NO314149B1 - Fremgangsmåter for fremstilling av 9,11-epoksysteroider og mellomproduktertil bruk ved fremgangsmåtene - Google Patents

Fremgangsmåter for fremstilling av 9,11-epoksysteroider og mellomproduktertil bruk ved fremgangsmåtene Download PDF

Info

Publication number: NO314149B1
Authority: NO; Norway
Prior art keywords: formula; group; chr; hydrogen; compound
Prior art date: 1996-12-11

Application number

NO19992825A

Other languages

English (en)

Norwegian (no)

Other versions

NO992825L (no

NO992825D0 (no

Inventor

John S Ng

Chin Liu

Dennis K Anderson

Jon P Lawson

Joseph Wieczorek

Sastry A Kunda

Leo J Letendre

Mark J Pozzo

Yuen-Lung L Sing

Ping T Wang

Edward E Yonan

Richard M Weier

Thomas R Kowar

Julio A Baez

Bernhard Erb

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.)

1996-12-11

Filing date

1999-06-10

Publication date

2003-02-03

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26709541&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=NO314149(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

1999-06-10 Application filed by Searle & Co filed Critical Searle & Co

1999-06-10 Publication of NO992825D0 publication Critical patent/NO992825D0/no

1999-07-29 Publication of NO992825L publication Critical patent/NO992825L/no

2003-02-03 Publication of NO314149B1 publication Critical patent/NO314149B1/no

Links

238000000034 method Methods 0.000 title claims abstract description 219
230000008569 process Effects 0.000 title claims description 132
238000002360 preparation method Methods 0.000 title claims description 58
150000003431 steroids Chemical class 0.000 title claims description 35
239000004593 Epoxy Substances 0.000 title claims description 9
239000000543 intermediate Substances 0.000 title abstract description 98
150000001875 compounds Chemical class 0.000 claims abstract description 573
238000006243 chemical reaction Methods 0.000 claims abstract description 293
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 236
239000001257 hydrogen Substances 0.000 claims abstract description 236
125000000217 alkyl group Chemical group 0.000 claims abstract description 183
125000003545 alkoxy group Chemical group 0.000 claims abstract description 133
-1 hydroxycarbonylalkyl Chemical group 0.000 claims abstract description 130
125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 124
125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 114
125000004104 aryloxy group Chemical group 0.000 claims abstract description 104
125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 98
ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims abstract description 88
125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 77
125000005041 acyloxyalkyl group Chemical group 0.000 claims abstract description 66
125000002252 acyl group Chemical group 0.000 claims abstract description 65
125000000623 heterocyclic group Chemical group 0.000 claims abstract description 47
125000002837 carbocyclic group Chemical group 0.000 claims abstract description 46
125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 22
125000001475 halogen functional group Chemical group 0.000 claims abstract 29
125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims abstract 21
239000000758 substrate Substances 0.000 claims description 152
150000002431 hydrogen Chemical class 0.000 claims description 142
229910052736 halogen Inorganic materials 0.000 claims description 118
150000002367 halogens Chemical class 0.000 claims description 116
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 112
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 88
238000004519 manufacturing process Methods 0.000 claims description 61
239000002253 acid Substances 0.000 claims description 59
229910052799 carbon Inorganic materials 0.000 claims description 42
239000002585 base Substances 0.000 claims description 38
239000003153 chemical reaction reagent Substances 0.000 claims description 38
239000001301 oxygen Substances 0.000 claims description 35
229910052760 oxygen Inorganic materials 0.000 claims description 35
125000000468 ketone group Chemical group 0.000 claims description 33
229930194542 Keto Natural products 0.000 claims description 30
238000006735 epoxidation reaction Methods 0.000 claims description 26
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
230000007062 hydrolysis Effects 0.000 claims description 23
238000006460 hydrolysis reaction Methods 0.000 claims description 23
150000003839 salts Chemical class 0.000 claims description 20
125000001424 substituent group Chemical group 0.000 claims description 18
125000004423 acyloxy group Chemical group 0.000 claims description 17
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
238000007254 oxidation reaction Methods 0.000 claims description 16
230000003647 oxidation Effects 0.000 claims description 15
239000012190 activator Substances 0.000 claims description 14
150000002596 lactones Chemical class 0.000 claims description 13
150000002978 peroxides Chemical class 0.000 claims description 10
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 9
230000002378 acidificating effect Effects 0.000 claims description 9
229910001508 alkali metal halide Inorganic materials 0.000 claims description 7
150000008045 alkali metal halides Chemical class 0.000 claims description 7
239000002168 alkylating agent Substances 0.000 claims description 7
229940100198 alkylating agent Drugs 0.000 claims description 7
229960002256 spironolactone Drugs 0.000 claims description 7
LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound 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 claims description 6
230000003301 hydrolyzing effect Effects 0.000 claims description 5
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
125000003342 alkenyl group Chemical group 0.000 claims description 4
150000001350 alkyl halides Chemical class 0.000 claims description 4
238000005979 thermal decomposition reaction Methods 0.000 claims description 4
PSAKKOKLSDIKEK-UHFFFAOYSA-N 2-chloro-2,2-difluoroacetamide Chemical group NC(=O)C(F)(F)Cl PSAKKOKLSDIKEK-UHFFFAOYSA-N 0.000 claims description 3
OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 3
125000001188 haloalkyl group Chemical group 0.000 claims description 3
RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium Chemical compound [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 claims description 3
FOBJABJCODOMEO-UHFFFAOYSA-N 2,2,3,3,4,4,4-heptafluorobutanamide Chemical compound NC(=O)C(F)(F)C(F)(F)C(F)(F)F FOBJABJCODOMEO-UHFFFAOYSA-N 0.000 claims description 2
125000000304 alkynyl group Chemical group 0.000 claims description 2
125000004966 cyanoalkyl group Chemical group 0.000 claims description 2
239000007800 oxidant agent Substances 0.000 claims description 2
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 5
230000029936 alkylation Effects 0.000 claims 4
238000005804 alkylation reaction Methods 0.000 claims 4
229920001577 copolymer Chemical group 0.000 claims 2
239000002243 precursor Substances 0.000 claims 2
238000009833 condensation Methods 0.000 claims 1
230000005494 condensation Effects 0.000 claims 1
229920006395 saturated elastomer Polymers 0.000 claims 1
230000015572 biosynthetic process Effects 0.000 abstract description 50
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 35
229960001208 eplerenone Drugs 0.000 abstract description 35
238000003786 synthesis reaction Methods 0.000 abstract description 32
125000004356 hydroxy functional group Chemical group O* 0.000 abstract 2
239000000047 product Substances 0.000 description 121
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 110
229960005057 canrenone Drugs 0.000 description 110
239000000243 solution Substances 0.000 description 100
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 99
239000002904 solvent Substances 0.000 description 99
238000000855 fermentation Methods 0.000 description 78
239000000203 mixture Substances 0.000 description 76
230000004151 fermentation Effects 0.000 description 75
239000008103 glucose Substances 0.000 description 74
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 72
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 66
230000000875 corresponding effect Effects 0.000 description 62
239000001963 growth medium Substances 0.000 description 57
239000002054 inoculum Substances 0.000 description 50
229910001868 water Inorganic materials 0.000 description 50
239000000725 suspension Substances 0.000 description 49
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
238000007792 addition Methods 0.000 description 41
238000002474 experimental method Methods 0.000 description 39
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
239000011541 reaction mixture Substances 0.000 description 36
125000005594 diketone group Chemical group 0.000 description 34
239000002609 medium Substances 0.000 description 33
235000015097 nutrients Nutrition 0.000 description 33
230000009466 transformation Effects 0.000 description 33
244000005700 microbiome Species 0.000 description 31
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
229910052783 alkali metal Inorganic materials 0.000 description 28
238000000605 extraction Methods 0.000 description 27
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
240000004808 Saccharomyces cerevisiae Species 0.000 description 23
239000007788 liquid Substances 0.000 description 23
229940041514 candida albicans extract Drugs 0.000 description 22
238000004809 thin layer chromatography Methods 0.000 description 22
239000012138 yeast extract Substances 0.000 description 22
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 21
238000001914 filtration Methods 0.000 description 21
238000005805 hydroxylation reaction Methods 0.000 description 21
XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 20
150000001721 carbon Chemical group 0.000 description 20
210000004027 cell Anatomy 0.000 description 20
150000002148 esters Chemical class 0.000 description 19
125000000457 gamma-lactone group Chemical group 0.000 description 19
239000003960 organic solvent Substances 0.000 description 19
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
238000013019 agitation Methods 0.000 description 18
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 18
230000012010 growth Effects 0.000 description 18
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 18
239000002245 particle Substances 0.000 description 18
150000002081 enamines Chemical class 0.000 description 17
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 16
239000001888 Peptone Substances 0.000 description 16
108010080698 Peptones Proteins 0.000 description 16
229960005471 androstenedione Drugs 0.000 description 16
AEMFNILZOJDQLW-UHFFFAOYSA-N androstenedione Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 AEMFNILZOJDQLW-UHFFFAOYSA-N 0.000 description 16
230000008901 benefit Effects 0.000 description 16
235000019441 ethanol Nutrition 0.000 description 16
235000019319 peptone Nutrition 0.000 description 16
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
229920001817 Agar Polymers 0.000 description 15
240000008042 Zea mays Species 0.000 description 15
235000002017 Zea mays subsp mays Nutrition 0.000 description 15
239000008272 agar Substances 0.000 description 15
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 15
239000003795 chemical substances by application Substances 0.000 description 15
239000012043 crude product Substances 0.000 description 15
ADZYJDJNIBFOQE-RGKMBJPFSA-N mexrenone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 ADZYJDJNIBFOQE-RGKMBJPFSA-N 0.000 description 15
229910052757 nitrogen Inorganic materials 0.000 description 15
230000002829 reductive effect Effects 0.000 description 15
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 14
238000005273 aeration Methods 0.000 description 14
235000005822 corn Nutrition 0.000 description 14
239000000284 extract Substances 0.000 description 14
239000012071 phase Substances 0.000 description 14
239000007787 solid Substances 0.000 description 14
230000001954 sterilising effect Effects 0.000 description 14
238000012546 transfer Methods 0.000 description 14
239000002028 Biomass Substances 0.000 description 13
238000011218 seed culture Methods 0.000 description 13
238000004659 sterilization and disinfection Methods 0.000 description 13
238000003756 stirring Methods 0.000 description 13
238000005406 washing Methods 0.000 description 13
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
150000004703 alkoxides Chemical class 0.000 description 12
230000000694 effects Effects 0.000 description 12
229910052500 inorganic mineral Inorganic materials 0.000 description 12
235000010755 mineral Nutrition 0.000 description 12
239000011707 mineral Substances 0.000 description 12
YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 12
OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 11
238000004128 high performance liquid chromatography Methods 0.000 description 11
230000033444 hydroxylation Effects 0.000 description 11
238000002156 mixing Methods 0.000 description 11
229910052698 phosphorus Inorganic materials 0.000 description 11
239000011574 phosphorus Substances 0.000 description 11
238000011084 recovery Methods 0.000 description 11
UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical compound OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 description 10
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 10
241000122824 Aspergillus ochraceus Species 0.000 description 10
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
238000004458 analytical method Methods 0.000 description 10
230000036983 biotransformation Effects 0.000 description 10
239000006227 byproduct Substances 0.000 description 10
238000011081 inoculation Methods 0.000 description 10
125000004043 oxo group Chemical group O=* 0.000 description 10
238000001556 precipitation Methods 0.000 description 10
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 9
LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 9
239000008346 aqueous phase Substances 0.000 description 9
238000004821 distillation Methods 0.000 description 9
235000019253 formic acid Nutrition 0.000 description 9
239000012535 impurity Substances 0.000 description 9
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
239000003242 anti bacterial agent Substances 0.000 description 8
229940088710 antibiotic agent Drugs 0.000 description 8
239000012984 antibiotic solution Substances 0.000 description 8
239000000872 buffer Substances 0.000 description 8
238000010790 dilution Methods 0.000 description 8
239000012895 dilution Substances 0.000 description 8
ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 8
238000003379 elimination reaction Methods 0.000 description 8
238000003306 harvesting Methods 0.000 description 8
238000011534 incubation Methods 0.000 description 8
150000002576 ketones Chemical class 0.000 description 8
241000228245 Aspergillus niger Species 0.000 description 7
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
235000019764 Soybean Meal Nutrition 0.000 description 7
229960000583 acetic acid Drugs 0.000 description 7
235000011054 acetic acid Nutrition 0.000 description 7
150000008044 alkali metal hydroxides Chemical class 0.000 description 7
238000005119 centrifugation Methods 0.000 description 7
238000004587 chromatography analysis Methods 0.000 description 7
238000002425 crystallisation Methods 0.000 description 7
230000008025 crystallization Effects 0.000 description 7
239000002274 desiccant Substances 0.000 description 7
239000013067 intermediate product Substances 0.000 description 7
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 7
239000007791 liquid phase Substances 0.000 description 7
239000002244 precipitate Substances 0.000 description 7
238000010992 reflux Methods 0.000 description 7
239000004455 soybean meal Substances 0.000 description 7
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
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
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
125000004432 carbon atom Chemical group C* 0.000 description 6
238000001816 cooling Methods 0.000 description 6
238000006704 dehydrohalogenation reaction Methods 0.000 description 6
150000004820 halides Chemical class 0.000 description 6
230000026030 halogenation Effects 0.000 description 6
238000005658 halogenation reaction Methods 0.000 description 6
LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 6
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
238000002955 isolation Methods 0.000 description 6
KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
230000014759 maintenance of location Effects 0.000 description 6
238000013411 master cell bank Methods 0.000 description 6
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
239000012074 organic phase Substances 0.000 description 6
230000001590 oxidative effect Effects 0.000 description 6
235000011007 phosphoric acid Nutrition 0.000 description 6
BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 6
230000035484 reaction time Effects 0.000 description 6
230000002441 reversible effect Effects 0.000 description 6
239000007858 starting material Substances 0.000 description 6
238000011282 treatment Methods 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
229920000858 Cyclodextrin Polymers 0.000 description 5
FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
240000005384 Rhizopus oryzae Species 0.000 description 5
235000013752 Rhizopus oryzae Nutrition 0.000 description 5
241000235546 Rhizopus stolonifer Species 0.000 description 5
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
150000007513 acids Chemical class 0.000 description 5
230000009471 action Effects 0.000 description 5
239000007795 chemical reaction product Substances 0.000 description 5
239000007810 chemical reaction solvent Substances 0.000 description 5
239000008367 deionised water Substances 0.000 description 5
229910021641 deionized water Inorganic materials 0.000 description 5
238000006073 displacement reaction Methods 0.000 description 5
238000009826 distribution Methods 0.000 description 5
238000001704 evaporation Methods 0.000 description 5
230000008020 evaporation Effects 0.000 description 5
230000002349 favourable effect Effects 0.000 description 5
239000000463 material Substances 0.000 description 5
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 5
150000002924 oxiranes Chemical class 0.000 description 5
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
239000008223 sterile water Substances 0.000 description 5
UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 5
UJVLDDZCTMKXJK-UHFFFAOYSA-N 10,13-dimethylspiro[2,8,9,11,12,14,15,16-octahydro-1h-cyclopenta[a]phenanthrene-17,5'-oxolane]-2',3-dione Chemical compound CC12CCC(C3(CCC(=O)C=C3C=C3)C)C3C1CCC21CCC(=O)O1 UJVLDDZCTMKXJK-UHFFFAOYSA-N 0.000 description 4
241001225321 Aspergillus fumigatus Species 0.000 description 4
241000894006 Bacteria Species 0.000 description 4
241000223221 Fusarium oxysporum Species 0.000 description 4
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
241000215410 Trichothecium roseum Species 0.000 description 4
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
150000008065 acid anhydrides Chemical class 0.000 description 4
239000000654 additive Substances 0.000 description 4
230000000996 additive effect Effects 0.000 description 4
239000012670 alkaline solution Substances 0.000 description 4
150000001336 alkenes Chemical class 0.000 description 4
229910000148 ammonium phosphate Inorganic materials 0.000 description 4
150000003863 ammonium salts Chemical class 0.000 description 4
239000002518 antifoaming agent Substances 0.000 description 4
239000003125 aqueous solvent Substances 0.000 description 4
229940091771 aspergillus fumigatus Drugs 0.000 description 4
230000031709 bromination Effects 0.000 description 4
238000005893 bromination reaction Methods 0.000 description 4
239000000460 chlorine Substances 0.000 description 4
MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
238000007269 dehydrobromination reaction Methods 0.000 description 4
229910000396 dipotassium phosphate Inorganic materials 0.000 description 4
239000012153 distilled water Substances 0.000 description 4
238000001035 drying Methods 0.000 description 4
239000012065 filter cake Substances 0.000 description 4
150000004676 glycans Chemical class 0.000 description 4
AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 4
229910052751 metal Inorganic materials 0.000 description 4
239000002184 metal Substances 0.000 description 4
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
239000008188 pellet Substances 0.000 description 4
229920001282 polysaccharide Polymers 0.000 description 4
239000005017 polysaccharide Substances 0.000 description 4
239000011591 potassium Substances 0.000 description 4
229910052700 potassium Inorganic materials 0.000 description 4
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
238000004007 reversed phase HPLC Methods 0.000 description 4
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 4
239000002002 slurry Substances 0.000 description 4
239000012265 solid product Substances 0.000 description 4
239000008174 sterile solution Substances 0.000 description 4
230000003637 steroidlike Effects 0.000 description 4
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 4
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
241000351920 Aspergillus nidulans Species 0.000 description 3
241000751139 Beauveria bassiana Species 0.000 description 3
241000609455 Corynespora cassiicola Species 0.000 description 3
241000010216 Cunninghamella blakesleeana Species 0.000 description 3
241000223211 Curvularia lunata Species 0.000 description 3
241001492222 Epicoccum Species 0.000 description 3
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 3
PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 3
238000005481 NMR spectroscopy Methods 0.000 description 3
241000187654 Nocardia Species 0.000 description 3
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
241001450870 Thamnostylum piriforme Species 0.000 description 3
DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 description 3
239000003463 adsorbent Substances 0.000 description 3
238000005054 agglomeration Methods 0.000 description 3
230000002776 aggregation Effects 0.000 description 3
229910000318 alkali metal phosphate Inorganic materials 0.000 description 3
229910052784 alkaline earth metal Inorganic materials 0.000 description 3
150000001413 amino acids Chemical class 0.000 description 3
239000012267 brine Substances 0.000 description 3
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
150000001732 carboxylic acid derivatives Chemical group 0.000 description 3
ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 3
229940106164 cephalexin Drugs 0.000 description 3
239000013078 crystal Substances 0.000 description 3
125000004122 cyclic group Chemical group 0.000 description 3
230000018044 dehydration Effects 0.000 description 3
238000006297 dehydration reaction Methods 0.000 description 3
238000011161 development Methods 0.000 description 3
230000018109 developmental process Effects 0.000 description 3
235000019797 dipotassium phosphate Nutrition 0.000 description 3
230000008034 disappearance Effects 0.000 description 3
125000006575 electron-withdrawing group Chemical group 0.000 description 3
230000008030 elimination Effects 0.000 description 3
230000032050 esterification Effects 0.000 description 3
238000005886 esterification reaction Methods 0.000 description 3
239000000706 filtrate Substances 0.000 description 3
238000005187 foaming Methods 0.000 description 3
230000008570 general process Effects 0.000 description 3
238000010438 heat treatment Methods 0.000 description 3
150000002373 hemiacetals Chemical class 0.000 description 3
230000006872 improvement Effects 0.000 description 3
238000011065 in-situ storage Methods 0.000 description 3
150000007529 inorganic bases Chemical class 0.000 description 3
239000006166 lysate Substances 0.000 description 3
230000007246 mechanism Effects 0.000 description 3
230000000737 periodic effect Effects 0.000 description 3
150000003013 phosphoric acid derivatives Chemical class 0.000 description 3
235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
229920000053 polysorbate 80 Polymers 0.000 description 3
230000001376 precipitating effect Effects 0.000 description 3
230000001681 protective effect Effects 0.000 description 3
238000005086 pumping Methods 0.000 description 3
238000000746 purification Methods 0.000 description 3
239000002516 radical scavenger Substances 0.000 description 3
230000008929 regeneration Effects 0.000 description 3
238000011069 regeneration method Methods 0.000 description 3
239000011347 resin Substances 0.000 description 3
229920005989 resin Polymers 0.000 description 3
239000000523 sample Substances 0.000 description 3
HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 3
239000000741 silica gel Substances 0.000 description 3
229910002027 silica gel Inorganic materials 0.000 description 3
239000001632 sodium acetate Substances 0.000 description 3
235000017281 sodium acetate Nutrition 0.000 description 3
238000000638 solvent extraction Methods 0.000 description 3
239000011877 solvent mixture Substances 0.000 description 3
238000003860 storage Methods 0.000 description 3
239000000126 substance Substances 0.000 description 3
239000004094 surface-active agent Substances 0.000 description 3
IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 3
239000012808 vapor phase Substances 0.000 description 3
YCIHPQHVWDULOY-FMZCEJRJSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O YCIHPQHVWDULOY-FMZCEJRJSA-N 0.000 description 2
ZZHNYTLKRMBVAI-NLPXPOPTSA-N (8r,9s,10r,13s,14s)-13-(hydroxymethyl)-10-methyl-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthrene-3,17-dione Chemical compound C([C@]1(CO)C(=O)CC[C@H]1[C@@H]1CC2)C[C@@H]1[C@]1(C)C2=CC(=O)CC1 ZZHNYTLKRMBVAI-NLPXPOPTSA-N 0.000 description 2
RXYPXQSKLGGKOL-UHFFFAOYSA-N 1,4-dimethylpiperazine Chemical compound CN1CCN(C)CC1 RXYPXQSKLGGKOL-UHFFFAOYSA-N 0.000 description 2
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
241000235390 Absidia glauca Species 0.000 description 2
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
239000004254 Ammonium phosphate Substances 0.000 description 2
241000134991 Aspergillus flavipes Species 0.000 description 2
241001302652 Bassiana Species 0.000 description 2
241000233866 Fungi Species 0.000 description 2
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
241000186365 Mycobacterium fortuitum Species 0.000 description 2
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
229910019142 PO4 Inorganic materials 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 2
GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
LFMFPKKYRXFHHZ-UHFFFAOYSA-N R24 Chemical compound C1=C(Cl)C(C)=CC=C1NC1=NC(N)=C(C=CC=C2)C2=N1 LFMFPKKYRXFHHZ-UHFFFAOYSA-N 0.000 description 2
241000187560 Saccharopolyspora Species 0.000 description 2
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
241000736855 Syncephalastrum racemosum Species 0.000 description 2
240000006474 Theobroma bicolor Species 0.000 description 2
MUCRYNWJQNHDJH-OADIDDRXSA-N Ursonic acid Chemical compound C1CC(=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C MUCRYNWJQNHDJH-OADIDDRXSA-N 0.000 description 2
241000082085 Verticillium <Phyllachorales> Species 0.000 description 2
239000003929 acidic solution Substances 0.000 description 2
239000002170 aldosterone antagonist Substances 0.000 description 2
229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
150000008041 alkali metal carbonates Chemical class 0.000 description 2
150000001340 alkali metals Chemical class 0.000 description 2
150000003973 alkyl amines Chemical class 0.000 description 2
125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 2
150000001412 amines Chemical class 0.000 description 2
239000000908 ammonium hydroxide Substances 0.000 description 2
235000019289 ammonium phosphates Nutrition 0.000 description 2
239000003708 ampul Substances 0.000 description 2
239000012736 aqueous medium Substances 0.000 description 2
125000000732 arylene group Chemical group 0.000 description 2
WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
238000005266 casting Methods 0.000 description 2
230000015556 catabolic process Effects 0.000 description 2
239000003518 caustics Substances 0.000 description 2
239000006285 cell suspension Substances 0.000 description 2
150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol 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)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
238000003776 cleavage reaction Methods 0.000 description 2
239000012141 concentrate Substances 0.000 description 2
230000001186 cumulative effect Effects 0.000 description 2
150000001923 cyclic compounds Chemical class 0.000 description 2
230000002354 daily effect Effects 0.000 description 2
VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 description 2
238000006731 degradation reaction Methods 0.000 description 2
238000006356 dehydrogenation reaction Methods 0.000 description 2
238000010511 deprotection reaction Methods 0.000 description 2
238000010586 diagram Methods 0.000 description 2
MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 2
239000012973 diazabicyclooctane Substances 0.000 description 2
238000007865 diluting Methods 0.000 description 2
150000002084 enol ethers Chemical class 0.000 description 2
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
239000002024 ethyl acetate extract Substances 0.000 description 2
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
230000028564 filamentous growth Effects 0.000 description 2
239000012467 final product Substances 0.000 description 2
239000010419 fine particle Substances 0.000 description 2
239000006260 foam Substances 0.000 description 2
238000004108 freeze drying Methods 0.000 description 2
239000012433 hydrogen halide Substances 0.000 description 2
229910000039 hydrogen halide Inorganic materials 0.000 description 2
238000001802 infusion Methods 0.000 description 2
229910052740 iodine Inorganic materials 0.000 description 2
239000003456 ion exchange resin Substances 0.000 description 2
229920003303 ion-exchange polymer Polymers 0.000 description 2
OOYGSFOGFJDDHP-KMCOLRRFSA-N kanamycin A sulfate Chemical compound OS(O)(=O)=O.O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N OOYGSFOGFJDDHP-KMCOLRRFSA-N 0.000 description 2
229960002064 kanamycin sulfate Drugs 0.000 description 2
239000010410 layer Substances 0.000 description 2
230000000670 limiting effect Effects 0.000 description 2
235000013372 meat Nutrition 0.000 description 2
239000002207 metabolite Substances 0.000 description 2
NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 2
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
235000019796 monopotassium phosphate Nutrition 0.000 description 2
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
150000007524 organic acids Chemical class 0.000 description 2
238000009928 pasteurization Methods 0.000 description 2
150000004965 peroxy acids Chemical class 0.000 description 2
235000021317 phosphate Nutrition 0.000 description 2
239000002798 polar solvent Substances 0.000 description 2
SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 description 2
159000000001 potassium salts Chemical class 0.000 description 2
125000006239 protecting group Chemical group 0.000 description 2
239000012429 reaction media Substances 0.000 description 2
239000012266 salt solution Substances 0.000 description 2
238000000926 separation method Methods 0.000 description 2
239000000377 silicon dioxide Substances 0.000 description 2
235000012239 silicon dioxide Nutrition 0.000 description 2
239000011734 sodium Substances 0.000 description 2
229910052708 sodium Inorganic materials 0.000 description 2
229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
235000017557 sodium bicarbonate Nutrition 0.000 description 2
229910000029 sodium carbonate Inorganic materials 0.000 description 2
239000011780 sodium chloride Substances 0.000 description 2
229910052938 sodium sulfate Inorganic materials 0.000 description 2
GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
235000011152 sodium sulphate Nutrition 0.000 description 2
239000007790 solid phase Substances 0.000 description 2
229910001220 stainless steel Inorganic materials 0.000 description 2
239000010935 stainless steel Substances 0.000 description 2
YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
229910021653 sulphate ion Inorganic materials 0.000 description 2
239000006228 supernatant Substances 0.000 description 2
230000009469 supplementation Effects 0.000 description 2
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 description 2
238000012360 testing method Methods 0.000 description 2
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
238000000844 transformation Methods 0.000 description 2
WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
230000007306 turnover Effects 0.000 description 2
230000000007 visual effect Effects 0.000 description 2
238000001238 wet grinding Methods 0.000 description 2
RJTDWMKVQUPGSY-GOAYFHFKSA-N (10r,11r,13s,17r)-11-hydroxy-10,13-dimethylspiro[2,8,9,11,12,14,15,16-octahydro-1h-cyclopenta[a]phenanthrene-17,5'-oxolane]-2',3-dione Chemical compound C([C@H](O)C[C@@]12C)([C@]3(CCC(=O)C=C3C=C3)C)C3C1CC[C@@]21CCC(=O)O1 RJTDWMKVQUPGSY-GOAYFHFKSA-N 0.000 description 1
OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 1
HJCYYXYYDSEGBB-MLJUHNDRSA-N (7R,8S,9S,10R,13R,14S,17R)-17-(2-carboxy-2-hydroxyethyl)-10,13-dimethyl-3-oxo-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthrene-7-carboxylic acid Chemical compound C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2CC(C(=O)O)O)[C@@H](CC4=CC(=O)CC[C@]34C)C(=O)O HJCYYXYYDSEGBB-MLJUHNDRSA-N 0.000 description 1
MSEZLHAVPJYYIQ-VMXHOPILSA-N (8s,9s,10r,13s,14s)-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 MSEZLHAVPJYYIQ-VMXHOPILSA-N 0.000 description 1
KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 1
SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 1
VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 1
HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
MWFMGBPGAXYFAR-UHFFFAOYSA-N 2-hydroxy-2-methylpropanenitrile Chemical compound CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 description 1
VNJOEUSYAMPBAK-UHFFFAOYSA-N 2-methylbenzenesulfonic acid;hydrate Chemical compound O.CC1=CC=CC=C1S(O)(=O)=O VNJOEUSYAMPBAK-UHFFFAOYSA-N 0.000 description 1
OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 1
KPRGOTLNGIBVFL-GINZOMEDSA-N 7-ketodehydroepiandrosterone Chemical group C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3C(=O)C=C21 KPRGOTLNGIBVFL-GINZOMEDSA-N 0.000 description 1
241000235389 Absidia Species 0.000 description 1
241000186361 Actinobacteria <class> Species 0.000 description 1
240000005007 Actinomucor elegans Species 0.000 description 1
235000013650 Actinomucor elegans Nutrition 0.000 description 1
PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
239000005695 Ammonium acetate Substances 0.000 description 1
241000892910 Aspergillus foetidus Species 0.000 description 1
241000122818 Aspergillus ustus Species 0.000 description 1
241000194107 Bacillus megaterium Species 0.000 description 1
239000004342 Benzoyl peroxide Substances 0.000 description 1
OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
101000856746 Bos taurus Cytochrome c oxidase subunit 7A1, mitochondrial Proteins 0.000 description 1
238000009631 Broth culture Methods 0.000 description 1
101100283604 Caenorhabditis elegans pigk-1 gene Proteins 0.000 description 1
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
241000577959 Calonectria Species 0.000 description 1
239000004215 Carbon black (E152) Substances 0.000 description 1
CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
206010054936 Cardiac cirrhosis Diseases 0.000 description 1
241001114511 Cephalotrichum microsporum Species 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
241000589519 Comamonas Species 0.000 description 1
241001290628 Cunninghamella echinulata Species 0.000 description 1
241000235556 Cunninghamella elegans Species 0.000 description 1
241000371652 Curvularia clavata Species 0.000 description 1
XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
102000004190 Enzymes Human genes 0.000 description 1
108090000790 Enzymes Proteins 0.000 description 1
VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
239000005977 Ethylene Substances 0.000 description 1
IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
241000223218 Fusarium Species 0.000 description 1
241000223195 Fusarium graminearum Species 0.000 description 1
241000237858 Gastropoda Species 0.000 description 1
206010019280 Heart failures Diseases 0.000 description 1
241000223198 Humicola Species 0.000 description 1
206010020772 Hypertension Diseases 0.000 description 1
241000221929 Hypomyces Species 0.000 description 1
241000221930 Hypomyces chrysospermus Species 0.000 description 1
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 description 1
241000908271 Ilyonectria destructans Species 0.000 description 1
HETCEOQFVDFGSY-UHFFFAOYSA-N Isopropenyl acetate Chemical compound CC(=C)OC(C)=O HETCEOQFVDFGSY-UHFFFAOYSA-N 0.000 description 1
239000003810 Jones reagent Substances 0.000 description 1
239000007836 KH2PO4 Substances 0.000 description 1
241001121966 Lecanicillium muscarium Species 0.000 description 1
241001305961 Lichtheimia hyalospora Species 0.000 description 1
FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
239000012359 Methanesulfonyl chloride Substances 0.000 description 1
238000006845 Michael addition reaction Methods 0.000 description 1
241000235575 Mortierella Species 0.000 description 1
102000006386 Myelin Proteins Human genes 0.000 description 1
108010083674 Myelin Proteins Proteins 0.000 description 1
HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
241001021847 Nocardia canicruria ATCC 31548 Species 0.000 description 1
ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical class OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
241000932914 Physalospora obtusa Species 0.000 description 1
241000203720 Pimelobacter simplex Species 0.000 description 1
241000305299 Pithomyces Species 0.000 description 1
241000720793 Pithomyces cynodontis Species 0.000 description 1
239000002202 Polyethylene glycol Substances 0.000 description 1
239000004743 Polypropylene Substances 0.000 description 1
229920001213 Polysorbate 20 Polymers 0.000 description 1
241000589516 Pseudomonas Species 0.000 description 1
241001303076 Pseudomonas cruciviae Species 0.000 description 1
241000305298 Pseudopithomyces atro-olivaceus Species 0.000 description 1
241000235527 Rhizopus Species 0.000 description 1
241000158504 Rhodococcus hoagii Species 0.000 description 1
241000187693 Rhodococcus rhodochrous Species 0.000 description 1
241000634742 Saccharopolyspora erythraea NRRL 2338 Species 0.000 description 1
241001279813 Sepedonium Species 0.000 description 1
239000004280 Sodium formate Substances 0.000 description 1
206010041277 Sodium retention Diseases 0.000 description 1
241001400950 Stachylidium bicolor Species 0.000 description 1
229920002472 Starch Polymers 0.000 description 1
241000187747 Streptomyces Species 0.000 description 1
241001062464 Streptomyces fradiae ATCC 10745 = DSM 40063 Species 0.000 description 1
241000187391 Streptomyces hygroscopicus Species 0.000 description 1
241000187410 Streptomyces purpurascens Species 0.000 description 1
239000004098 Tetracycline Substances 0.000 description 1
241000908169 Thamnostylum Species 0.000 description 1
241001494489 Thielavia Species 0.000 description 1
241000631893 Tieghemella Species 0.000 description 1
GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 description 1
208000035873 Ventilator-induced diaphragmatic dysfunction Diseases 0.000 description 1
241000012481 Xiha Species 0.000 description 1
235000016383 Zea mays subsp huehuetenangensis Nutrition 0.000 description 1
238000010521 absorption reaction Methods 0.000 description 1
PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
239000003377 acid catalyst Substances 0.000 description 1
239000004480 active ingredient Substances 0.000 description 1
150000001260 acyclic compounds Chemical class 0.000 description 1
150000001266 acyl halides Chemical class 0.000 description 1
230000002411 adverse Effects 0.000 description 1
230000001476 alcoholic effect Effects 0.000 description 1
229960002478 aldosterone Drugs 0.000 description 1
229940083712 aldosterone antagonist Drugs 0.000 description 1
239000003513 alkali Substances 0.000 description 1
150000001342 alkaline earth metals Chemical class 0.000 description 1
150000001351 alkyl iodides Chemical class 0.000 description 1
125000000746 allylic group Chemical group 0.000 description 1
AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
150000001408 amides Chemical class 0.000 description 1
239000004469 amino acid formulation Substances 0.000 description 1
229910021529 ammonia Inorganic materials 0.000 description 1
235000019257 ammonium acetate Nutrition 0.000 description 1
229940043376 ammonium acetate Drugs 0.000 description 1
150000001441 androstanes Chemical class 0.000 description 1
239000003957 anion exchange resin Substances 0.000 description 1
230000002280 anti-androgenic effect Effects 0.000 description 1
239000011260 aqueous acid Substances 0.000 description 1
239000006286 aqueous extract Substances 0.000 description 1
239000007864 aqueous solution Substances 0.000 description 1
239000008135 aqueous vehicle Substances 0.000 description 1
125000003118 aryl group Chemical group 0.000 description 1
125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
238000010533 azeotropic distillation Methods 0.000 description 1
JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
MVIOINXPSFUJEN-UHFFFAOYSA-N benzenesulfonic acid;hydrate Chemical compound O.OS(=O)(=O)C1=CC=CC=C1 MVIOINXPSFUJEN-UHFFFAOYSA-N 0.000 description 1
CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
235000019400 benzoyl peroxide Nutrition 0.000 description 1
150000003939 benzylamines Chemical class 0.000 description 1
LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 1
230000004071 biological effect Effects 0.000 description 1
SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
239000005388 borosilicate glass Substances 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
239000011575 calcium Substances 0.000 description 1
229910052791 calcium Inorganic materials 0.000 description 1
229940077731 carbohydrate nutrients Drugs 0.000 description 1
150000001720 carbohydrates Chemical class 0.000 description 1
235000014633 carbohydrates Nutrition 0.000 description 1
235000011089 carbon dioxide Nutrition 0.000 description 1
238000006473 carboxylation reaction Methods 0.000 description 1
150000001734 carboxylic acid salts Chemical class 0.000 description 1
150000001735 carboxylic acids Chemical class 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
239000003729 cation exchange resin Substances 0.000 description 1
150000001768 cations Chemical class 0.000 description 1
235000013339 cereals Nutrition 0.000 description 1
230000008859 change Effects 0.000 description 1
229910052801 chlorine Inorganic materials 0.000 description 1
235000012000 cholesterol Nutrition 0.000 description 1
229940107161 cholesterol Drugs 0.000 description 1
230000007882 cirrhosis Effects 0.000 description 1
238000004140 cleaning Methods 0.000 description 1
230000001010 compromised effect Effects 0.000 description 1
235000008504 concentrate Nutrition 0.000 description 1
239000006184 cosolvent Substances 0.000 description 1
239000000287 crude extract Substances 0.000 description 1
150000001916 cyano esters Chemical class 0.000 description 1
229940097362 cyclodextrins Drugs 0.000 description 1
210000000805 cytoplasm Anatomy 0.000 description 1
238000007255 decyanation reaction Methods 0.000 description 1
230000002950 deficient Effects 0.000 description 1
239000012024 dehydrating agents‎ Substances 0.000 description 1
230000005595 deprotonation Effects 0.000 description 1
238000010537 deprotonation reaction Methods 0.000 description 1
125000005265 dialkylamine group Chemical group 0.000 description 1
150000001990 dicarboxylic acid derivatives Chemical class 0.000 description 1
150000001991 dicarboxylic acids Chemical class 0.000 description 1
235000014113 dietary fatty acids Nutrition 0.000 description 1
ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
238000000132 electrospray ionisation Methods 0.000 description 1
239000003480 eluent Substances 0.000 description 1
239000000839 emulsion Substances 0.000 description 1
150000002085 enols Chemical group 0.000 description 1
238000006345 epimerization reaction Methods 0.000 description 1
125000003700 epoxy group Chemical group 0.000 description 1
125000004185 ester group Chemical group 0.000 description 1
239000012374 esterification agent Substances 0.000 description 1
CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
150000002170 ethers Chemical class 0.000 description 1
238000011156 evaluation Methods 0.000 description 1
230000003203 everyday effect Effects 0.000 description 1
230000029142 excretion Effects 0.000 description 1
239000000194 fatty acid Substances 0.000 description 1
229930195729 fatty acid Natural products 0.000 description 1
150000004665 fatty acids Chemical class 0.000 description 1
238000003818 flash chromatography Methods 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 1
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
238000013467 fragmentation Methods 0.000 description 1
238000006062 fragmentation reaction Methods 0.000 description 1
239000011521 glass Substances 0.000 description 1
239000008187 granular material Substances 0.000 description 1
230000005484 gravity Effects 0.000 description 1
229940093915 gynecological organic acid Drugs 0.000 description 1
125000005843 halogen group Chemical group 0.000 description 1
239000002815 homogeneous catalyst Substances 0.000 description 1
150000004678 hydrides Chemical class 0.000 description 1
229930195733 hydrocarbon Natural products 0.000 description 1
150000002430 hydrocarbons Chemical class 0.000 description 1
XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
238000005984 hydrogenation reaction Methods 0.000 description 1
238000007654 immersion Methods 0.000 description 1
238000009655 industrial fermentation Methods 0.000 description 1
239000011261 inert gas Substances 0.000 description 1
230000002401 inhibitory effect Effects 0.000 description 1
230000000977 initiatory effect Effects 0.000 description 1
229910017053 inorganic salt Inorganic materials 0.000 description 1
229910001867 inorganic solvent Inorganic materials 0.000 description 1
239000003049 inorganic solvent Substances 0.000 description 1
230000002452 interceptive effect Effects 0.000 description 1
INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
150000002500 ions Chemical class 0.000 description 1
229910052742 iron Inorganic materials 0.000 description 1
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 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
229960000318 kanamycin Drugs 0.000 description 1
229930027917 kanamycin Natural products 0.000 description 1
SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
229930182823 kanamycin A Natural products 0.000 description 1
239000005453 ketone based solvent Substances 0.000 description 1
WOFDVDFSGLBFAC-UHFFFAOYSA-N lactonitrile Chemical compound CC(O)C#N WOFDVDFSGLBFAC-UHFFFAOYSA-N 0.000 description 1
JORQDGTZGKHEEO-UHFFFAOYSA-N lithium cyanide Chemical compound [Li+].N#[C-] JORQDGTZGKHEEO-UHFFFAOYSA-N 0.000 description 1
210000004185 liver Anatomy 0.000 description 1
238000000464 low-speed centrifugation Methods 0.000 description 1
239000011777 magnesium Substances 0.000 description 1
229910052749 magnesium Inorganic materials 0.000 description 1
235000009973 maize Nutrition 0.000 description 1
238000005360 mashing Methods 0.000 description 1
238000004949 mass spectrometry Methods 0.000 description 1
238000005259 measurement Methods 0.000 description 1
230000001404 mediated effect Effects 0.000 description 1
125000005905 mesyloxy group Chemical group 0.000 description 1
230000004060 metabolic process Effects 0.000 description 1
229910021645 metal ion Inorganic materials 0.000 description 1
IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 1
QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
ZYDNRZOTRVTMRC-IIYDDONESA-N methyl (7r,8s,9s,10r,11r,13s,14s,17r)-11-hydroxy-10,13-dimethyl-3,5'-dioxospiro[2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthrene-17,2'-oxolane]-7-carboxylate Chemical compound C([C@@H]1[C@]2(C)C[C@@H](O)[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)C(=O)OC)C[C@@]21CCC(=O)O1 ZYDNRZOTRVTMRC-IIYDDONESA-N 0.000 description 1
230000005012 migration Effects 0.000 description 1
238000013508 migration Methods 0.000 description 1
235000013336 milk Nutrition 0.000 description 1
239000008267 milk Substances 0.000 description 1
210000004080 milk Anatomy 0.000 description 1
230000004048 modification Effects 0.000 description 1
238000012986 modification Methods 0.000 description 1
235000013379 molasses Nutrition 0.000 description 1
150000002763 monocarboxylic acids Chemical class 0.000 description 1
210000005012 myelin Anatomy 0.000 description 1
HHQJWDKIRXRTLS-UHFFFAOYSA-N n'-bromobutanediamide Chemical compound NC(=O)CCC(=O)NBr HHQJWDKIRXRTLS-UHFFFAOYSA-N 0.000 description 1
230000007935 neutral effect Effects 0.000 description 1
239000002736 nonionic surfactant Substances 0.000 description 1
238000010899 nucleation Methods 0.000 description 1
230000006911 nucleation Effects 0.000 description 1
230000035764 nutrition Effects 0.000 description 1
235000016709 nutrition Nutrition 0.000 description 1
239000003921 oil Substances 0.000 description 1
235000019198 oils Nutrition 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
239000012044 organic layer Substances 0.000 description 1
125000001477 organic nitrogen group Chemical group 0.000 description 1
238000006053 organic reaction Methods 0.000 description 1
TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
230000020477 pH reduction Effects 0.000 description 1
239000005022 packaging material Substances 0.000 description 1
230000037361 pathway Effects 0.000 description 1
238000005191 phase separation Methods 0.000 description 1
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
239000010452 phosphate Substances 0.000 description 1
PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
229920001223 polyethylene glycol Polymers 0.000 description 1
239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
229920001155 polypropylene Polymers 0.000 description 1
239000011148 porous material Substances 0.000 description 1
239000013641 positive control Substances 0.000 description 1
235000011056 potassium acetate Nutrition 0.000 description 1
XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
229910000027 potassium carbonate Inorganic materials 0.000 description 1
GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
239000003286 potassium sparing diuretic agent Substances 0.000 description 1
229940097241 potassium-sparing diuretic Drugs 0.000 description 1
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
102000004196 processed proteins & peptides Human genes 0.000 description 1
108090000765 processed proteins & peptides Proteins 0.000 description 1
238000012545 processing Methods 0.000 description 1
229940002612 prodrug Drugs 0.000 description 1
239000000651 prodrug Substances 0.000 description 1
239000013587 production medium Substances 0.000 description 1
230000000750 progressive effect Effects 0.000 description 1
230000000644 propagated effect Effects 0.000 description 1
230000001902 propagating effect Effects 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
102000004169 proteins and genes Human genes 0.000 description 1
108090000623 proteins and genes Proteins 0.000 description 1
238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
230000005588 protonation Effects 0.000 description 1
239000012264 purified product Substances 0.000 description 1
HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
230000006340 racemization Effects 0.000 description 1
150000003254 radicals Chemical class 0.000 description 1
238000001953 recrystallisation Methods 0.000 description 1
230000001105 regulatory effect Effects 0.000 description 1
238000011160 research Methods 0.000 description 1
230000004044 response Effects 0.000 description 1
230000000717 retained effect Effects 0.000 description 1
102220104593 rs879254294 Human genes 0.000 description 1
239000012488 sample solution Substances 0.000 description 1
238000005070 sampling Methods 0.000 description 1
238000013341 scale-up Methods 0.000 description 1
230000007017 scission Effects 0.000 description 1
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
230000035040 seed growth Effects 0.000 description 1
238000010956 selective crystallization Methods 0.000 description 1
238000010898 silica gel chromatography Methods 0.000 description 1
229950005143 sitosterol Drugs 0.000 description 1
MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
235000019254 sodium formate Nutrition 0.000 description 1
159000000000 sodium salts Chemical class 0.000 description 1
235000010265 sodium sulphite Nutrition 0.000 description 1
238000001179 sorption measurement Methods 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000008107 starch Substances 0.000 description 1
230000000707 stereoselective effect Effects 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
238000006277 sulfonation reaction Methods 0.000 description 1
BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
239000013589 supplement Substances 0.000 description 1
230000000153 supplemental effect Effects 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
230000008685 targeting Effects 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
229960002180 tetracycline Drugs 0.000 description 1
229930101283 tetracycline Natural products 0.000 description 1
235000019364 tetracycline Nutrition 0.000 description 1
150000003522 tetracyclines Chemical class 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
239000011573 trace mineral Substances 0.000 description 1
235000013619 trace mineral Nutrition 0.000 description 1
230000001052 transient effect Effects 0.000 description 1
229910052723 transition metal Inorganic materials 0.000 description 1
150000003624 transition metals Chemical class 0.000 description 1
ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
125000005270 trialkylamine group Chemical group 0.000 description 1
GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
125000004953 trihalomethyl group Chemical group 0.000 description 1
238000001665 trituration Methods 0.000 description 1
238000000870 ultraviolet spectroscopy Methods 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
229940088594 vitamin Drugs 0.000 description 1
235000013343 vitamin Nutrition 0.000 description 1
239000011782 vitamin Substances 0.000 description 1
229930003231 vitamin Natural products 0.000 description 1
239000003643 water by type Substances 0.000 description 1

Classifications

- 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
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
- C07D301/12—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with hydrogen peroxide or inorganic peroxides or peracids
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
- 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
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
- 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
- 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
- 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

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
General Health & Medical Sciences (AREA)
Wood Science & Technology (AREA)
Life Sciences & Earth Sciences (AREA)
Engineering & Computer Science (AREA)
Zoology (AREA)
General Engineering & Computer Science (AREA)
Microbiology (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Biochemistry (AREA)
Bioinformatics & Cheminformatics (AREA)
Biotechnology (AREA)
Genetics & Genomics (AREA)
Toxicology (AREA)
Inorganic Chemistry (AREA)
Steroid Compounds (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Saccharide Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Epoxy Compounds (AREA)
Catalysts (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)
Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

NO19992825A 1996-12-11 1999-06-10 Fremgangsmåter for fremstilling av 9,11-epoksysteroider og mellomproduktertil bruk ved fremgangsmåtene NO314149B1 (no)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US3331596P	1996-12-11	1996-12-11
US4938897P	1997-06-11	1997-06-11
PCT/US1997/023090 WO1998025948A2 (en)	1996-12-11	1997-12-11	Processes for preparation of 9,11-epoxy steroids and intermediates useful therein

Publications (3)

Publication Number	Publication Date
NO992825D0 NO992825D0 (no)	1999-06-10
NO992825L NO992825L (no)	1999-07-29
NO314149B1 true NO314149B1 (no)	2003-02-03

Family

ID=26709541

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
NO19992825A NO314149B1 (no)	1996-12-11	1999-06-10	Fremgangsmåter for fremstilling av 9,11-epoksysteroider og mellomproduktertil bruk ved fremgangsmåtene

Country Status (21)

Country	Link
US (1)	US6610844B2 (de)
EP (1)	EP0944644B1 (de)
JP (1)	JP2001509792A (de)
KR (1)	KR100523409B1 (de)
CN (1)	CN100369927C (de)
AT (2)	ATE225367T1 (de)
AU (1)	AU733559B2 (de)
BR (1)	BR9714510A (de)
CA (1)	CA2273343C (de)
DE (2)	DE69738225T2 (de)
DK (1)	DK0944644T3 (de)
ES (2)	ES2293944T3 (de)
HK (1)	HK1043370B (de)
IL (1)	IL130182A0 (de)
NO (1)	NO314149B1 (de)
NZ (1)	NZ336004A (de)
PL (1)	PL189459B1 (de)
PT (1)	PT944644E (de)
RO (1)	RO120710B1 (de)
RU (1)	RU2005121439A (de)
WO (1)	WO1998025948A2 (de)

Families Citing this family (34)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
UA74141C2 (uk)	1998-12-09	2005-11-15	Дж.Д. Сірл Енд Ко.	Фармацевтична композиція на основі тонкоподрібненого еплеренону (варіанти), спосіб її одержання та спосіб лікування розладів, опосередкованих альдостероном (варіанти)
EP1505072A3 (de) *	1999-12-08	2006-06-21	Pharmacia Corporation	Kristalline Form von Eplerenon mit verbesserter Lösegeschwindigkeit
JP2003516414A (ja) *	1999-12-08	2003-05-13	ファルマシアコーポレイション	より高い溶解速度を示すエプレレノン結晶形
EA008449B1 (ru) *	1999-12-08	2007-06-29	Фармация Корпорейшн	Кристаллическая форма эплеренона
EP1580193A3 (de) *	1999-12-08	2010-06-23	Pharmacia Corporation	Kristalline Form von Eplerenon
US6716829B2 (en)	2000-07-27	2004-04-06	Pharmacia Corporation	Aldosterone antagonist and cyclooxygenase-2 inhibitor combination therapy to prevent or treat inflammation-related cardiovascular disorders
DK1313485T3 (da) *	2000-08-28	2005-12-27	Pharmacia Corp	Anvendelse af en aldosteronreceptorantagonist til forbedring af kognitiv funktion
AU2002241768A1 (en)	2000-10-30	2002-06-18	Pharmacia Corporation	Aspergillus ochraceus 11 alpha hydroxylase and oxidoreductase
US7235655B2 (en)	2002-03-22	2007-06-26	Pharmacia & Upjohn Company	Processes to prepare eplerenone
EP1490390A2 (de) *	2002-03-22	2004-12-29	Pharmacia Corporation	C-17-spirolactonisierung und 6,7-oxidation von steroiden
AU2003213807A1 (en)	2002-11-06	2004-06-03	Pharmacia & Upjohn Company Llc	Processes for preparing 7-carboxy substituted steroids
TWI280133B (en) *	2002-11-07	2007-05-01	Upjohn Co	Process for preparing C-7 substituted steroids
CL2004000574A1 (es) *	2003-03-21	2005-02-11	Pharmacia Corp Sa Organizada B	Proceso para preparar un compuesto 17-espirolactona o la sal de lactona abierta por carbonilacion del correspondiente 17-alquenil o alquinil derivado, los intermediarios que se usan y su proceso de obtencion.
US7781421B2 (en) *	2003-05-29	2010-08-24	Washington University	Neuroactive 13, 24-cyclo-18, 21-dinorcholanes and structurally related pentacyclic steriods
CN1934126A (zh) *	2004-03-22	2007-03-21	法玛西雅厄普约翰有限责任公司	9,11环氧甾族化合物的改进制备方法
ATE534876T1 (de) *	2004-09-21	2011-12-15	Iglesias Vives Joan	Verfahren und maschine zum sintern und/oder trocknen von pulvermaterialien unter verwendung von infrarotstrahlung
CA2525205C (en) *	2004-11-08	2013-06-25	Ecolab Inc.	Foam cleaning and brightening composition, and methods
HUP0402466A2 (en) *	2004-11-30	2006-07-28	Richter Gedeon Vegyeszet	Industrial process for preparing 17-hydroxy-6-betha, 7-betha, 15-betha, 16-betha-bis-methylene-3-oxo-17-alpha-pregn-4-ene-21-carboxylic acid gamma lacton and the main, intermediates of the process
CN1321128C (zh) *	2005-07-15	2007-06-13	浙江医药股份有限公司新昌制药厂	孕甾－4－烯－7，21－二甲酸，9，11－环氧－17－羟基－3－氧代，γ－内酯，甲酯，(7α,11α,17α)－的制备方法
EP2367808A4 (de) *	2008-11-25	2012-05-09	Evestra Inc	PROGESTATIVE 3-(6,6-ETHYLEN-17b-HYDROXY-3-OXO-17a-PREGNA-4-EN-17a-YL) PROPIONSÄURE-g-LACTONE
ES2641144T3 (es)	2010-05-10	2017-11-07	Inserm (Institut National De La Santé Et De La Recherche Medicale)	Métodos y composiciones para el tratamiento de la acumulación de líquido en y/o bajo la retina
US9241944B2 (en)	2010-06-16	2016-01-26	Institut National De La Santé Et De La Recherche Médicale (Inserm)	Methods and compositions for stimulating reepithelialisation during wound healing
CN104844681B (zh) *	2014-02-13	2016-06-01	合肥久诺医药科技有限公司	一种l晶型依普利酮的精制方法
EP3009443B1 (de)	2014-10-17	2018-09-12	INDUSTRIALE CHIMICA S.r.l.	Verfahren zur herstellung von 7alfa-(methoxycarbonyl)-3-oxo-17alfa-pregn-4,9(11)-dien-21,17-carbolacton, nützliches zwischenprodukt zur synthese von molekülen mit pharmakologischer wirkung
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
US20180280414A1 (en)	2015-10-13	2018-10-04	Inserm (Institut National De La Sante Et De La Recherche Medicale)	Methods and pharmaceutical compositions for the treatment of choroidal neovascularisation
CN105541960A (zh) *	2016-02-22	2016-05-04	浙江仙琚制药股份有限公司	17α-羟基-3-氧代-γ-内酯-孕甾-4-烯-（7α，9α）-二羧酸内酯的制备方法
WO2018019843A1 (en)	2016-07-26	2018-02-01	INSERM (Institut National de la Santé et de la Recherche Médicale)	Antagonist of mineralocorticoid receptor for the treatment of osteoarthritis
CN106349326A (zh) *	2016-07-29	2017-01-25	北京万全德众医药生物技术有限公司	依普利酮杂质a的制备方法
CN107602652A (zh) *	2017-10-11	2018-01-19	浙江仙琚制药股份有限公司	制备6β‑甲基泼尼松龙的方法
CN108445236B (zh) *	2018-02-07	2021-04-20	深圳市新产业生物医学工程股份有限公司	甾体类衍生物和其保存液以及其应用
CN110698529A (zh) *	2019-11-19	2020-01-17	湖南新合新生物医药有限公司	一种依普利酮中间体△9,11烯酯的制备方法
WO2023031277A1 (en)	2021-08-31	2023-03-09	INSERM (Institut National de la Santé et de la Recherche Médicale)	Methods for the treatment of ocular rosacea
CN115433252A (zh) *	2022-08-24	2022-12-06	浙江亚瑟医药有限公司	一种δ9(11)-坎利酮的制备方法

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US3053856A (en) *	1958-10-29	1962-09-11	Shell Oil Co	Epoxidation of ethylenic compounds with peroxycarboximidic acids
US3200113A (en)	1963-01-09	1965-08-10	Sterling Drug Inc	7-cyano steroids and derivatives thereof
US3300489A (en)	1964-07-24	1967-01-24	Smith Kline French Lab	Steroidal c-17 spirolactones and processes and intermediates used in the preparation thereof
US3413288A (en)	1965-07-07	1968-11-26	Parke Davis & Co	Process for the production of steroidal c-17 spirolactones
US3759791A (en)	1970-12-10	1973-09-18	Searle & Co	Selective microbiological preparation of androst-4-ene-3,17-dione
FR2216273B1 (de)	1973-02-06	1977-07-22	Roussel Uclaf
DE2404948C2 (de) *	1973-02-06	1983-04-14	Roussel-Uclaf, 75007 Paris	7α-Acylthio-Steroidspirolactonderivate
GB1455220A (de) *	1973-09-14	1976-11-10	Searle & Co
DE2349022A1 (de)	1973-09-26	1975-04-10	Schering Ag	Neue d-homo-steroide
FR2260569B1 (de)	1974-02-08	1978-06-16	Ugine Kuhlmann
CH631462A5 (de)	1976-03-05	1982-08-13	Schering Ag	Verfahren zur herstellung von neuen steroiden der androstan- oder oestranreihe.
YU41412B (en)	1978-08-15	1987-04-30	Gist Brocades Nv	Process for obtaining 17 beta-hydroxy -3-dxo-17 alpha-pregn-4-en-21-carboxylic acid
US4270994A (en)	1980-02-20	1981-06-02	G. D. Searle & Co.	Electrochemical dehydrogenation of steroidal Δ3,5 enol ethers under basic conditions to provide steroidal Δ4,6 dienones
JPS58179498A (ja) *	1982-04-13	1983-10-20	Dainippon Ink & Chem Inc	微生物による１１α−ヒドロキシル化アンドロスタン系化合物の製造方法
US4559332A (en) *	1983-04-13	1985-12-17	Ciba Geigy Corporation	20-Spiroxanes and analogues having an open ring E, processes for their manufacture, and pharmaceutical preparations thereof
EP0123734A1 (de)	1983-04-29	1984-11-07	Gist-Brocades N.V.	17-(Isocyano-sulfonylmethylen)-Steroide, 17-(Formamido-sulfonylmethylen)-Steroide und ihre Herstellung
US4670551A (en) *	1984-06-21	1987-06-02	Ciba-Geigy Corporation	Epoxy steroids
NZ222103A (en)	1986-10-10	1990-08-28	Gist Brocades Nv	9-alpha-hydroxy steroids and pharmaceutical preparations containing them
US5502222A (en)	1994-06-01	1996-03-26	Schering Corporation	Process for preparing delta 9,11 and 21-chloro corticosteroids
CN100384866C (zh) *	1995-12-11	2008-04-30	G·D·瑟尔公司	制备7α-羧基9,11-环氧甾族化合物的方法和其中使用的中间体以及烯双键环氧化作用的一般方法

1997
- 1997-12-11 PT PT97954126T patent/PT944644E/pt unknown
- 1997-12-11 EP EP97954126A patent/EP0944644B1/de not_active Expired - Lifetime
- 1997-12-11 NZ NZ336004A patent/NZ336004A/en unknown
- 1997-12-11 KR KR10-2004-7021389A patent/KR100523409B1/ko not_active Expired - Fee Related
- 1997-12-11 ES ES01111209T patent/ES2293944T3/es not_active Expired - Lifetime
- 1997-12-11 AT AT97954126T patent/ATE225367T1/de not_active IP Right Cessation
- 1997-12-11 DE DE69738225T patent/DE69738225T2/de not_active Expired - Fee Related
- 1997-12-11 AU AU57983/98A patent/AU733559B2/en not_active Ceased
- 1997-12-11 WO PCT/US1997/023090 patent/WO1998025948A2/en not_active Ceased
- 1997-12-11 CN CNB971817375A patent/CN100369927C/zh not_active Expired - Fee Related
- 1997-12-11 ES ES97954126T patent/ES2186017T3/es not_active Expired - Lifetime
- 1997-12-11 DE DE69716116T patent/DE69716116T2/de not_active Expired - Fee Related
- 1997-12-11 CA CA002273343A patent/CA2273343C/en not_active Expired - Fee Related
- 1997-12-11 JP JP52703298A patent/JP2001509792A/ja not_active Ceased
- 1997-12-11 BR BR9714510-6A patent/BR9714510A/pt not_active Application Discontinuation
- 1997-12-11 DK DK97954126T patent/DK0944644T3/da active
- 1997-12-11 PL PL97334084A patent/PL189459B1/pl not_active IP Right Cessation
- 1997-12-11 RO RO99-00668A patent/RO120710B1/ro unknown
- 1997-12-11 AT AT01111209T patent/ATE375992T1/de not_active IP Right Cessation
- 1997-12-11 IL IL13018297A patent/IL130182A0/xx not_active IP Right Cessation
1999
- 1999-06-10 NO NO19992825A patent/NO314149B1/no not_active IP Right Cessation
2002
- 2002-03-29 US US10/112,355 patent/US6610844B2/en not_active Expired - Fee Related
- 2002-04-24 HK HK02103077.8A patent/HK1043370B/en not_active IP Right Cessation
2005
- 2005-07-07 RU RU2005121439/04A patent/RU2005121439A/ru not_active Application Discontinuation

Also Published As

Publication number	Publication date
RU2005121439A (ru)	2007-01-20
US6610844B2 (en)	2003-08-26
AU733559B2 (en)	2001-05-17
WO1998025948A3 (en)	1998-10-15
DK0944644T3 (da)	2003-02-03
NO992825L (no)	1999-07-29
EP0944644A2 (de)	1999-09-29
PT944644E (pt)	2003-02-28
DE69716116T2 (de)	2003-09-04
RO120710B1 (ro)	2006-06-30
ATE375992T1 (de)	2007-11-15
CN100369927C (zh)	2008-02-20
CA2273343A1 (en)	1998-06-18
JP2001509792A (ja)	2001-07-24
ES2186017T3 (es)	2003-05-01
DE69738225T2 (de)	2008-07-17
ES2293944T3 (es)	2008-04-01
KR100523409B1 (ko)	2005-10-24
PL334084A1 (en)	2000-01-31
HK1043370A1 (en)	2002-09-13
NO992825D0 (no)	1999-06-10
EP0944644B1 (de)	2002-10-02
PL189459B1 (pl)	2005-08-31
NZ336004A (en)	2001-04-27
ATE225367T1 (de)	2002-10-15
AU5798398A (en)	1998-07-03
KR20050009765A (ko)	2005-01-25
WO1998025948A2 (en)	1998-06-18
HK1043370B (en)	2008-08-01
CN1253564A (zh)	2000-05-17
US20030055274A1 (en)	2003-03-20
DE69738225D1 (de)	2007-11-29
DE69716116D1 (de)	2002-11-07
IL130182A0 (en)	2000-06-01
CA2273343C (en)	2006-10-10
BR9714510A (pt)	2000-11-28

Legal Events

Date	Code	Title	Description
2010-07-19	MM1K	Lapsed by not paying the annual fees

Publication	Publication Date	Title
AU733559B2 (en)	2001-05-17	Processes for preparation of 9,11-epoxy steroids and intermediates useful therein
US6331622B1 (en)	2001-12-18	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
US6887991B1 (en)	2005-05-03	Processes for preparation of 9, 11-epoxy steroids and intermediates useful therein
EP1148061A2 (de)	2001-10-24	Verfahren zur Herstellung von 9,11-Epoxysteroid Verbindungen und Zwischenprodukte dieses Verfahrens
EP1170299A2 (de)	2002-01-09	Zwischenprodukte zur Herstellung von 9,11-Epoxysteroiden und Verfahren zu ihrer Herstellung
RU2261865C2 (ru)	2005-10-10	СПОСОБ ПОЛУЧЕНИЯ 3-КЕТО-7α-АЛКОКСИКАРБОНИЛЗАМЕЩЕННОГО Δ4,5-СТЕРОИДА, СПОСОБЫ ПОЛУЧЕНИЯ ПРОМЕЖУТОЧНЫХ СОЕДИНЕНИЙ, ПРОМЕЖУТОЧНЫЕ СОЕДИНЕНИЯ
AU1355197A (en)	1997-07-03	Process for preparation of 7 alpha-carboxyl 9, 11-epoxy steroids and intermediates useful therein
KR100506007B1 (ko)	2005-08-04	9,11-에폭시 스테로이드의 제조방법 및 이 제조방법에 유용한 중간체
AU744223B2 (en)	2002-02-21	Process for the epoxidation of olefinic double bonds
AU747959B2 (en)	2002-05-30	Processes and intermediates for the preparation of 9, 11-epoxy steroids
CA2550659A1 (en)	1998-06-18	Processes for preparation of 9,11-epoxy steroids and intermediates useful therein