CA2550659A1 - Procedes de production de 9,11-epoxy steroides et intermediaires appropries a cet effet - Google Patents

Procedes de production de 9,11-epoxy steroides et intermediaires appropries a cet effet Download PDF

Info

Publication number: CA2550659A1
Authority: CA; Canada
Prior art keywords: formula; group; compound; hydroxy; hydrogen
Prior art date: 1996-12-11
Legal status (The legal status 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 status listed.): Abandoned

Application number

CA002550659A

Other languages

English (en)

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

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

GD Searle LLC

Original Assignee

Individual

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

1997-12-11

Publication date

1998-06-18

1997-12-11 Application filed by Individual filed Critical Individual

1997-12-11 Priority claimed from CA002273343A external-priority patent/CA2273343C/fr

1998-06-18 Publication of CA2550659A1 publication Critical patent/CA2550659A1/fr

Status Abandoned legal-status Critical Current

Links

238000000034 method Methods 0.000 title abstract description 184
239000000543 intermediate Substances 0.000 title abstract description 104
230000008569 process Effects 0.000 title description 135
238000002360 preparation method Methods 0.000 title description 65
150000003431 steroids Chemical class 0.000 title description 31
239000004593 Epoxy Substances 0.000 title description 8
150000001875 compounds Chemical class 0.000 claims abstract description 517
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 163
239000001257 hydrogen Substances 0.000 claims abstract description 161
125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 102
125000000217 alkyl group Chemical group 0.000 claims abstract description 78
125000003545 alkoxy group Chemical group 0.000 claims abstract description 63
125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 45
125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 39
125000004104 aryloxy group Chemical group 0.000 claims abstract description 39
125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 38
125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 37
125000001475 halogen functional group Chemical group 0.000 claims abstract description 32
ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims abstract description 32
125000000623 heterocyclic group Chemical group 0.000 claims abstract description 27
125000005041 acyloxyalkyl group Chemical group 0.000 claims abstract description 26
125000002837 carbocyclic group Chemical group 0.000 claims abstract description 26
125000002252 acyl group Chemical group 0.000 claims abstract description 25
125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract 47
-1 hydroxycarbonylalkyl Chemical group 0.000 claims description 114
229910052760 oxygen Inorganic materials 0.000 claims description 35
239000001301 oxygen Substances 0.000 claims description 34
150000003839 salts Chemical class 0.000 claims description 22
125000004423 acyloxy group Chemical group 0.000 claims description 15
125000003118 aryl group Chemical group 0.000 claims description 2
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238000006243 chemical reaction Methods 0.000 abstract description 296
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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 38
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OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 117
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YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 106
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IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 50
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125000005594 diketone group Chemical group 0.000 description 39
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229940041514 candida albicans extract Drugs 0.000 description 37
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239000012138 yeast extract Substances 0.000 description 37
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150000002431 hydrogen Chemical class 0.000 description 34
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239000002585 base Substances 0.000 description 29
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239000001888 Peptone Substances 0.000 description 27
108010080698 Peptones Proteins 0.000 description 27
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
235000019319 peptone Nutrition 0.000 description 27
230000001954 sterilising effect Effects 0.000 description 27
238000006735 epoxidation reaction Methods 0.000 description 26
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229910052757 nitrogen Inorganic materials 0.000 description 25
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
238000004128 high performance liquid chromatography Methods 0.000 description 24
125000002887 hydroxy group Chemical group [H]O* 0.000 description 24
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 23
150000002081 enamines Chemical class 0.000 description 23
238000001914 filtration Methods 0.000 description 23
230000012010 growth Effects 0.000 description 23
238000005805 hydroxylation reaction Methods 0.000 description 23
229910052698 phosphorus Inorganic materials 0.000 description 23
XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 22
125000005843 halogen group Chemical group 0.000 description 22
YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 22
239000008367 deionised water Substances 0.000 description 21
229910021641 deionized water Inorganic materials 0.000 description 21
125000000468 ketone group Chemical group 0.000 description 21
229930194542 Keto Natural products 0.000 description 20
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 20
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 20
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125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 20
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239000002245 particle Substances 0.000 description 20
238000003756 stirring Methods 0.000 description 20
229920001817 Agar Polymers 0.000 description 19
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 19
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
239000008272 agar Substances 0.000 description 19
210000004027 cell Anatomy 0.000 description 19
230000007062 hydrolysis Effects 0.000 description 19
238000006460 hydrolysis reaction Methods 0.000 description 19
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
239000012071 phase Substances 0.000 description 19
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 18
238000004821 distillation Methods 0.000 description 18
239000002054 inoculum Substances 0.000 description 18
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 18
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
240000008042 Zea mays Species 0.000 description 17
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150000002596 lactones Chemical class 0.000 description 13
238000012546 transfer Methods 0.000 description 13
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 12
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 12
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UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical compound OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 description 10
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238000005481 NMR spectroscopy Methods 0.000 description 10
MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 10
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238000004458 analytical method Methods 0.000 description 10
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VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
235000011054 acetic acid Nutrition 0.000 description 9
239000000654 additive Substances 0.000 description 9
LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 9
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241000235389 Absidia Species 0.000 description 8
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NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
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241000215410 Trichothecium roseum Species 0.000 description 8
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
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ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 8
238000010438 heat treatment Methods 0.000 description 8
238000011534 incubation Methods 0.000 description 8
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FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 7
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
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DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 description 7
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HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
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125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 5
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WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 description 5
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229920001223 polyethylene glycol Polymers 0.000 description 1
239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
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229920001155 polypropylene Polymers 0.000 description 1
239000011148 porous material Substances 0.000 description 1
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229910000027 potassium carbonate Inorganic materials 0.000 description 1
FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 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
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KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
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
238000004611 spectroscopical analysis Methods 0.000 description 1
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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
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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
238000006467 substitution reaction Methods 0.000 description 1
229910052717 sulfur Inorganic materials 0.000 description 1
239000013589 supplement Substances 0.000 description 1
DGQOCLATAPFASR-UHFFFAOYSA-N tetrahydroxy-1,4-benzoquinone Chemical compound OC1=C(O)C(=O)C(O)=C(O)C1=O DGQOCLATAPFASR-UHFFFAOYSA-N 0.000 description 1
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
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
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
235000015112 vegetable and seed oil Nutrition 0.000 description 1
239000008158 vegetable oil Substances 0.000 description 1
235000013343 vitamin Nutrition 0.000 description 1
239000011782 vitamin Substances 0.000 description 1
229940088594 vitamin Drugs 0.000 description 1
229930003231 vitamin Natural products 0.000 description 1

Landscapes

Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)

CA002550659A 1996-12-11 1997-12-11 Procedes de production de 9,11-epoxy steroides et intermediaires appropries a cet effet Abandoned CA2550659A1 (fr)

Applications Claiming Priority (5)

Application Number	Priority Date	Filing Date	Title
US3331596P	1996-12-11	1996-12-11
US60/033,315		1996-12-11
US4938897P	1997-06-11	1997-06-11
US60/049,388		1997-06-11
CA002273343A CA2273343C (fr)	1996-12-11	1997-12-11	Procedes de production de 9,11-epoxy steroides et intermediaires appropries a cet effet

Related Parent Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002273343A Division CA2273343C (fr)	1996-12-11	1997-12-11	Procedes de production de 9,11-epoxy steroides et intermediaires appropries a cet effet

Publications (1)

Publication Number	Publication Date
CA2550659A1 true CA2550659A1 (fr)	1998-06-18

Family

ID=36955355

Family Applications (2)

Application Number	Title	Priority Date	Filing Date
CA002550897A Abandoned CA2550897A1 (fr)	1996-12-11	1997-12-11	Methodes de preparation de 9,11-epoxysteroides et intermediaires connexes
CA002550659A Abandoned CA2550659A1 (fr)	1996-12-11	1997-12-11	Procedes de production de 9,11-epoxy steroides et intermediaires appropries a cet effet

Family Applications Before (1)

Application Number	Title	Priority Date	Filing Date
CA002550897A Abandoned CA2550897A1 (fr)	1996-12-11	1997-12-11	Methodes de preparation de 9,11-epoxysteroides et intermediaires connexes

Country Status (1)

Country	Link
CA (2)	CA2550897A1 (fr)

1997
- 1997-12-11 CA CA002550897A patent/CA2550897A1/fr not_active Abandoned
- 1997-12-11 CA CA002550659A patent/CA2550659A1/fr not_active Abandoned

Also Published As

Publication number	Publication date
CA2550897A1 (fr)	1998-06-18

Publication	Publication Date	Title
CA2273343C (fr)	2006-10-10	Procedes de production de 9,11-epoxy steroides et intermediaires appropries a cet effet
CN100384866C (zh)	2008-04-30	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
WO1998025948A9 (fr)	1998-11-19	Procedes de production de 9,11-epoxy steroides et intermediaires appropries a cet effet
US7112669B2 (en)	2006-09-26	Processes for preparation of 9,11-epoxy steroids and intermediates useful therein
EP1148061B1 (fr)	2007-10-17	Procédé d'époxydation
EP1170299A2 (fr)	2002-01-09	Produits intermédiares pour la production des steroides 9,11-époxy et un procédépour leur production
CA2347345C (fr)	2007-05-15	Procedes de preparation de steroides 7 alpha-carboxylyl9,11-epoxy et intermediaires utiles dans ces procedes et procede general d'epoxydation de liaisons olefiniques doubles
CA2550659A1 (fr)	1998-06-18	Procedes de production de 9,11-epoxy steroides et intermediaires appropries a cet effet
KR100506007B1 (ko)	2005-08-04	9,11-에폭시 스테로이드의 제조방법 및 이 제조방법에 유용한 중간체
AU2002300873B2 (en)	2005-04-14	Processes for preparation of 9, 11-epoxy steriods and intermediates useful therein
AU744223B2 (en)	2002-02-21	Process for the epoxidation of olefinic double bonds
CA2553378A1 (fr)	1997-06-19	Procedes de preparation de steroides 7.alpha.-carboxylyl9,11-epoxy et intermediaires utiles dans ces procedes et procede general d'epoxydation de liaisons olefiniques doubles

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