CA2648537C - Methode de preparation de 4-[17.beta.-methoxy-17.alpha.-methoxymethyl-3-oxoestra-4,9-dien-11.beta.-yl]benzaldehyde (e)-oxime (asoprisnil) - Google Patents
Methode de preparation de 4-[17.beta.-methoxy-17.alpha.-methoxymethyl-3-oxoestra-4,9-dien-11.beta.-yl]benzaldehyde (e)-oxime (asoprisnil) Download PDFInfo
- Publication number
- CA2648537C CA2648537C CA2648537A CA2648537A CA2648537C CA 2648537 C CA2648537 C CA 2648537C CA 2648537 A CA2648537 A CA 2648537A CA 2648537 A CA2648537 A CA 2648537A CA 2648537 C CA2648537 C CA 2648537C
- Authority
- CA
- Canada
- Prior art keywords
- beta
- asoprisnil
- hydroxyestradienone
- alpha
- drying
- Prior art date
- 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.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 77
- GJMNAFGEUJBOCE-MEQIQULJSA-N asoprisnil Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@]([C@]3(C2)C)(COC)OC)=CC=C(\C=N\O)C=C1 GJMNAFGEUJBOCE-MEQIQULJSA-N 0.000 title claims abstract description 61
- 229950003620 asoprisnil Drugs 0.000 title claims abstract description 61
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 title abstract description 14
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 title abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 99
- 238000006243 chemical reaction Methods 0.000 claims description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 51
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 38
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 31
- MLMJCNNPMGMWII-FOSLCNLBSA-N (9r,10s,13s)-13-(hydroxymethyl)-2,3,4,5,6,7,9,10,11,12-decahydro-1h-cyclopenta[a]phenanthren-17-one Chemical compound C([C@@H]1[C@H]2CC3)CCCC1CCC2=C1[C@@]3(CO)C(=O)C=C1 MLMJCNNPMGMWII-FOSLCNLBSA-N 0.000 claims description 29
- 239000000047 product Substances 0.000 claims description 27
- 238000001035 drying Methods 0.000 claims description 26
- 239000012071 phase Substances 0.000 claims description 22
- 150000001299 aldehydes Chemical class 0.000 claims description 18
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 claims description 16
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 claims description 16
- -1 dimethoxy acetal Chemical class 0.000 claims description 15
- 238000005907 ketalization reaction Methods 0.000 claims description 15
- 239000011859 microparticle Substances 0.000 claims description 15
- 230000003647 oxidation Effects 0.000 claims description 15
- 238000007254 oxidation reaction Methods 0.000 claims description 15
- 239000002245 particle Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- 238000001694 spray drying Methods 0.000 claims description 13
- 150000003431 steroids Chemical class 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 150000002500 ions Chemical class 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 9
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 6
- RXYLXDKWPRPXMI-UHFFFAOYSA-N 1-bromo-2-(dimethoxymethyl)benzene Chemical compound COC(OC)C1=CC=CC=C1Br RXYLXDKWPRPXMI-UHFFFAOYSA-N 0.000 claims description 5
- 238000003747 Grignard reaction Methods 0.000 claims description 5
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 238000005507 spraying Methods 0.000 claims description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 238000010533 azeotropic distillation Methods 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- 239000012530 fluid Substances 0.000 claims description 4
- 238000011010 flushing procedure Methods 0.000 claims description 4
- 238000009736 wetting Methods 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 230000008021 deposition Effects 0.000 claims description 3
- 239000007921 spray Substances 0.000 claims description 3
- 230000009885 systemic effect Effects 0.000 claims description 3
- BHTWZQKERRCPRZ-RYRKJORJSA-N Estra-4,9-diene-3,17-dione Chemical compound C1CC(=O)C=C2CC[C@@H]([C@H]3[C@@](C)(C(CC3)=O)CC3)C3=C21 BHTWZQKERRCPRZ-RYRKJORJSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 238000011109 contamination Methods 0.000 claims description 2
- SDZRMTOYMKCDIO-UHFFFAOYSA-M di(propan-2-yloxy)alumanyl 2,2,2-trifluoroacetate Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].[O-]C(=O)C(F)(F)F SDZRMTOYMKCDIO-UHFFFAOYSA-M 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 239000007791 liquid phase Substances 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 5
- 238000006036 Oppenauer oxidation reaction Methods 0.000 claims 3
- PUQSDJZESAQGQS-OWSLCNJRSA-N (8s,13s,14s,17s)-17-hydroxy-13-methyl-2,6,7,8,11,12,14,15,16,17-decahydro-1h-cyclopenta[a]phenanthren-3-one Chemical compound C1CC(=O)C=C2CC[C@@H]([C@H]3[C@@](C)([C@H](CC3)O)CC3)C3=C21 PUQSDJZESAQGQS-OWSLCNJRSA-N 0.000 claims 2
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 15
- 239000007787 solid Substances 0.000 abstract description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 28
- 239000012074 organic phase Substances 0.000 description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- 239000004480 active ingredient Substances 0.000 description 17
- 239000000203 mixture Substances 0.000 description 17
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000004821 distillation Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- 239000001117 sulphuric acid Substances 0.000 description 11
- 235000011149 sulphuric acid Nutrition 0.000 description 11
- 238000002425 crystallisation Methods 0.000 description 10
- 230000008025 crystallization Effects 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 239000007789 gas Substances 0.000 description 9
- 239000006227 byproduct Substances 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 6
- 238000009826 distribution Methods 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000000113 differential scanning calorimetry Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 229940117975 chromium trioxide Drugs 0.000 description 3
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 3
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- YEOAIJNHLPFTRM-AOIWGVFYSA-N (8s,13s,14s)-3,3-dimethoxy-13-methyl-1,2,4,6,7,8,12,14,15,16-decahydrocyclopenta[a]phenanthren-17-one Chemical compound C1C=C2C(CCC(C3)(OC)OC)=C3CC[C@H]2[C@@H]2CCC(=O)[C@]21C YEOAIJNHLPFTRM-AOIWGVFYSA-N 0.000 description 2
- VXEGSRKPIUDPQT-UHFFFAOYSA-N 4-[4-(4-methoxyphenyl)piperazin-1-yl]aniline Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C=CC(N)=CC=2)CC1 VXEGSRKPIUDPQT-UHFFFAOYSA-N 0.000 description 2
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000004133 Sodium thiosulphate Substances 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000006359 acetalization reaction Methods 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000004411 aluminium Substances 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 2
- AZFLJNIPTRTECV-FUMNGEBKSA-N dienogest Chemical compound C1CC(=O)C=C2CC[C@@H]([C@H]3[C@@](C)([C@](CC3)(O)CC#N)CC3)C3=C21 AZFLJNIPTRTECV-FUMNGEBKSA-N 0.000 description 2
- 229960003309 dienogest Drugs 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- VBZWSGALLODQNC-UHFFFAOYSA-N hexafluoroacetone Chemical compound FC(F)(F)C(=O)C(F)(F)F VBZWSGALLODQNC-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000005049 silicon tetrachloride Substances 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 description 2
- NULYJUJAALNWOJ-GAZPGATBSA-N (7r,8r,13s,14s)-7-(methoxymethyl)-13-methyl-2,6,7,8,11,12,14,15,16,17-decahydro-1h-cyclopenta[a]phenanthren-3-one Chemical compound C1C[C@]2(C)CCC[C@H]2[C@@H]2[C@H](COC)CC3=CC(=O)CCC3=C21 NULYJUJAALNWOJ-GAZPGATBSA-N 0.000 description 1
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- TWFNGPDYMFEHOB-UHFFFAOYSA-N 1-bromo-4-(dimethoxymethyl)benzene Chemical compound COC(OC)C1=CC=C(Br)C=C1 TWFNGPDYMFEHOB-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical group CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001844 chromium Chemical class 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000001687 destabilization Effects 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000010349 pulsation Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000010802 sludge Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
-
- 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
- C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
- C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/36—Antigestagens
-
- 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
-
- 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
- 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
- C07J1/0081—Substituted in position 17 alfa and 17 beta
-
- 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
- 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
- C07J71/001—Oxiranes
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Reproductive Health (AREA)
- Epidemiology (AREA)
- Steroid Compounds (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)
- Medicinal Preparation (AREA)
Abstract
L'invention porte sur une méthode de préparation de 4-[17.beta.-methoxy-17.alpha.-méthoxyméthyl-3-oxoestra-4,9-dien-11.beta.-yl]benzaldéhyde (e)-oxime (asoprisnil) à l'échelle pilote et à l'échelle de fabrication. L'asoprisnil, préparé par cette méthode, qui se distingue par une très bonne stabilité physique, est donc particulièrement adapté à la fabrication de formes pharmaceutiques solides (comprimés, comprimés pelliculés, etc.).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2839228A CA2839228A1 (fr) | 2006-04-18 | 2007-04-17 | Methode de preparation de 4-[17.beta.-methoxy-17.alpha.-methoxymethyl-3-oxoestra-4,9-dien-11.beta.-yl]benzaldehyde (e)-oxime (asoprisnil) |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102006018888.8 | 2006-04-18 | ||
| DE102006018888A DE102006018888A1 (de) | 2006-04-18 | 2006-04-18 | Verfahren zur Herstellung von 4-[17beta-Methoxy-17alpha-methoxymethyl-3-oxoestra-4,9-dien-11beta-yl]benzaldehyd-(E)-oxims (Asoprisnil) |
| PCT/EP2007/003723 WO2007118717A2 (fr) | 2006-04-18 | 2007-04-17 | MÉTHODE DE PRÉPARATION DE 4-[17β-METHOXY-17α-MÉTHOXYMÉTHYL-3-OXOESTRA-4,9-DIEN-11β-YL]BENZALDÉHYDE (E)-OXIME (ASOPRISNIL) |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2839228A Division CA2839228A1 (fr) | 2006-04-18 | 2007-04-17 | Methode de preparation de 4-[17.beta.-methoxy-17.alpha.-methoxymethyl-3-oxoestra-4,9-dien-11.beta.-yl]benzaldehyde (e)-oxime (asoprisnil) |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2648537A1 CA2648537A1 (fr) | 2007-10-25 |
| CA2648537C true CA2648537C (fr) | 2014-09-23 |
Family
ID=38536818
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2648537A Active CA2648537C (fr) | 2006-04-18 | 2007-04-17 | Methode de preparation de 4-[17.beta.-methoxy-17.alpha.-methoxymethyl-3-oxoestra-4,9-dien-11.beta.-yl]benzaldehyde (e)-oxime (asoprisnil) |
| CA2839228A Abandoned CA2839228A1 (fr) | 2006-04-18 | 2007-04-17 | Methode de preparation de 4-[17.beta.-methoxy-17.alpha.-methoxymethyl-3-oxoestra-4,9-dien-11.beta.-yl]benzaldehyde (e)-oxime (asoprisnil) |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2839228A Abandoned CA2839228A1 (fr) | 2006-04-18 | 2007-04-17 | Methode de preparation de 4-[17.beta.-methoxy-17.alpha.-methoxymethyl-3-oxoestra-4,9-dien-11.beta.-yl]benzaldehyde (e)-oxime (asoprisnil) |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP2010555A2 (fr) |
| JP (1) | JP2009534345A (fr) |
| KR (1) | KR20080110629A (fr) |
| CN (1) | CN101466724A (fr) |
| AU (1) | AU2007237457A1 (fr) |
| BR (1) | BRPI0710517A2 (fr) |
| CA (2) | CA2648537C (fr) |
| DE (1) | DE102006018888A1 (fr) |
| MX (2) | MX2007000450A (fr) |
| RU (1) | RU2008145098A (fr) |
| WO (1) | WO2007118717A2 (fr) |
| ZA (1) | ZA200809787B (fr) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108003210A (zh) * | 2018-01-24 | 2018-05-08 | 四川理工学院 | 一种雌甾-4,9-二烯-3,17-二酮的制备方法 |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR5183M (fr) * | 1966-03-04 | 1967-06-19 | ||
| ZA8231B (en) * | 1981-01-09 | 1982-11-24 | Roussel Uclaf | New 11 -substituted steroid derivatives, their preparation, their use as medicaments, the compositions containing them and the new intermediates thus obtained |
| DD296931A5 (de) * | 1987-08-28 | 1991-12-19 | Jenapharm Gmbh Jena,De | Verfahren zur herstellung von 13 beta-alkyl-5(10),9(11)-gonadienderivaten |
| US4910191A (en) * | 1988-06-28 | 1990-03-20 | Merrell Dow Pharmaceuticals Inc. | 19-substituted progesterone derivatives useful as 19-hydroxylase inhibitors |
| DE4332283A1 (de) * | 1993-09-20 | 1995-04-13 | Jenapharm Gmbh | Neue 11-Benzaldoximestradien-Derivate, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel |
| EP1157996A1 (fr) * | 2000-05-23 | 2001-11-28 | JENAPHARM GmbH | Nouveaux formes solides du mesoprogestin 11beta-(4E-(hxdroxyiminomethyl)-phenyl)-17alpha-methoxymethyl-17beta-methoxy-estra-4,9-dien-3-on |
| DE10056675A1 (de) * | 2000-11-10 | 2002-05-16 | Jenapharm Gmbh | Verfahren zur Herstellung von 4-(17alpha-Methylsubstituierten 3-Oxoestra-4,9-dien-11ß-yl)-benzaldehyd-(1E oder 1Z)-oximen |
| DE10056676A1 (de) * | 2000-11-10 | 2002-05-16 | Jenapharm Gmbh | Verfahren zur Herstellung von 4-/17alpha-substituierten-3-oxoestra-4,9-dien-11beta-yl)benzaldehyd-(1E oder 1Z)-oximen |
| JP4197890B2 (ja) * | 2001-05-24 | 2008-12-17 | 興和創薬株式会社 | 第一級アリルアルコール類の酸化方法 |
| DE10311092A1 (de) * | 2003-03-07 | 2004-10-07 | Schering Ag | Verfahren zur Oxidation der 17-Hydroxylfunktion in Steroiden und die Verwendung von Trifluoressigsäure und Cyclohexanon zur Herstellung von steroidalen 17-Ketonen mittels Oppenauer Oxidation |
| DE102004021060A1 (de) * | 2004-04-29 | 2005-11-24 | Schering Ag | Wiederfindung von Arzneistoffen im ppm-Bereich in Produktionsanlagen |
-
2006
- 2006-04-18 DE DE102006018888A patent/DE102006018888A1/de not_active Ceased
-
2007
- 2007-01-12 MX MX2007000450A patent/MX2007000450A/es not_active Application Discontinuation
- 2007-04-17 RU RU2008145098/04A patent/RU2008145098A/ru not_active Application Discontinuation
- 2007-04-17 CN CNA2007800212624A patent/CN101466724A/zh active Pending
- 2007-04-17 KR KR1020087025453A patent/KR20080110629A/ko not_active Application Discontinuation
- 2007-04-17 JP JP2009505800A patent/JP2009534345A/ja active Pending
- 2007-04-17 MX MX2008013336A patent/MX2008013336A/es unknown
- 2007-04-17 CA CA2648537A patent/CA2648537C/fr active Active
- 2007-04-17 CA CA2839228A patent/CA2839228A1/fr not_active Abandoned
- 2007-04-17 WO PCT/EP2007/003723 patent/WO2007118717A2/fr active Application Filing
- 2007-04-17 EP EP07724653A patent/EP2010555A2/fr not_active Withdrawn
- 2007-04-17 BR BRPI0710517-7A patent/BRPI0710517A2/pt not_active IP Right Cessation
- 2007-04-17 AU AU2007237457A patent/AU2007237457A1/en not_active Abandoned
-
2008
- 2008-11-17 ZA ZA200809787A patent/ZA200809787B/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MX2007000450A (es) | 2009-02-11 |
| KR20080110629A (ko) | 2008-12-18 |
| CN101466724A (zh) | 2009-06-24 |
| CA2839228A1 (fr) | 2007-10-25 |
| WO2007118717A2 (fr) | 2007-10-25 |
| MX2008013336A (es) | 2008-10-31 |
| WO2007118717A3 (fr) | 2008-04-24 |
| BRPI0710517A2 (pt) | 2011-08-16 |
| AU2007237457A1 (en) | 2007-10-25 |
| EP2010555A2 (fr) | 2009-01-07 |
| JP2009534345A (ja) | 2009-09-24 |
| CA2648537A1 (fr) | 2007-10-25 |
| DE102006018888A1 (de) | 2007-10-25 |
| RU2008145098A (ru) | 2010-05-27 |
| ZA200809787B (en) | 2010-01-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU711369B2 (en) | 11-(substituted-phenyl)-estra-4,9-diene derivatives | |
| JPH09309897A (ja) | コレステロール低下剤およびアテローム硬化症抑制剤を製造するためのステロイドグリコシドの使用 | |
| AU736064B2 (en) | 16-hydroxy-11-(substituted phenyl)-estra-4,9-diene derivatives | |
| AU2006323005B2 (en) | High purity 17alpha-cyanomethyl-17beta-hydroxy-estra-4,9-diene-3-one and process for the synthesis thereof | |
| HU209949B (en) | Process for the production of 11beta-4-estrene-derivatives and pharmaceutical compositions containing them | |
| EP0776904B1 (fr) | Procédé de préparation des cétals de stéroides | |
| US20040092492A1 (en) | 17alpha-fluoroalkyl-11beta-benzaldoxime steroids, process for their production, pharmaceutical preparations that contain these steroids as well as their use for the production of pharmaceutical agents | |
| CA2648537C (fr) | Methode de preparation de 4-[17.beta.-methoxy-17.alpha.-methoxymethyl-3-oxoestra-4,9-dien-11.beta.-yl]benzaldehyde (e)-oxime (asoprisnil) | |
| CN114302889B (zh) | 用于制备高纯度的雌四醇的工业方法 | |
| SK135195A3 (en) | Crystaline spirostalnylglycosidal, its monohydrate pharmaceutical agent on its base and method of production of crystaline steroid glycoside | |
| US8324412B2 (en) | Method for preparing 4-[17β-methoxy-17α-methoxymethyl-3-oxoestra-4,9-dien-11β-yl]benzaldehyde (E)-oxime (asoprisnil) | |
| JP2005536463A (ja) | １７α−フルオロアルキル−１１β−ベンズアルドキシムステロイド、それらの製造方法、これらのステロイド類を含有する製剤及び医薬品製造のためのそれらの使用 | |
| RU2802820C2 (ru) | Промышленный способ получения высокочистого эстетрола | |
| EP4000688A1 (fr) | Procédé pour la préparation d'acétate trenbolone ayant une distribution granulométrique définie | |
| JP2834721B2 (ja) | １７α−シアノメチルエストラ−４，９−ジエン誘導体、その製造方法および該化合物を含有する医薬品 | |
| EA042770B1 (ru) | Промышленный способ получения высокочистого эстетрола | |
| CZ253499A3 (cs) | Deriváty estra-4,9-dienu a farmaceutický prostředek |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |