IL124631A - Processes for preparations of steroids and intermediates useful therein - Google Patents

Processes for preparations of steroids and intermediates useful therein

Info

Publication number: IL124631A
Authority: IL; Israel
Prior art keywords: formula; compound; group; reaction; sup
Prior art date: 1995-12-11

Application number

IL12463196A

Other languages

English (en)

Other versions

IL124631A0 (en

Original Assignee

Searle & Co

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1995-12-11

Filing date

1996-12-11

Publication date

2004-03-28

1996-12-11 Application filed by Searle & Co filed Critical Searle & Co

1996-12-11 Priority to IL158857A priority Critical patent/IL158857A/en

1999-01-26 Publication of IL124631A0 publication Critical patent/IL124631A0/xx

2004-03-28 Publication of IL124631A publication Critical patent/IL124631A/en

Links

238000000034 method Methods 0.000 title claims abstract description 188
230000008569 process Effects 0.000 title claims description 151
238000002360 preparation method Methods 0.000 title claims description 55
239000000543 intermediate Substances 0.000 title abstract description 60
150000003431 steroids Chemical class 0.000 title description 21
238000006243 chemical reaction Methods 0.000 claims abstract description 296
150000001875 compounds Chemical class 0.000 claims abstract description 291
239000001257 hydrogen Substances 0.000 claims abstract description 63
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 63
125000003545 alkoxy group Chemical group 0.000 claims abstract description 35
125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 33
125000000217 alkyl group Chemical group 0.000 claims abstract description 31
125000001475 halogen functional group Chemical group 0.000 claims abstract description 28
125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 23
125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 23
125000004104 aryloxy group Chemical group 0.000 claims abstract description 21
125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 21
ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims abstract description 19
125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 18
125000000623 heterocyclic group Chemical group 0.000 claims abstract description 15
125000002252 acyl group Chemical group 0.000 claims abstract description 14
125000002837 carbocyclic group Chemical group 0.000 claims abstract description 14
125000005041 acyloxyalkyl group Chemical group 0.000 claims abstract description 11
239000000047 product Substances 0.000 claims description 156
-1 aikoxyaikyl Chemical group 0.000 claims description 121
239000002904 solvent Substances 0.000 claims description 113
239000002253 acid Substances 0.000 claims description 49
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 38
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
229910052783 alkali metal Inorganic materials 0.000 claims description 31
239000001301 oxygen Substances 0.000 claims description 30
229910052760 oxygen Inorganic materials 0.000 claims description 30
239000003960 organic solvent Substances 0.000 claims description 21
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 20
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 19
235000019253 formic acid Nutrition 0.000 claims description 19
XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 16
150000003839 salts Chemical class 0.000 claims description 16
239000003795 chemical substances by application Substances 0.000 claims description 15
125000004423 acyloxy group Chemical group 0.000 claims description 13
238000001556 precipitation Methods 0.000 claims description 12
150000004820 halides Chemical class 0.000 claims description 11
239000012359 Methanesulfonyl chloride Substances 0.000 claims description 9
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 9
125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 8
239000006227 byproduct Substances 0.000 claims description 8
WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 claims description 8
230000001376 precipitating effect Effects 0.000 claims description 6
230000035484 reaction time Effects 0.000 claims description 6
150000001340 alkali metals Chemical group 0.000 claims description 5
239000002516 radical scavenger Substances 0.000 claims description 5
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 5
239000012433 hydrogen halide Substances 0.000 claims description 4
229910000039 hydrogen halide Inorganic materials 0.000 claims description 4
150000001266 acyl halides Chemical class 0.000 claims description 3
125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 3
150000001768 cations Chemical class 0.000 claims description 3
125000005905 mesyloxy group Chemical group 0.000 claims description 3
BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 3
229910052727 yttrium Inorganic materials 0.000 claims 4
125000004390 alkyl sulfonyl group Chemical group 0.000 claims 2
101100439663 Arabidopsis thaliana CHR7 gene Proteins 0.000 claims 1
101100244083 Arabidopsis thaliana PKL gene Proteins 0.000 claims 1
229910001420 alkaline earth metal ion Inorganic materials 0.000 claims 1
125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims 1
125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims 1
229910001428 transition metal ion Inorganic materials 0.000 claims 1
JUKPWJGBANNWMW-VWBFHTRKSA-N eplerenone Chemical compound C([C@@H]1[C@]2(C)C[C@H]3O[C@]33[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 JUKPWJGBANNWMW-VWBFHTRKSA-N 0.000 abstract description 41
229960001208 eplerenone Drugs 0.000 abstract description 41
230000015572 biosynthetic process Effects 0.000 abstract description 31
238000003786 synthesis reaction Methods 0.000 abstract description 18
125000004356 hydroxy functional group Chemical group O* 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 213
239000000243 solution Substances 0.000 description 192
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 156
239000000203 mixture Substances 0.000 description 150
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 147
UJVLDDZCTMKXJK-WNHSNXHDSA-N canrenone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CCC(=O)C=C3C=C2)C)CC[C@@]11C)C[C@@]11CCC(=O)O1 UJVLDDZCTMKXJK-WNHSNXHDSA-N 0.000 description 135
229960005057 canrenone Drugs 0.000 description 133
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 132
239000000758 substrate Substances 0.000 description 123
229910001868 water Inorganic materials 0.000 description 112
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 99
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 94
239000008103 glucose Substances 0.000 description 93
238000007792 addition Methods 0.000 description 84
239000011541 reaction mixture Substances 0.000 description 81
238000000855 fermentation Methods 0.000 description 78
230000004151 fermentation Effects 0.000 description 78
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 66
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 59
239000001963 growth medium Substances 0.000 description 58
239000000725 suspension Substances 0.000 description 57
239000007787 solid Substances 0.000 description 49
239000003153 chemical reaction reagent Substances 0.000 description 46
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 45
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 42
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
239000002609 medium Substances 0.000 description 42
238000013019 agitation Methods 0.000 description 41
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
238000004519 manufacturing process Methods 0.000 description 38
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
229940041514 candida albicans extract Drugs 0.000 description 36
238000004128 high performance liquid chromatography Methods 0.000 description 36
235000015097 nutrients Nutrition 0.000 description 36
239000012138 yeast extract Substances 0.000 description 36
239000010410 layer Substances 0.000 description 35
238000003756 stirring Methods 0.000 description 35
125000005594 diketone group Chemical group 0.000 description 34
238000000605 extraction Methods 0.000 description 34
229910052757 nitrogen Inorganic materials 0.000 description 33
239000012071 phase Substances 0.000 description 32
240000004808 Saccharomyces cerevisiae Species 0.000 description 31
238000010992 reflux Methods 0.000 description 31
238000011218 seed culture Methods 0.000 description 31
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 29
230000009466 transformation Effects 0.000 description 28
238000001914 filtration Methods 0.000 description 27
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
239000001888 Peptone Substances 0.000 description 24
108010080698 Peptones Proteins 0.000 description 24
235000019319 peptone Nutrition 0.000 description 24
UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical compound OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 description 23
238000006735 epoxidation reaction Methods 0.000 description 22
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 21
150000002081 enamines Chemical class 0.000 description 21
230000012010 growth Effects 0.000 description 21
238000004809 thin layer chromatography Methods 0.000 description 21
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
240000008042 Zea mays Species 0.000 description 20
235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 20
235000002017 Zea mays subsp mays Nutrition 0.000 description 20
239000002585 base Substances 0.000 description 20
235000005822 corn Nutrition 0.000 description 20
238000004821 distillation Methods 0.000 description 20
239000012074 organic phase Substances 0.000 description 20
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
210000004027 cell Anatomy 0.000 description 19
239000000284 extract Substances 0.000 description 19
150000002431 hydrogen Chemical class 0.000 description 19
239000000463 material Substances 0.000 description 19
239000002245 particle Substances 0.000 description 19
239000002054 inoculum Substances 0.000 description 18
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 17
125000000457 gamma-lactone group Chemical group 0.000 description 17
239000002002 slurry Substances 0.000 description 17
229920001817 Agar Polymers 0.000 description 16
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 16
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 16
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
239000008272 agar Substances 0.000 description 16
229910052799 carbon Inorganic materials 0.000 description 16
ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 16
238000005805 hydroxylation reaction Methods 0.000 description 16
239000012044 organic layer Substances 0.000 description 16
230000002829 reductive effect Effects 0.000 description 16
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
239000012267 brine Substances 0.000 description 15
238000003379 elimination reaction Methods 0.000 description 15
239000012065 filter cake Substances 0.000 description 15
230000001965 increasing effect Effects 0.000 description 15
239000007788 liquid Substances 0.000 description 15
244000005700 microbiome Species 0.000 description 15
230000001954 sterilising effect Effects 0.000 description 15
238000005273 aeration Methods 0.000 description 14
238000010438 heat treatment Methods 0.000 description 14
LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 14
YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 14
GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 14
238000004659 sterilization and disinfection Methods 0.000 description 14
241000122824 Aspergillus ochraceus Species 0.000 description 13
239000002028 Biomass Substances 0.000 description 13
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 13
238000004458 analytical method Methods 0.000 description 13
238000001035 drying Methods 0.000 description 13
230000035611 feeding Effects 0.000 description 13
238000003306 harvesting Methods 0.000 description 13
229910052698 phosphorus Inorganic materials 0.000 description 13
238000011084 recovery Methods 0.000 description 13
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
238000002156 mixing Methods 0.000 description 12
OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 11
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
235000019764 Soybean Meal Nutrition 0.000 description 11
230000008901 benefit Effects 0.000 description 11
239000011574 phosphorus Substances 0.000 description 11
239000012265 solid product Substances 0.000 description 11
239000004455 soybean meal Substances 0.000 description 11
238000005406 washing Methods 0.000 description 11
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
241000187747 Streptomyces Species 0.000 description 10
239000012190 activator Substances 0.000 description 10
239000003242 anti bacterial agent Substances 0.000 description 10
229940088710 antibiotic agent Drugs 0.000 description 10
238000002425 crystallisation Methods 0.000 description 10
230000008025 crystallization Effects 0.000 description 10
230000008030 elimination Effects 0.000 description 10
239000012535 impurity Substances 0.000 description 10
230000003647 oxidation Effects 0.000 description 10
238000007254 oxidation reaction Methods 0.000 description 10
150000002978 peroxides Chemical class 0.000 description 10
239000002244 precipitate Substances 0.000 description 10
238000012546 transfer Methods 0.000 description 10
239000008346 aqueous phase Substances 0.000 description 9
238000001816 cooling Methods 0.000 description 9
238000010790 dilution Methods 0.000 description 9
239000012895 dilution Substances 0.000 description 9
230000000694 effects Effects 0.000 description 9
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
238000011081 inoculation Methods 0.000 description 9
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 9
239000003921 oil Substances 0.000 description 9
235000019198 oils Nutrition 0.000 description 9
239000011780 sodium chloride Substances 0.000 description 9
HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 8
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 description 8
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
239000000654 additive Substances 0.000 description 8
LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 8
239000012984 antibiotic solution Substances 0.000 description 8
239000000872 buffer Substances 0.000 description 8
229910000396 dipotassium phosphate Inorganic materials 0.000 description 8
229910052500 inorganic mineral Inorganic materials 0.000 description 8
239000007791 liquid phase Substances 0.000 description 8
KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
235000010755 mineral Nutrition 0.000 description 8
239000011707 mineral Substances 0.000 description 8
239000000523 sample Substances 0.000 description 8
229920000858 Cyclodextrin Polymers 0.000 description 7
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
150000008044 alkali metal hydroxides Chemical class 0.000 description 7
AEMFNILZOJDQLW-QAGGRKNESA-N androst-4-ene-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 AEMFNILZOJDQLW-QAGGRKNESA-N 0.000 description 7
238000005119 centrifugation Methods 0.000 description 7
239000012141 concentrate Substances 0.000 description 7
150000002576 ketones Chemical class 0.000 description 7
238000013411 master cell bank Methods 0.000 description 7
235000010265 sodium sulphite Nutrition 0.000 description 7
230000000153 supplemental effect Effects 0.000 description 7
238000011282 treatment Methods 0.000 description 7
238000010626 work up procedure Methods 0.000 description 7
NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 6
UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 6
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
241000235546 Rhizopus stolonifer Species 0.000 description 6
241000215410 Trichothecium roseum Species 0.000 description 6
150000007513 acids Chemical class 0.000 description 6
230000000996 additive effect Effects 0.000 description 6
PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 6
239000007795 chemical reaction product Substances 0.000 description 6
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239000000706 filtrate Substances 0.000 description 6
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AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 6
230000002441 reversible effect Effects 0.000 description 6
229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
229910052938 sodium sulfate Inorganic materials 0.000 description 6
235000011152 sodium sulphate Nutrition 0.000 description 6
239000007858 starting material Substances 0.000 description 6
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 6
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 5
241000351920 Aspergillus nidulans Species 0.000 description 5
241000228245 Aspergillus niger Species 0.000 description 5
241000751139 Beauveria bassiana Species 0.000 description 5
239000004593 Epoxy Substances 0.000 description 5
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
229910019142 PO4 Inorganic materials 0.000 description 5
229910001508 alkali metal halide Inorganic materials 0.000 description 5
150000008045 alkali metal halides Chemical class 0.000 description 5
230000031709 bromination Effects 0.000 description 5
238000005893 bromination reaction Methods 0.000 description 5
239000007810 chemical reaction solvent Substances 0.000 description 5
238000006704 dehydrohalogenation reaction Methods 0.000 description 5
239000008367 deionised water Substances 0.000 description 5
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238000009826 distribution Methods 0.000 description 5
230000008020 evaporation Effects 0.000 description 5
238000002474 experimental method Methods 0.000 description 5
230000026030 halogenation Effects 0.000 description 5
238000005658 halogenation reaction Methods 0.000 description 5
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238000002955 isolation Methods 0.000 description 5
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238000011160 research Methods 0.000 description 1
230000004044 response Effects 0.000 description 1
230000000717 retained effect Effects 0.000 description 1
238000002390 rotary evaporation Methods 0.000 description 1
239000011833 salt mixture Substances 0.000 description 1
239000012488 sample solution Substances 0.000 description 1
238000005070 sampling Methods 0.000 description 1
229920006395 saturated elastomer Polymers 0.000 description 1
230000035040 seed growth Effects 0.000 description 1
230000035945 sensitivity Effects 0.000 description 1
238000010008 shearing Methods 0.000 description 1
238000010898 silica gel chromatography Methods 0.000 description 1
KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
229950005143 sitosterol Drugs 0.000 description 1
150000003385 sodium Chemical class 0.000 description 1
MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
235000019345 sodium thiosulphate Nutrition 0.000 description 1
238000004611 spectroscopical analysis Methods 0.000 description 1
LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical group C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 description 1
229940032091 stigmasterol Drugs 0.000 description 1
BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 description 1
235000016831 stigmasterol Nutrition 0.000 description 1
239000013589 supplement Substances 0.000 description 1
DGQOCLATAPFASR-UHFFFAOYSA-N tetrahydroxy-1,4-benzoquinone Chemical compound OC1=C(O)C(=O)C(O)=C(O)C1=O DGQOCLATAPFASR-UHFFFAOYSA-N 0.000 description 1
HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
125000003944 tolyl group Chemical group 0.000 description 1
229910052723 transition metal Inorganic materials 0.000 description 1
150000003624 transition metals Chemical class 0.000 description 1
125000005270 trialkylamine group Chemical group 0.000 description 1
ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical class Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
125000004953 trihalomethyl group Chemical group 0.000 description 1
108010050327 trypticase-soy broth Proteins 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
235000013343 vitamin Nutrition 0.000 description 1
239000011782 vitamin Substances 0.000 description 1
229940088594 vitamin Drugs 0.000 description 1
229930003231 vitamin Natural products 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J21/001—Lactones
- C07J21/003—Lactones at position 17
- 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
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
- C07J53/002—Carbocyclic rings fused
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
- C07J71/0015—Oxiranes at position 9(11)
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P33/00—Preparation of steroids
- C12P33/005—Degradation of the lateral chains at position 17
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P33/00—Preparation of steroids
- C12P33/06—Hydroxylating
- C12P33/08—Hydroxylating at 11 position
- C12P33/10—Hydroxylating at 11 position at 11 alpha-position
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Wood Science & Technology (AREA)
Engineering & Computer Science (AREA)
Zoology (AREA)
Biotechnology (AREA)
Microbiology (AREA)
Biochemistry (AREA)
Bioinformatics & Cheminformatics (AREA)
General Engineering & Computer Science (AREA)
Genetics & Genomics (AREA)
Proteomics, Peptides & Aminoacids (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Physics & Mathematics (AREA)
Biophysics (AREA)
Analytical Chemistry (AREA)
Immunology (AREA)
Molecular Biology (AREA)
Steroid Compounds (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Epoxy Compounds (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)

IL12463196A 1995-12-11 1996-12-11 Processes for preparations of steroids and intermediates useful therein IL124631A (en)

Priority Applications (1)

Application Number	Priority Date	Filing Date	Title
IL158857A IL158857A (en)	1995-12-11	1996-12-11	Processes for preparation of steroids and intermediates useful therein

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US845595P	1995-12-11	1995-12-11
US08/763,910 US5981744A (en)	1995-12-11	1996-12-11	Processes for preparation of 9,11-epoxy steroids and intermediates useful therein
PCT/US1996/020780 WO1997021720A2 (en)	1995-12-11	1996-12-11	Processes for preparation of 7 alpha-carboxyl 9,11-epoxy steroids and intermediates useful therein and a general process for the epoxidation of olifinic double bonds

Publications (2)

Publication Number	Publication Date
IL124631A0 IL124631A0 (en)	1999-01-26
IL124631A true IL124631A (en)	2004-03-28

Family

ID=26678218

Family Applications (2)

Application Number	Title	Priority Date	Filing Date
IL12463196A IL124631A (en)	1995-12-11	1996-12-11	Processes for preparations of steroids and intermediates useful therein
IL175299A IL175299A0 (en)	1995-12-11	2006-04-27	Steroids, processes for their preparation and intermediates useful therein

Family Applications After (1)

Application Number	Title	Priority Date	Filing Date
IL175299A IL175299A0 (en)	1995-12-11	2006-04-27	Steroids, processes for their preparation and intermediates useful therein

Country Status (12)

Country	Link
US (13)	US5981744A (de)
EP (1)	EP0973791B1 (de)
JP (2)	JP4146897B2 (de)
CN (1)	CN100384866C (de)
AT (1)	ATE365171T1 (de)
DE (1)	DE69637140T2 (de)
DK (1)	DK0973791T3 (de)
EA (1)	EA009176B1 (de)
ES (1)	ES2287943T3 (de)
IL (2)	IL124631A (de)
PT (1)	PT973791E (de)
WO (1)	WO1997021720A2 (de)

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WO2017055248A1 (en)	2015-09-28	2017-04-06	INSERM (Institut National de la Santé et de la Recherche Médicale)	Methods and pharmaceutical compositions for the treatment of heart failure
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CN105753930A (zh) *	2016-03-30	2016-07-13	北京万全德众医药生物技术有限公司	依普利酮的一种合成方法
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1996
- 1996-12-11 US US08/763,910 patent/US5981744A/en not_active Expired - Fee Related
- 1996-12-11 CN CNB961999616A patent/CN100384866C/zh not_active Expired - Fee Related
- 1996-12-11 EA EA199800449A patent/EA009176B1/ru not_active IP Right Cessation
- 1996-12-11 DE DE69637140T patent/DE69637140T2/de not_active Expired - Fee Related
- 1996-12-11 ES ES96945103T patent/ES2287943T3/es not_active Expired - Lifetime
- 1996-12-11 WO PCT/US1996/020780 patent/WO1997021720A2/en not_active Ceased
- 1996-12-11 EP EP96945103A patent/EP0973791B1/de not_active Expired - Lifetime
- 1996-12-11 PT PT96945103T patent/PT973791E/pt unknown
- 1996-12-11 DK DK96945103T patent/DK0973791T3/da active
- 1996-12-11 AT AT96945103T patent/ATE365171T1/de not_active IP Right Cessation
- 1996-12-11 JP JP52230497A patent/JP4146897B2/ja not_active Expired - Fee Related
- 1996-12-11 IL IL12463196A patent/IL124631A/en not_active IP Right Cessation
1999
- 1999-02-08 US US09/246,204 patent/US6331622B1/en not_active Expired - Fee Related
- 1999-02-09 US US09/246,908 patent/US6180780B1/en not_active Expired - Fee Related
2000
- 2000-05-30 US US09/583,137 patent/US6258946B1/en not_active Expired - Fee Related
- 2000-05-30 US US09/583,158 patent/US6335441B1/en not_active Expired - Fee Related
2001
- 2001-04-03 US US09/826,406 patent/US20020016455A1/en not_active Abandoned
- 2001-04-04 US US09/826,434 patent/US20020019522A1/en not_active Abandoned
- 2001-08-07 US US09/923,977 patent/US6630587B2/en not_active Expired - Fee Related
- 2001-08-31 US US09/943,117 patent/US6586591B2/en not_active Expired - Fee Related
2003
- 2003-06-27 US US10/608,101 patent/US7038040B2/en not_active Expired - Fee Related
- 2003-09-26 US US10/672,680 patent/US6953851B2/en not_active Expired - Fee Related
2005
- 2005-06-20 US US11/156,418 patent/US7129345B2/en not_active Expired - Fee Related
2006
- 2006-04-27 IL IL175299A patent/IL175299A0/en unknown
- 2006-07-21 US US11/459,040 patent/US20070060746A1/en not_active Abandoned
2007
- 2007-10-12 JP JP2007265977A patent/JP2008100996A/ja not_active Withdrawn

Also Published As

Publication number	Publication date
US20020042507A1 (en)	2002-04-11
US20070060746A1 (en)	2007-03-15
JP2002504077A (ja)	2002-02-05
EP0973791A2 (de)	2000-01-26
US6586591B2 (en)	2003-07-01
US20050239761A1 (en)	2005-10-27
PT973791E (pt)	2007-09-26
EA009176B1 (ru)	2007-12-28
EP0973791B1 (de)	2007-06-20
US7129345B2 (en)	2006-10-31
US6258946B1 (en)	2001-07-10
US6335441B1 (en)	2002-01-01
US20030100541A1 (en)	2003-05-29
US6180780B1 (en)	2001-01-30
US20020019522A1 (en)	2002-02-14
US6953851B2 (en)	2005-10-11
DE69637140T2 (de)	2008-04-10
JP4146897B2 (ja)	2008-09-10
US6331622B1 (en)	2001-12-18
US20020016455A1 (en)	2002-02-07
CN100384866C (zh)	2008-04-30
IL175299A0 (en)	2006-09-05
EA199800449A1 (ru)	1999-02-25
JP2008100996A (ja)	2008-05-01
IL124631A0 (en)	1999-01-26
ES2287943T3 (es)	2007-12-16
US6630587B2 (en)	2003-10-07
US20040191874A1 (en)	2004-09-30
WO1997021720A3 (en)	1997-10-30
US5981744A (en)	1999-11-09
DK0973791T3 (da)	2007-09-17
WO1997021720A2 (en)	1997-06-19
ATE365171T1 (de)	2007-07-15
DE69637140D1 (de)	2007-08-02
CN1209136A (zh)	1999-02-24
US7038040B2 (en)	2006-05-02
US20040067917A1 (en)	2004-04-08

Legal Events

Date	Code	Title
2004-09-27	KB	Patent renewed
2007-02-12	KB	Patent renewed
2011-07-31	MM9K	Patent not in force due to non-payment of renewal fees

Publication	Publication Date	Title
US6331622B1 (en)	2001-12-18	Processes for preparation of 9, 11-epoxy steroids and intermediates useful therein
US6610844B2 (en)	2003-08-26	Processes for preparation of 9,11-epoxy steroids and intermediates useful therein
WO1998025948A9 (en)	1998-11-19	Processes for preparation of 9,11-epoxy steroids and intermediates useful therein
US7112669B2 (en)	2006-09-26	Processes for preparation of 9,11-epoxy steroids and intermediates useful therein
EP1170299A2 (de)	2002-01-09	Zwischenprodukte zur Herstellung von 9,11-Epoxysteroiden und Verfahren zu ihrer Herstellung
EP1148061B1 (de)	2007-10-17	Epoxidierungsverfahren
CA2347345C (en)	2007-05-15	Process for preparation of 7 alpha-carboxyl 9,11-epoxy steroids and intermediates useful therein and a general process for the epoxidation of olefinic double bonds
AU2002300873B2 (en)	2005-04-14	Processes for preparation of 9, 11-epoxy steriods and intermediates useful therein
IL158857A (en)	2006-08-20	Processes for preparation of steroids and intermediates useful therein
CA2552449A1 (en)	1997-06-19	Processes for preparation of 7 alpha-carboxyl 9,11-epoxy steroids and intermediates useful therein and a general process for the epoxidation of olifinic double bonds
AU1843900A (en)	2000-05-11	Process for the epoxidation of olefinic double bonds