KR100473297B1 - 드로스피레논의 제조 방법, 및 17α-(3-히드록시-1-프로필)-6β,7β；15β,16β-디메틸렌-5β-안드로스탄-3β,5,17β-트리올 및 6β,7β；15β,16β-디메틸렌-5β-히드록시-3-옥소-17α-안드로스탄-21,17-카르보락톤 - Google Patents
드로스피레논의 제조 방법, 및 17α-(3-히드록시-1-프로필)-6β,7β；15β,16β-디메틸렌-5β-안드로스탄-3β,5,17β-트리올 및 6β,7β；15β,16β-디메틸렌-5β-히드록시-3-옥소-17α-안드로스탄-21,17-카르보락톤 Download PDFInfo
- Publication number
- KR100473297B1 KR100473297B1 KR10-1999-7001166A KR19997001166A KR100473297B1 KR 100473297 B1 KR100473297 B1 KR 100473297B1 KR 19997001166 A KR19997001166 A KR 19997001166A KR 100473297 B1 KR100473297 B1 KR 100473297B1
- Authority
- KR
- South Korea
- Prior art keywords
- dimethylene
- hydroxy
- oxo
- carbolactone
- androstan
- Prior art date
Links
- METQSPRSQINEEU-UHFFFAOYSA-N dihydrospirorenone Natural products CC12CCC(C3(CCC(=O)C=C3C3CC33)C)C3C1C1CC1C21CCC(=O)O1 METQSPRSQINEEU-UHFFFAOYSA-N 0.000 title claims abstract description 23
- METQSPRSQINEEU-HXCATZOESA-N drospirenone Chemical compound C([C@]12[C@H]3C[C@H]3[C@H]3[C@H]4[C@@H]([C@]5(CCC(=O)C=C5[C@@H]5C[C@@H]54)C)CC[C@@]31C)CC(=O)O2 METQSPRSQINEEU-HXCATZOESA-N 0.000 title claims abstract description 15
- 229960004845 drospirenone Drugs 0.000 title claims abstract description 13
- METQSPRSQINEEU-OLKMEILKSA-N drospirenone Chemical compound C([C@]12[C@H]3C[C@H]3C3C4[C@@H]([C@]5(CCC(=O)C=C5[C@@H]5C[C@@H]54)C)CC[C@@]31C)CC(=O)O2 METQSPRSQINEEU-OLKMEILKSA-N 0.000 title claims abstract description 10
- 101000605827 Homo sapiens Pinin Proteins 0.000 title claims abstract 3
- 102100038374 Pinin Human genes 0.000 title claims abstract 3
- 238000000034 method Methods 0.000 title abstract description 12
- 230000008569 process Effects 0.000 title abstract description 8
- -1 3-hydroxy-1-propyl Chemical group 0.000 claims abstract description 16
- 239000002253 acid Substances 0.000 claims description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 150000003303 ruthenium Chemical class 0.000 claims description 2
- 239000000356 contaminant Substances 0.000 claims 1
- 230000018044 dehydration Effects 0.000 claims 1
- 238000006297 dehydration reaction Methods 0.000 claims 1
- 230000001590 oxidative effect Effects 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 7
- 239000013067 intermediate product Substances 0.000 abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- GXGJIOMUZAGVEH-UHFFFAOYSA-N Chamazulene Chemical group CCC1=CC=C(C)C2=CC=C(C)C2=C1 GXGJIOMUZAGVEH-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001845 chromium compounds Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 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
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- 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
- C07J53/004—3 membered carbocyclic rings
- C07J53/007—3 membered carbocyclic rings in position 6-7
-
- 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
- C07J53/004—3 membered carbocyclic rings
- C07J53/008—3 membered carbocyclic rings in position 15/16
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pyrane Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Fats And Perfumes (AREA)
- Polyesters Or Polycarbonates (AREA)
Abstract
본 발명은 드로스피레논 (6β,7β;15β,16β-디메틸렌-3-옥소-17α-프레근-4-엔-21,17-카르보락톤, DRSP) (I)의 제조 방법 및 제조 방법의 중간 생성물로서 17α-(3-히드록시-1-프로필)-6β,7β;15β,16β-디메틸렌-5β-안드로스탄-3β,5,17β-트리올 (ZK 92836) 및 6β,7β;15β,16β-디메틸렌-5β-히드록시-3-옥소-17α-안드로스탄-21,17-카르보락톤 (ZK 90965)에 관한 것이다.
Description
6β,7β;15β,16β-디메틸렌-5β-히드록시-3-옥소-17α-안드로스탄-21,17-카르보락톤
17α-(3-히드록시-1-프로피닐)-6β,7β;15β,16β-디메틸렌-5β-안드로스탄-3β,5,17β-트리올 50 g을 탄소 상의 팔라듐 (10%) 10 g 및 피리딘 3 ㎖의 존재하에 THF 1000 ㎖에서, 2당량의 수소가 소모될 때까지 수소화시켰다. 이어서, 촉매를 여과 제거하고, 용액을 무수 상태로 증발시켜 17α-(3-히드록시-1-프로필)-6β,7β;15β,16β-디메틸렌-5β-안드로스탄-3β,5,17β-트리올 52.7 g을 얻었고, 이것을 정제없이 더 반응시켰다.
17α-(3-히드록시-1-프로필)-6β,7β;15β,16β-디메틸렌-5β-안드로스탄-3β,5,17β-트리올 50.2 g을 아세토니트릴 250 ㎖ 중에 현탁시키고 45 ℃까지 가열하였다. 물 10 ㎖에 용해시킨 삼염화루테늄 0.52 g 및 물 250 ㎖에 용해시킨 브롬화나트륨 62.46 g을 상기 용액에 적가하였다. 이것을 50 ℃에서 2 시간 이상 동안 교반하고, 이어서 용액을 물 1000 ㎖를 첨가하여 급냉시켰다. 에틸 아세테이트 200 ㎖를 첨가하고, 상을 분리한 다음, 수상을 에틸 아세테이트 600 ㎖로 추출하였다. 합한 유기상을 황산마그네슘 상에서 건조시킨 다음, 무수 상태로 증발시켰다. 이 경우, 6β,7β;15β,16β-디메틸렌-5β-히드록시-3-옥소-17α-안드로스탄-21,17-카르보락톤 43.44 g을 조생성물로 얻었다. 아세톤-이소에테르로 재결정하여 융점이 216-218 ℃인 6β,7β;15β,16β-디메틸렌-5β-히드록시-3-옥소-17α-안드로스탄-21,17-카르보락톤 35.7 g을 얻었다. 회전은 약 -65.6˚ (나트륨선, CHCl3 중에 c = 1.02)이었다.
6β,7β;15β,16β-디메틸렌-3-옥소-17α-프레근-4-엔-21,17-카르보락톤
6β,7β;15β,16β-디메틸렌-5β-히드록시-3-옥소-17α-안드로스탄-21,17-카르보락톤 28 g을 THF 280 ㎖에 현탁시킨 다음, p-톨루엔술폰산 1.5 g의 10 몰%와 함께 혼합하였다. 30분 후, NaCl 포화 용액 125 ㎖ 및 1N NaOH 용액 8.2 ㎖를 첨가하였다. 상을 분리한 후, 유기상을 황산마그네슘 상에서 건조시킨 다음, 무수 상태로 증발시켜 6β,7β;15β,16β-디메틸렌-3-옥소-17α-프레근-4-엔-21,17-카르보락톤 25.67 g을 조생성물로 얻었고, 이것의 순도는 HPLC 측정에 따르면 약 93 %이었다.
크로마토그래피로 더 정제하였다.
크로마토그래피된 물질의 융점은 약 197.5-200 ℃이었다.
본 발명은 드로스피레논 (6β,7β;15β,16β-디메틸렌-3-옥소-17α-프레근-4-엔-21,17-카르보락톤, DRSP)의 제조 방법 및 제조 방법의 중간 생성물로서의 17α-(3-히드록시-1-프로필)-6β,7β;15β,16β-디메틸렌-5β-안드로스탄-3β,5,17β-트리올 (ZK 92836) 및 6β,7β;15β,16β-디메틸렌-5β-히드록시-3-옥소-17α-안드로스탄-21,17-카르보락톤 (ZK 90965)에 관한 것이다.
드로스피레논 (6β,7β;15β,16β-디메틸렌-3-옥소-17α-프레근-4-엔-21,17-카르보락톤, DRSP, INN)은 스테로이드성 활성 성분으로 오랫동안 공지되어 왔고 (독일 특허 제26 52 761 C2호 및 제30 22 337 A1호), 마지막 4단계의 제조는 단일 용기 반응으로 행해지고, 여기서 디메틸렌 프로핀올 ZK 34506이 수소화된 후, 통과하는 중간 단계의 디메틸렌 프로판올 및 5-β-OH-DRSP 중 어느 것도 분리되지 않는다 (하기 반응식 참조).
디메틸렌 프로핀올 ZK 34506을 팔라듐-탄소 상에서 수소를 사용하여 테트라히드로푸란 중에서 디메틸렌 프로판올 ZK 92836으로 수소화시킨다. 주생성물로 프로판올 ZK 92836을 함유하고 락톨의 비율을 가변시켜 얻은 수소화 용액을 분리하지 않고 반응시키고 중간체를 후처리하여 드로스피레논 ZK 30595 (DRSP)를 얻는다.
상기 목적을 위해, 먼저 테트라히드로푸란에서 디메틸포름아미드로 용매를 변화시킨 다음, 프로판올은 피리디늄 디크로메이트 (PDC) 3.7 당량의 과량으로 40 ℃에서 산화시켜 DRSP 및 5-β-OH-DRSP의 혼합물을 얻는다. 모든 경우에서 더 열역학적으로 안정한 생성물이 드로스피레논내 Δ-4,5-불포화 케톤의 형성으로 얻어지기 때문에, 산화 생성물내 5-β-OH기는 승온에서 산, 루이스산 및 염기성 조건에 따라 변하기 쉽다. 5-β-OH-DRSP내의 β-OH 기를 제거하여 더 열역학적으로 안정한 드로스피레논을 생성하고, 이것은 억제될 수 없다.
일반적으로 혼합물은 상이한 비율의 두 성분을 함유하고, 일반적으로 5-β-OH-DRSP는 주성분으로서 2-3:1의 비율로 존재한다. 단일 용기 반응의 마지막 단계에서, 두 성분 혼합물을 준농축된 염산을 첨가하므로써 조 DRSP로 전환시킨다.
하기 표에, 마지막 4개의 작동 제조를 요약한다.
| 제조 | 수율, 조 (%) | 순도 (100 % 방법) |
| 537201 | 57.2 | 98.9 |
| 202 | 63.7 | 99.09 |
| 203 | 46.5 | 99.18 |
| 204 | 58.3 | 98.81 |
| 합계 | 평균 수율: 56.4 | 평균 순도: 98.9 |
디메틸렌 프로핀올로부터 출발하는 모든 작동 제조에 의하면, HPLC 순도 98.9 %의 조 DRSP를 이론적 수율 56 %로 달성한다.
본 발명의 목적은 선행 기술 보다 더 선택적이고, 실행이 간단하며, 또한 생태학적인 (삼산화크롬 산화물의 감소), 드로스피레논의 신규 제조 방법을 제공하는 것이다.
이 목적은 특허청구의 범위의 교시에 따라 달성된다.
본 발명은 17α-(3-히드록시-1-프로피닐)-6β,7β;15β,16β-디메틸렌-5β-안드로스탄-3β,5,17β-트리올 (ZK 34506)
을 17α-(3-히드록시-1-프로필)-6β,7β;15β,16β-디메틸렌-5β-안드로스탄-3β,5,17β-트리올 (ZK 92836)
으로 촉매 수소화시킨 다음, 아세토니트릴, 클로로포름, 염화메틸렌, 사염화탄소, 물, 테트라히드로푸란, t-부탄올, 에틸 아세테이트 또는 이들의 혼합물과 같은 용매, 바람직하게는 아세토니트릴:물 = 1:1 조성의 아세토니트릴-물 혼합물 중에서 시판용 루테늄 염, 예를 들어 RuCl3, RuO2, KRuO4, K2RuO4을 사용하여, 바람직하게는 촉매량의 RuCl3 (1 몰%) 및 종래의 간단한 산화제, 예를 들어 t-부틸 히드로퍼옥시드, N-메틸-모르폴린-N-옥시드, M2S2O8 (M=Na, K), MXOy (M = Li, Na, K; X = B, Cl, Br, I; y = 1-4), 바람직하게는 NaBrO3 1-3 당량의 존재하에 6β,7β;15β,16β-디메틸렌-5β-히드록시-3-옥소-17α-안드로스탄-21,17-카르보락톤 (ZK 90965)
로 산화시키고 후속적으로 탈수시키는, 드로스피레논 (6β,7β;15β,16β-디메틸렌 -3-옥소-17α-프레근-4-엔-21,17-카르보락톤, DRSP)
의 제조 방법을 포함한다.
중요한 반응으로서, 본 발명은 디메틸렌 프로판올 ZK 92836의 5-β-OH-DRSP ZK 90965로의 루테늄 촉매 작용의 산화 및 드로스피레논 ZK 30595로의 후속 물의 제거반응을 2 단계 방법으로 포함한다.
선행 기술로부터 공지된 방법과 유사하게, 본 발명의 방법에 따르면 디메틸렌 프로핀올 ZK 34506을 팔라듐-탄소 상에서 수소를 사용하여 테트라히드로푸란 중에서 수소화시킨다. 이어서, 수소화 용액의 용매를 테트라히드로푸란에서 아세토니트릴로 변화시킨다. 아세토니트릴 용액을 40 내지 60 ℃에서 촉매량의 삼염화루테늄 (1 몰%) 및 3 당량의 브롬화나트륨을 사용하여 특히, 5-β-OH-DRSP로 산화시킨다. 모든 경우에서 열역학적으로 더 안정한 Δ-4,5-불포화 케톤을 형성하기 위한 높은 추진력이 될 수 있는, 산, 루이스산, 예를 들어 선행 작동 공정에서의 크롬 화합물, 강염기 또는 고온에 따라 5-β-OH-DRSP가 상당히 변하기 쉬움에도 불구하고, 5-β-OH-DRSP의 선택적인 합성을 드로스피레논의 형성이 관찰되지 않으면서 선택된 반응 조건하에 달성할 수 있다. 5-β-OH-DRSP를 (작동상) 이행하기가 간단한 물의 침전에 의해 반응 용액으로부터 분리할 수 있다.
수율은 2단계: 수소화 및 후속 산화를 통하여 68 % 내지 75 % 범위내이다.
일부 시험으로부터, 산성 작용의 경우 드로스피레논은 2 반응 경로를 통하여 산성 작용으로 분해할 수 있다. 한 경우는 산성 조건하에 드로스피레논이 용이하게 에피머 이소락톤 ZK 35096
으로 전환된다.
제2 부산물은 6,7-메틸렌기 상의 HCl 공격으로 제조되고, 고리 개방형 생성물 ZK 95673
을 생성한다.
부산물 둘다 신규 방법의 반응 조건하에 0.2 % 미만으로만 관찰될 수 있는 정도로 생성된다.
제거반응에서, 이론치의 96 % 수율을 달성한다. 따라서, 신규 방법의 총수율은 이론치의 65 % 내지 72 % 범위내이다.
선행 기술과 비교하여 본 발명에 따른 방법의 또다른 매우 기본적인 이점은 생태학의 범위내에 있다. 산화용 피리디늄 디크로메이트염의 형태로 지금까지 사용되어 왔고 후속적으로 용액 형태로 폐기되어야만 하는 이전에 사용된 독성 크롬 화합물을 촉매량의 금속에 의해 대체할 수 있다. 또한, 사용한 아세토니트릴-물 혼합물을 공비 증류에 의해 재활용할 수 있어, 또한 환경에 대한 위험이 없다.
또한, 본 발명은 중간체 생성물 17α-(3-히드록시-1-프로필)-6β,7β;15β,16β-디메틸렌-5β-안드로스탄-3β,5,17β-트리올 (ZK 92836) 및 6β,7β;15β,16β-디메틸렌-5β-히드록시-3-옥소-17α-안드로스탄-21,17-카르보락톤 (90965)를 포함한다.
Claims (5)
- (i) 하기 화학식의 17α-(3-히드록시-1-프로피닐)-6β,7β;15β,16β-디메틸렌-5β-안드로스탄-3β,5,17β-트리올을 하기 화학식의 17α-(3-히드록시-1-프로필)-6β,7β;15β,16β-디메틸렌-5β-안드로스탄-3β,5,17β-트리올로 촉매 수소화시키는 단계;(ii) 생성된 17α-(3-히드록시-1-프로필)-6β,7β;15β,16β-디메틸렌-5β-안드로스탄-3β,5,17β-트리올을 루테늄염의 존재하에 하기 화학식의 6β,7β;15β,16β-디메틸렌-5β-히드록시-3-옥소-17α-안드로스탄-21,17-카르보락톤으로 산화시키는 단계;(iii) 생성된 6β,7β;15β,16β-디메틸렌-5β-히드록시-3-옥소-17α-안드로스탄-21,17-카르보락톤을 후속 탈수시키는 단계를 포함하는, 하기 화학식의 드로스피레논 (6β,7β;15β,16β-디메틸렌-3-옥소-17α-프레근-4-엔-21,17-카르보락톤, DRSP)의 제조 방법.
- 삭제
- 하기 화학식의 6β,7β;15β,16β-디메틸렌-5β-히드록시-3-옥소-17α-안드로스탄-21,17-카르보락톤.
- 제1항에 있어서, 얻어지는 생성물에, 하기 화학식의 이소락톤및 6,7-메틸렌기에 대한 산 공격에 의해 제조된 6,7-고리 개방형 생성물로부터의 오염 물질이 0.2% 미만 함유됨을 특징으로 하는 드로스피레논의 제조 방법.
- 삭제
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19633685.6 | 1996-08-12 | ||
| DE19633685A DE19633685C1 (de) | 1996-08-12 | 1996-08-12 | Verfahren zur Herstellung von Drospirenon (6beta,7beta;15 beta,16beta-Dimethyl-en-3-oxo-17alpha-pregn-4-en-21,17-carbolacton, DRSP) sowie 7alpha-(3-Hydroxy-1-propyl)-6beta,7beta;15beta, 16beta-dimethylen-5beta-androstan-3beta,5,17beta-triol (ZK 92836) und 6beta,7beta;15beta,16beta-dimethylen-5beta-hydroxy-3-oxo-17alpha-androstan-21,17-carbolacton (90965) als Zwischenprodukte des Verfahrens |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20000029939A KR20000029939A (ko) | 2000-05-25 |
| KR100473297B1 true KR100473297B1 (ko) | 2005-03-07 |
Family
ID=7803224
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR10-1999-7001166A KR100473297B1 (ko) | 1996-08-12 | 1997-08-11 | 드로스피레논의 제조 방법, 및 17α-(3-히드록시-1-프로필)-6β,7β；15β,16β-디메틸렌-5β-안드로스탄-3β,5,17β-트리올 및 6β,7β；15β,16β-디메틸렌-5β-히드록시-3-옥소-17α-안드로스탄-21,17-카르보락톤 |
Country Status (27)
| Country | Link |
|---|---|
| US (2) | US6121465A (ko) |
| EP (4) | EP1149840B2 (ko) |
| JP (1) | JP3333524B2 (ko) |
| KR (1) | KR100473297B1 (ko) |
| CN (1) | CN1158300C (ko) |
| AT (3) | ATE420098T1 (ko) |
| AU (1) | AU729149B2 (ko) |
| BG (1) | BG62776B1 (ko) |
| BR (1) | BR9711060A (ko) |
| CA (1) | CA2261137C (ko) |
| CZ (1) | CZ297255B6 (ko) |
| DE (4) | DE19633685C1 (ko) |
| DK (4) | DK1149840T5 (ko) |
| EA (1) | EA001947B1 (ko) |
| ES (4) | ES2335860T3 (ko) |
| HK (1) | HK1021190A1 (ko) |
| HU (1) | HU223106B1 (ko) |
| IL (1) | IL127963A (ko) |
| IS (1) | IS2100B (ko) |
| NZ (1) | NZ333697A (ko) |
| PL (1) | PL187474B1 (ko) |
| PT (4) | PT2168974E (ko) |
| SI (3) | SI0918791T1 (ko) |
| SK (1) | SK283546B6 (ko) |
| TR (1) | TR199900262T2 (ko) |
| UA (1) | UA55423C2 (ko) |
| WO (1) | WO1998006738A1 (ko) |
Families Citing this family (49)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19633685C1 (de) | 1996-08-12 | 1997-10-09 | Schering Ag | Verfahren zur Herstellung von Drospirenon (6beta,7beta;15 beta,16beta-Dimethyl-en-3-oxo-17alpha-pregn-4-en-21,17-carbolacton, DRSP) sowie 7alpha-(3-Hydroxy-1-propyl)-6beta,7beta;15beta, 16beta-dimethylen-5beta-androstan-3beta,5,17beta-triol (ZK 92836) und 6beta,7beta;15beta,16beta-dimethylen-5beta-hydroxy-3-oxo-17alpha-androstan-21,17-carbolacton (90965) als Zwischenprodukte des Verfahrens |
| EP2305267A3 (en) | 1999-08-31 | 2011-08-17 | Bayer Schering Pharma Aktiengesellschaft | Pharmaceutical combination of ethinylestradiol and drospirenone for use as a contraceptive |
| US6787531B1 (en) * | 1999-08-31 | 2004-09-07 | Schering Ag | Pharmaceutical composition for use as a contraceptive |
| KR101019361B1 (ko) | 1999-08-31 | 2011-03-07 | 바이엘 쉐링 파마 악티엔게젤샤프트 | 피임약으로서의 사용을 위한 에티닐에스트라디올과드로스피렌온의 약학적 조합 |
| US20020132801A1 (en) * | 2001-01-11 | 2002-09-19 | Schering Aktiengesellschaft | Drospirenone for hormone replacement therapy |
| ES2332226T3 (es) * | 2000-01-18 | 2010-01-29 | Bayer Schering Pharma Aktiengesellschaft | Composiciones farmaceuticas que comprenden drospirenona. |
| JP2004521951A (ja) | 2001-07-13 | 2004-07-22 | シエーリング アクチエンゲゼルシャフト | Ｈｒｔのためのドロスピレノン及びエストロゲンスルファメートの組み合わせ |
| AU2003239162A1 (en) | 2002-04-26 | 2003-11-10 | Schering Ag | Treatment of hypertension in women receiving hormone replacement therapy |
| US7786101B2 (en) * | 2002-11-05 | 2010-08-31 | Bayer Schering Pharma Ag | Cardiovascular protection using anti-aldosteronic progestins |
| 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. |
| ITMI20040367A1 (it) * | 2004-03-01 | 2004-06-01 | Ind Chimica Srl | Processo per la preparazione di drospirenone |
| HUP0402465A2 (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 |
| 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 |
| DE102004058300B4 (de) * | 2004-12-02 | 2016-09-15 | Austriamicrosystems Ag | Schaltungsanordnung zur Erzeugung eines komplexen Signals und Verwendung in einem Hochfrequenz-Sender oder -Empfänger |
| ITMI20042338A1 (it) * | 2004-12-06 | 2005-03-06 | Ind Chimica Srl | Processo per la preparazione di drospirenone |
| DE502005004948D1 (de) * | 2005-07-21 | 2008-09-18 | Bayer Schering Pharma Ag | Verfahren zur Herstellung von 3-Oxo-pregn-4-en-21,17-carbolactonen durch die metallfreie Oxidation von 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanen |
| PL2527356T3 (pl) * | 2005-07-21 | 2018-06-29 | Bayer Intellectual Property Gmbh | Sposób wytwarzania 3-okso-pregn-4-eno-21,17-karbolaktonów za pomocą wolnego od metali utleniania 17-(3-hydroksypropylo)-3,17- dihydroksyandrostanów |
| US7319154B2 (en) | 2005-07-21 | 2008-01-15 | Bayer Schering Pharma Ag | Process for the production of 3-oxo-pregn-4-ene-21, 17-carbolactones by the metal free oxidation of 17-(3-hydroxypropyl)-3, 17-dihydroxyandrostanes |
| WO2007127266A2 (en) | 2006-04-27 | 2007-11-08 | Covidien Ag | Electrode pad packaging systems and methods |
| EP1902711A1 (en) * | 2006-09-20 | 2008-03-26 | KAIROSmed GmbH | Oral modified release formulations containing Drospirenon and 8-Prenylnaringenin for use in Hormone Replacement Therapy (HRT) |
| US20090023914A1 (en) * | 2007-05-01 | 2009-01-22 | Alessandro Pontiroli | Process for preparing drospirenone and intermediate thereof |
| DE102007030596B3 (de) * | 2007-06-28 | 2009-03-12 | Bayer Schering Pharma Aktiengesellschaft | Verfahren zur Herstellung von 17-(3-Hydroxypropyl)-17-hydroxysteroiden |
| WO2009111574A2 (en) * | 2008-03-05 | 2009-09-11 | Evestra, Inc. | BISMETHYLENE-17α CARBOLACTONES AND RELATED USES |
| WO2010068500A2 (en) * | 2008-11-25 | 2010-06-17 | Evestra, Inc. | PROGESTATIONAL 3-(6,6-ETHYLENE-17b-HYDROXY-3-OXO-17a-PREGNA-4-ENE-17a -YL) PROPIONIC ACID g-LACTONES |
| US20120114757A1 (en) | 2009-02-18 | 2012-05-10 | Bayer Pharma Aktiengesellschaft | Particles comprising drospirenone encapsulated in a polymer |
| EP2398461A1 (en) | 2009-02-18 | 2011-12-28 | Bayer Pharma Aktiengesellschaft | Formulation comprising drospirenone for subcutaneous or intramuscular administration |
| US8334375B2 (en) * | 2009-04-10 | 2012-12-18 | Evestra, Inc. | Methods for the preparation of drospirenone |
| EP2266998B1 (en) | 2009-06-16 | 2013-07-24 | Crystal Pharma, S.A.U. | Process for obtaining 17-spirolactones in steroids |
| DE102009031909B4 (de) | 2009-07-01 | 2017-02-09 | Heyl Chemisch-Pharmazeutische Fabrik Gmbh & Co. Kg | Verfahren zur Herstellung von Drospirenon aus Prasteron |
| US8921346B2 (en) | 2010-03-16 | 2014-12-30 | Taizhou Taifa Pharmaceuticals Co., Ltd. | Preparation method of drospirenone |
| CN101830959B (zh) * | 2010-05-27 | 2012-07-18 | 杭州龙山化工有限公司 | 一种曲螺酮的合成方法 |
| US10849857B2 (en) | 2010-07-28 | 2020-12-01 | Laboratorios Leon Farma Sa | Pharmaceutical compositions comprising active drugs, contraceptive kits comprising active drugs, and methods of administering the same |
| AR081670A1 (es) | 2010-06-29 | 2012-10-10 | Leon Farma Sa Lab | Composicion farmaceutica que comprende drospirenona y kit anticonceptivo |
| US11351122B1 (en) | 2010-07-28 | 2022-06-07 | Laboratorios Leon Farma Sa | Synthetic progestogens and pharmaceutical compositions comprising the same |
| US9603860B2 (en) | 2010-07-28 | 2017-03-28 | Laboratorios Leon Farma Sa | Pharmaceutical compositions comprising active drugs, contraceptive kits comprising active drugs, and methods of administering the same |
| EP2415778B1 (en) | 2010-08-03 | 2013-05-15 | Newchem S.p.A. | Methods for the preparation of Drospirenone and intermediates thereof |
| WO2012107513A1 (en) | 2011-02-10 | 2012-08-16 | Crystal Pharma, S.A.U. | Process for obtaining drospirenone |
| ITMI20111383A1 (it) | 2011-07-25 | 2013-01-26 | Ind Chimica Srl | Processo per la preparazione di drospirenone |
| WO2013064620A1 (de) * | 2011-11-04 | 2013-05-10 | Bayer Pharma Aktiengesellschaft | 18-METHYL-6,7-METHYLEN-3-OXO-17-PREGN-4-EN-21,17β-CARBOLACTONE, PHARMAZEUTISCHE PRÄPARATE ENTHALTEND DIE GENANNTEN VERBINDUNGEN UND DEREN ANWENDUNG BEI DER THERAPIE DER ENDOMETRIOSE |
| EP2597101A1 (en) | 2011-11-22 | 2013-05-29 | Industriale Chimica S.R.L. | Process for the preparation of drospirenone |
| WO2013076118A1 (en) | 2011-11-22 | 2013-05-30 | Industriale Chimica S.R.L. | Process for the preparation of drospirenone |
| EP2958929B1 (en) | 2013-02-20 | 2017-09-13 | Industriale Chimica S.R.L. | Process for the preparation of drospirenone |
| CA2909087C (en) | 2013-04-12 | 2020-01-07 | Industriale Chimica S.R.L. | Process for the preparation of drospirenone |
| DK3313408T3 (da) | 2015-06-23 | 2024-01-29 | Laboratorios Leon Farma Sa | Drospirenon-baseret svangerskabsforebyggende middel til en kvindelig patient, som lider af overvægt |
| EP3108889A1 (en) | 2015-06-23 | 2016-12-28 | Philippe Perrin | Drospirenone-based contraceptive for a female patient affected with excess weight |
| CN113387993A (zh) * | 2021-07-06 | 2021-09-14 | 江西百思康瑞药业有限公司 | 一种屈螺酮的合成方法 |
| EP4134082A1 (en) | 2021-08-12 | 2023-02-15 | Chemo Research, S.L. | Method for treating endometriosis and providing effective contraception |
| WO2023152658A1 (en) | 2022-02-10 | 2023-08-17 | Lupin Limited | Slow release drospirenone tablet composition |
| WO2023165988A1 (en) | 2022-03-01 | 2023-09-07 | Chemo Research, S.L. | Chewable oral contraceptive |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2652761C2 (de) | 1976-11-16 | 1985-11-21 | Schering AG, 1000 Berlin und 4709 Bergkamen | 15,16-Methylen-Spirolactone, Verfahren zu deren Herstellung und diese enthaltende Arzneimittel |
| DE3022337A1 (de) * | 1980-06-11 | 1982-01-07 | Schering Ag Berlin Und Bergkamen, 1000 Berlin | Praeparate zur kontrazeption und zur behandlung gynaekologischer stoerungen |
| DE3042136A1 (de) * | 1980-11-03 | 1982-06-09 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | Verfahren zur herstellung von 3 (beta), 7 (beta) -dihydroxy- (delta) (pfeil hoch)5(pfeil hoch) -steroiden |
| DE3265852D1 (en) * | 1981-09-21 | 1985-10-03 | Schering Ag | 3-beta,7-beta,15-alpha-trihydroxy-5-androsten-17-one, its 3,15-dipivalate, and its preparation |
| DE3414508A1 (de) * | 1984-04-13 | 1985-10-24 | Schering AG, 1000 Berlin und 4709 Bergkamen | Mehrfach tritiierte steroid-20.17-spirolactone und ihre verwendung als tracersubstanzen |
| DE3626838A1 (de) * | 1986-08-08 | 1988-02-11 | Schering Ag | Verfahren zur herstellung von 17(alpha)-pregnan-21,17-carbolactonen |
| US5106995A (en) * | 1989-05-05 | 1992-04-21 | Isp Investments Inc. | Production of lactones from diols |
| DE19633685C1 (de) | 1996-08-12 | 1997-10-09 | Schering Ag | Verfahren zur Herstellung von Drospirenon (6beta,7beta;15 beta,16beta-Dimethyl-en-3-oxo-17alpha-pregn-4-en-21,17-carbolacton, DRSP) sowie 7alpha-(3-Hydroxy-1-propyl)-6beta,7beta;15beta, 16beta-dimethylen-5beta-androstan-3beta,5,17beta-triol (ZK 92836) und 6beta,7beta;15beta,16beta-dimethylen-5beta-hydroxy-3-oxo-17alpha-androstan-21,17-carbolacton (90965) als Zwischenprodukte des Verfahrens |
-
1996
- 1996-08-12 DE DE19633685A patent/DE19633685C1/de not_active Expired - Fee Related
-
1997
- 1997-08-11 DE DE59712991T patent/DE59712991D1/de not_active Expired - Lifetime
- 1997-08-11 CN CNB971960356A patent/CN1158300C/zh not_active Expired - Lifetime
- 1997-08-11 JP JP50938998A patent/JP3333524B2/ja not_active Expired - Lifetime
- 1997-08-11 EP EP01250277.9A patent/EP1149840B2/de not_active Expired - Lifetime
- 1997-08-11 SI SI9730350T patent/SI0918791T1/xx unknown
- 1997-08-11 AT AT01250277T patent/ATE420098T1/de active
- 1997-08-11 EP EP09100011.7A patent/EP2168974B1/de not_active Revoked
- 1997-08-11 DE DE59713018T patent/DE59713018D1/de not_active Expired - Lifetime
- 1997-08-11 WO PCT/EP1997/004342 patent/WO1998006738A1/de active IP Right Grant
- 1997-08-11 PT PT91000117T patent/PT2168974E/pt unknown
- 1997-08-11 PL PL97331530A patent/PL187474B1/pl unknown
- 1997-08-11 PT PT01250278T patent/PT1149841E/pt unknown
- 1997-08-11 DE DE59706887T patent/DE59706887D1/de not_active Expired - Lifetime
- 1997-08-11 ES ES01250278T patent/ES2335860T3/es not_active Expired - Lifetime
- 1997-08-11 SI SI9730786T patent/SI1149840T2/sl unknown
- 1997-08-11 AU AU40144/97A patent/AU729149B2/en not_active Expired
- 1997-08-11 ES ES01250277T patent/ES2320626T5/es not_active Expired - Lifetime
- 1997-08-11 DK DK01250277.9T patent/DK1149840T5/da active
- 1997-08-11 PT PT01250277T patent/PT1149840E/pt unknown
- 1997-08-11 CA CA002261137A patent/CA2261137C/en not_active Expired - Lifetime
- 1997-08-11 US US09/242,334 patent/US6121465A/en not_active Expired - Lifetime
- 1997-08-11 EA EA199900153A patent/EA001947B1/ru not_active IP Right Cessation
- 1997-08-11 EP EP01250278A patent/EP1149841B1/de not_active Expired - Lifetime
- 1997-08-11 BR BR9711060A patent/BR9711060A/pt not_active IP Right Cessation
- 1997-08-11 AT AT01250278T patent/ATE446966T1/de active
- 1997-08-11 CZ CZ0047099A patent/CZ297255B6/cs not_active IP Right Cessation
- 1997-08-11 HU HU9903089A patent/HU223106B1/hu active Protection Beyond IP Right Term
- 1997-08-11 SK SK194-99A patent/SK283546B6/sk not_active IP Right Cessation
- 1997-08-11 TR TR1999/00262T patent/TR199900262T2/xx unknown
- 1997-08-11 ES ES97937562T patent/ES2175451T7/es active Active
- 1997-08-11 DK DK97937562T patent/DK0918791T3/da active
- 1997-08-11 ES ES09100011.7T patent/ES2438941T3/es not_active Expired - Lifetime
- 1997-08-11 PT PT97937562T patent/PT918791E/pt unknown
- 1997-08-11 AT AT97937562T patent/ATE215557T1/de active
- 1997-08-11 NZ NZ333697A patent/NZ333697A/xx not_active IP Right Cessation
- 1997-08-11 DK DK01250278.7T patent/DK1149841T3/da active
- 1997-08-11 IL IL12796397A patent/IL127963A/en not_active IP Right Cessation
- 1997-08-11 DK DK09100011.7T patent/DK2168974T3/da active
- 1997-08-11 KR KR10-1999-7001166A patent/KR100473297B1/ko not_active IP Right Cessation
- 1997-08-11 EP EP97937562A patent/EP0918791B3/de not_active Expired - Lifetime
- 1997-08-11 SI SI9730790T patent/SI1149841T1/sl unknown
- 1997-11-08 UA UA99031342A patent/UA55423C2/uk unknown
-
1998
- 1998-12-01 BG BG102976A patent/BG62776B1/bg unknown
-
1999
- 1999-01-29 IS IS4965A patent/IS2100B/is unknown
- 1999-12-09 HK HK99105743A patent/HK1021190A1/xx not_active IP Right Cessation
-
2000
- 2000-08-18 US US09/640,748 patent/US6933395B1/en not_active Expired - Lifetime
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100473297B1 (ko) | 드로스피레논의 제조 방법, 및 17α-(3-히드록시-1-프로필)-6β,7β；15β,16β-디메틸렌-5β-안드로스탄-3β,5,17β-트리올 및 6β,7β；15β,16β-디메틸렌-5β-히드록시-3-옥소-17α-안드로스탄-21,17-카르보락톤 | |
| EP1746101B2 (de) | Verfahren zur Herstellung von 3-Oxo-pregn-4-en-21,17-carbolactonen durch die metallfreie Oxidation von 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanen | |
| EP0122232A1 (de) | 20-Spiroxane und Analoge mit geöffnetem Ring E, Verfahren zu ihrer Herstellung, sowie pharmazeutische Präparate davon | |
| CN101679478A (zh) | 17β-氰基-19-去甲-雄甾-4-烯衍生物、其用途以及含有该衍生物的药物 | |
| EP1910403B1 (en) | Process for the production of 3-oxo-pregn-4-ene-21,17-carbolactones by the metal-free oxidation of 17-(3-hydroxypropyl)-3,17-dihydroxyandrostanes | |
| MXPA99001373A (en) | PROCESS FOR PRODUCING DROSPIRENONE (6ß,7ß;15ß,16ß-DIMETHYLENE-3-OXO-17&agr;-PREGN-4-EN-21, 17-CARBOLACTONE, DRSP | |
| DE2544701C2 (de) | D-Homosteroide, Verfahren zu deren Herstellung sowie diese enthaltende Präparate mit hormonaler Wirkung | |
| DE102009031908B4 (de) | Verfahren zur Herstellung von Drospirenon aus 15-Hydroxyandrostendion | |
| AT266333B (de) | Verfahren zur Herstellung von 17α-Halogenäthinyl-17β-hydroxy-östra-4,9(10)-dien-3-on-Verbindungen | |
| DE102009031907B4 (de) | Verfahren zur Herstellung von Drospirenon aus Androstendion | |
| NO136727B (ko) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| FPAY | Annual fee payment |
Payment date: 20130201 Year of fee payment: 9 |
|
| FPAY | Annual fee payment |
Payment date: 20140204 Year of fee payment: 10 |
|
| FPAY | Annual fee payment |
Payment date: 20150130 Year of fee payment: 11 |
|
| FPAY | Annual fee payment |
Payment date: 20160127 Year of fee payment: 12 |
|
| FPAY | Annual fee payment |
Payment date: 20170201 Year of fee payment: 13 |
|
| FPAY | Annual fee payment |
Payment date: 20180201 Year of fee payment: 14 |
|
| FPAY | Annual fee payment |
Payment date: 20190129 Year of fee payment: 15 |
|
| EXPY | Expiration of term |