aqueous NaSMe 1.0 ml, 21% solution in water
- the reaction mixture turned into a pale pink suspension.
- the reaction was quenched by the addition crushed ice and aqueous HC1 (12 ml, 10%).
- the white precipitate was filtered, washed with water and dried.
- the crude product was dissolved in a minimum amount of acetone and water was added until a beginning precipitation.
- the resulting solid was collected by filtration, washed with water and dried under reduced pressure to yield the title compound as a white solid (0.11 g, 51 %) with a purity of 90% by HPLC.
- Example 7 S-fluoromethyl 6 ⁇ ,9 ⁇ -difluoro-l 1 ⁇ -hydroxy- 16 ⁇ -methyl-3 -oxo- 17 ⁇ -pro ⁇ ionyloxyandrosta- 1,4- diene-17 ⁇ -carbothioate (fluticasone propionate) Charge a flask with 6 ⁇ ,9 ⁇ -difluoro-l 1 ⁇ -hydroxy- 16 ⁇ -methy 1-3 -oxo- 17 ⁇ -propiony 1-oxyandrosta- l,4-diene-17 ⁇ -carboxylic acid (0.30 g, 0.66 mmol) in DMA (30 ml) and heat the contents to -50 °C.
- the methanolic solution is heated to reflux and filtered. Temperate water (40 ml) is added slowly to the warm filtrate. The resulting suspension is left at room temperature for two hours before being transferred to a refrigerator. The precipitate which forms is collected by filtration, washed with water (40 ml) and dried under reduced pressure. The title compound is obtained as a solid.
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Abstract
Description
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Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2004226318A AU2004226318B2 (en) | 2003-04-04 | 2004-04-02 | Process for the preparation of steroidal carbothioic acid derivatives and intermediates |
EP04725301A EP1611149A1 (en) | 2003-04-04 | 2004-04-02 | Process for the preparation of steroidal carbothioic acid derivatives and intermediates |
JP2006504347A JP2006522028A (en) | 2003-04-04 | 2004-04-02 | Method for producing steroidal carbothioic acid derivative and intermediate |
CA002530680A CA2530680A1 (en) | 2003-04-04 | 2004-04-02 | Process for the preparation of steroidal carbothioic acid derivatives and intermediates |
US10/552,118 US20070270584A1 (en) | 2003-04-04 | 2004-04-02 | Process for the Preparation of Steroidal Carbothioic Acid Derivatives and Intermediates |
NO20054636A NO20054636L (en) | 2003-04-04 | 2005-10-10 | Process for the preparation of steroidal carbothioic acid derivatives and intermediates |
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EP03007756A EP1466920A1 (en) | 2003-04-04 | 2003-04-04 | Process for the preparation of steroidal 17 beta-carbothioates |
EP03007756.4 | 2003-04-04 | ||
DKPA200400449 | 2004-03-19 | ||
DK200400449 | 2004-03-19 |
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US (1) | US20070270584A1 (en) |
EP (1) | EP1611149A1 (en) |
JP (1) | JP2006522028A (en) |
AU (1) | AU2004226318B2 (en) |
CA (1) | CA2530680A1 (en) |
NO (1) | NO20054636L (en) |
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CN110317238A (en) * | 2018-03-31 | 2019-10-11 | 天津药业研究院有限公司 | A kind of preparation method of fluticasone furoate |
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US9303060B1 (en) * | 2014-10-03 | 2016-04-05 | Amphaster Pharmaceuticals, Inc. | Methods of preparing intermediate of fluticasone propionate |
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- 2004-04-02 US US10/552,118 patent/US20070270584A1/en not_active Abandoned
- 2004-04-02 EP EP04725301A patent/EP1611149A1/en not_active Withdrawn
- 2004-04-02 WO PCT/DK2004/000242 patent/WO2004087731A1/en active Application Filing
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CN110317238A (en) * | 2018-03-31 | 2019-10-11 | 天津药业研究院有限公司 | A kind of preparation method of fluticasone furoate |
CN110317238B (en) * | 2018-03-31 | 2022-08-09 | 天津药业研究院股份有限公司 | Preparation method of fluticasone furoate |
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NO20054636L (en) | 2005-12-27 |
CA2530680A1 (en) | 2004-10-14 |
EP1611149A1 (en) | 2006-01-04 |
US20070270584A1 (en) | 2007-11-22 |
JP2006522028A (en) | 2006-09-28 |
NO20054636D0 (en) | 2005-10-10 |
AU2004226318B2 (en) | 2008-06-05 |
AU2004226318A1 (en) | 2004-10-14 |
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