DK168539B1 - Speciel fremgangsmåde til fremstilling af 26,26,26,27,27,27-hexafluor-1alfa,25-dihydroxycholesterol og mellemprodukter til brug herved - Google Patents
Speciel fremgangsmåde til fremstilling af 26,26,26,27,27,27-hexafluor-1alfa,25-dihydroxycholesterol og mellemprodukter til brug herved Download PDFInfo
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- DK168539B1 DK168539B1 DK032684A DK32684A DK168539B1 DK 168539 B1 DK168539 B1 DK 168539B1 DK 032684 A DK032684 A DK 032684A DK 32684 A DK32684 A DK 32684A DK 168539 B1 DK168539 B1 DK 168539B1
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- Prior art keywords
- formula
- process according
- hexafluoro
- prepared
- compound
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- 238000000034 method Methods 0.000 title claims description 18
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 239000000543 intermediate Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 18
- 150000002118 epoxides Chemical class 0.000 claims 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 claims description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 8
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- VBZWSGALLODQNC-UHFFFAOYSA-N hexafluoroacetone Chemical compound FC(F)(F)C(=O)C(F)(F)F VBZWSGALLODQNC-UHFFFAOYSA-N 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 150000004702 methyl esters Chemical class 0.000 claims description 3
- MJGFBOZCAJSGQW-UHFFFAOYSA-N mercury sodium Chemical compound [Na].[Hg] MJGFBOZCAJSGQW-UHFFFAOYSA-N 0.000 claims description 2
- 229910001023 sodium amalgam Inorganic materials 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 4
- 238000006884 silylation reaction Methods 0.000 claims 2
- GEUPGXRTDHHMLS-UHFFFAOYSA-N [Na]S(=O)(=O)C1=CC=CC=C1 Chemical compound [Na]S(=O)(=O)C1=CC=CC=C1 GEUPGXRTDHHMLS-UHFFFAOYSA-N 0.000 claims 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 230000010933 acylation Effects 0.000 claims 1
- 238000005917 acylation reaction Methods 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims 1
- 230000031709 bromination Effects 0.000 claims 1
- 238000005893 bromination reaction Methods 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 150000002440 hydroxy compounds Chemical class 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000011782 vitamin Substances 0.000 description 13
- 229940088594 vitamin Drugs 0.000 description 13
- 150000003722 vitamin derivatives Chemical class 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 229930003231 vitamin Natural products 0.000 description 12
- 235000013343 vitamin Nutrition 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 239000012267 brine Substances 0.000 description 7
- 239000011575 calcium Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 229910052791 calcium Inorganic materials 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000003054 hormonal effect Effects 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 150000003457 sulfones Chemical class 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 2
- GMRQFYUYWCNGIN-UHFFFAOYSA-N 1,25-Dihydroxy-vitamin D3' Natural products C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2C1=CC=C1CC(O)CC(O)C1=C GMRQFYUYWCNGIN-UHFFFAOYSA-N 0.000 description 2
- GMRQFYUYWCNGIN-ZVUFCXRFSA-N 1,25-dihydroxy vitamin D3 Chemical compound C1([C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=CC=C1C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-ZVUFCXRFSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 239000003872 25-hydroxy-cholecalciferol Substances 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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 239000004380 Cholic acid Substances 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 229930003316 Vitamin D Natural products 0.000 description 2
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000005103 alkyl silyl group Chemical group 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 239000011612 calcitriol Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 2
- 229960002471 cholic acid Drugs 0.000 description 2
- 235000019416 cholic acid Nutrition 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 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
- 239000011710 vitamin D Substances 0.000 description 2
- 235000019166 vitamin D Nutrition 0.000 description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 description 2
- 229940046008 vitamin d Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FCKJYANJHNLEEP-OIMXRAFZSA-N 24,25-Dihydroxyvitamin D Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCC(O)C(C)(C)O)C)=C\C=C1\C[C@H](O)CCC1=C FCKJYANJHNLEEP-OIMXRAFZSA-N 0.000 description 1
- JWUBBDSIWDLEOM-UHFFFAOYSA-N 25-Hydroxycholecalciferol Natural products C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2C1=CC=C1CC(O)CCC1=C JWUBBDSIWDLEOM-UHFFFAOYSA-N 0.000 description 1
- 235000021318 Calcifediol Nutrition 0.000 description 1
- 241000282421 Canidae Species 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- WTYCHAVEQAWVIZ-UHFFFAOYSA-N FC1C(C(C(C=C1)(F)S(=O)(=O)C1(C(C(C(C=C1)F)(F)F)(F)F)F)(F)F)(F)F Chemical compound FC1C(C(C(C=C1)(F)S(=O)(=O)C1(C(C(C(C=C1)F)(F)F)(F)F)F)(F)F)(F)F WTYCHAVEQAWVIZ-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- XXFXTBNFFMQVKJ-UHFFFAOYSA-N [diphenyl(trityloxy)methyl]benzene Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)OC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 XXFXTBNFFMQVKJ-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 description 1
- 229960002535 alfacalcidol Drugs 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
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000001749 antrachitic effect Effects 0.000 description 1
- TXHIDIHEXDFONW-UHFFFAOYSA-N benzene;propan-2-one Chemical compound CC(C)=O.C1=CC=CC=C1 TXHIDIHEXDFONW-UHFFFAOYSA-N 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 230000003913 calcium metabolism Effects 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- OEERIBPGRSLGEK-UHFFFAOYSA-N carbon dioxide;methanol Chemical compound OC.O=C=O OEERIBPGRSLGEK-UHFFFAOYSA-N 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- KZTYYGOKRVBIMI-UHFFFAOYSA-N diphenyl sulfone Chemical compound C=1C=CC=CC=1S(=O)(=O)C1=CC=CC=C1 KZTYYGOKRVBIMI-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960002061 ergocalciferol Drugs 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000002222 fluorine compounds Chemical class 0.000 description 1
- 125000001153 fluoro group Chemical class F* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- -1 hexafluoro compound Chemical class 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000011837 pasties Nutrition 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
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- CASUWPDYGGAUQV-UHFFFAOYSA-M potassium;methanol;hydroxide Chemical compound [OH-].[K+].OC CASUWPDYGGAUQV-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000012958 reprocessing Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- GRONZTPUWOOUFQ-UHFFFAOYSA-M sodium;methanol;hydroxide Chemical compound [OH-].[Na+].OC GRONZTPUWOOUFQ-UHFFFAOYSA-M 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 238000005866 tritylation reaction Methods 0.000 description 1
- 239000011653 vitamin D2 Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- 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
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
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Description
i DK 168639 B1
Opfindelsen angår en særlig fremgangsmåde til fremstilling af den fra DK patentansøgning nr. 1370/83 kendte forbindelse 26,26,26,27,27,27-hexafluor-1a,25-dihydroxy-cholesterol, der let kan omdannes til en forbindelse, der 5 har vitamin D-lignende virkning, samt hidtil ukendte mellemprodukter til brug ved denne fremgangsmåde.
Vitamin er et velkendt middel til at kontrollere calcium- og phosphorhomeostase. Hos det normale dyr eller 10 menneske vides denne forbindelse at stimulere tarmcalci-umtransporten.
Det er nu også velkendt, at vitamin D^ for at være effektivt skal omdannes til de hydroxylerede former af vitami-15 net. F.eks. hydroxyleres vitaminet først i leveren til dannelse af 25-hydroxy-vitamin Dg og hydroxyleres yderligere i nyrerne til frembringelse af lo,25-dihydroxy vitamin Dg eller 24,25-dihydroxy vitamin Dg. Den lø-hydroxy-lerede form af vitaminet antages sædvanligvis at være den 20 fysiologisk aktive eller hormonale form af vitaminet og være ansvarlig for, hvad der betegnes vitamin D-lignende virkninger som f.eks. en forøgelse af tarmabsorptionen af calcium og phosphat, mobilisering af knoglemineral og tilbageholdelse af calcium i nyrerne.
25
Siden opdagelsen af de biologisk aktive metabolitter af vitamin D har der været stor interesse for fremstillingen af strukturelt analoge til disse metabolitter, fordi disse forbindelser kan udgøre værdifulde terapeutiske midler 30 til behandling af sygdomme, der skyldes sygelige tilstande i calciummetabolismen. En hel række vitamin D-lignende forbindelser er blevet syntetiserede. Se f.eks. USA patentskrifterne nr. 3 741 996, der omhandler la-hydroxy-cholecalciferol; nr. 3 907 843, der omhandler lø-hydroxy-35 ergocalciferol; nr. 3 786 062, der omhandler 22-dehydro-25-hydroxycholecalciferol, nr. 3 906 014, der omhandler 3-deoxy-lø-hydroxycholecalciferol og nr. 4 069 321, der DK 168539 B1 2 omhandler fremstillingen af forskellige sidekædefluorere-de vitamin derivater og sidekæde-fluorerede dihydrota-chysterolanaloge.
5 Et fluorderivat af den accepterede hormonale form af vitaminet, 1,25-dihydroxycholecalciferol (1,25-(011)20^) som er af særlig interesse er 24,24-difluor-l,25(0H)2D2, fordi denne forbindelse er karakteriseret ved i det mindste en lige så stor om ikke større virkning end Ι^δ-ίΟΗ^Ο^.
10 (Se USA patentskrift nr. 4 102 881).
Af interesse er også 26,26,26,27,27,27-hexafluorderivatet af 25-hydroxycholecalciferol (se USA patentskrift nr.
4 248 791) og 26,26,26,27,27,27-hexafluorderivatet af 15 la,25-dihydroxycholecalciferol (DK patentansøgning nr.
1376/83), der er karakteriseret ved i det væsentlige større vitamin D-lignende virkning end den hormonale form af vitaminet, 1,25-dihydroxycholecalciferol, ved forbindelsens evne til at stimulere calciumtransporten i tar-20 men, til at mobilisere calcium fra knogler og ved forbindelsens antirachitiske virkning efterprøvet ved rotteli-nieforsøget.
USA patentskrift nr. 4 248 791 beskriver en flertrins 25 fremgangsmåde til fremstilling af forbindelser, der er forskellige fra forbindelsen 11 i formelarket nedenfor (26,26,26,27,27,27-hexafluor-la,25-dihydroxycholesterol) ved at mangle en hydroxygruppe i la-stillingen. Forbindelsen, der allylbromeres i dette patent, er 30-acetoxy-30 derivatet.
Ved fremgangsmåden ifølge den foreliggende opfindelse anvendes derimod et alkylsilylderivat. Denne forskel er af afgørende betydning. Dersom den tidligere kendte forbin-35 delse også indeholdt en acetoxygruppe i den ene stilling, ville denne højst sandsynligt blive fjernet under omdannelsen. Når først en hydroxygruppe er fjernet i denne po- DK 168539 B1 3 sition, kan den ikke genindføres.
Det har nu overraskende vist sig, at nævnte forbindelse 11 (dvs. en hexafluorforbindelse med la og 25 hydroxy-5 grupper i molekylet) på sikker og simpel måde kan fremstilles ved den her omhandlede særlige fremgangsmåde, idet man går ud fra alkylsilylderivatet.
Man har således fundet en særlig fremgangsmåde til frem-10 stilling af 26,26,26,27,27,27-hexafluor-la, 25-dihydroxy-cholesterol, der er ejendommelig ved det i den kendetegnende del af krav 1 angivne. Ved fremgangsmåden opnås den ønskede forbindelse med udemærket udbytte. Denne forbindelse kan let omdannes til det højt aktive 26,26,26,27,-15 27,27-hexafluor-la,25-dihydroxycholecalciferol.
Herudover angår opfindelsen hidtil ukendte mellemprodukter til brug ved fremgangsmåden, der er ejendommelige ved det i krav lo, 11 og 12 angivne.
20
Ved fremgangsmåden, der er angivet i følgende reaktionsskema omdannes kommercielt tilgængelig cholensyre til esteren (1), der oxideres med dichlordicyanobenzoquinon (DDQ) til opnåelse af trienonen (2). Behandling af trie-25 nonen (2) med alkalisk hydrogenperoxid giver 1,2-epoxidet (3), der reduceres med metallisk lithium og ammoniumchlo-rid i flydende ammoniak-tetrahydrofuran til opnåelse af triolen (4) (65% udbytte). Efter tritylering efterfulgt af acetylering og hydrolyse fås 1,3-diacetatet (5) i 72% 30 udbytte. 24-ol'en (5) omdannes til bromidet (6) via 24-tosylat og herefter til phenylsulfonen (7).
Efter omdannelse til 1,3-ditriethylsilylderivatet (9) behandles sulfonen ved fremgangsmåden ifølge opfindelsen 35 med hexafluoracetone til opnåelse af hexafluor-phenylsul-fonen (10), efterfulgt af hydrolyse med HC1 til opnåelse af den tilsvarende triol og efterfølgende reduktion med DK 168539 B1 4 natriumamalgam giver 26,26,26,27,27,27-hexafluor-l,25-di-hydroxycholesterol (11) i udbytte på 72%.
rtV /0^°°"' /\,χ:εοοη· .ocr —> "VV o ,Vyl 1 2 3 10 •γ-ν^ΟΗ »VA „-Ca 15 4 5
Aco 7^S°2Ph _ Xo2^ /rØ
20 At»VV “"vV
6 7 i° ,x,x^so2ph ^;øT”/h
• HIT Et3si0 vV
8 Sfl,Ph 9 ?Λ0“ Λ0^°η3 X\j 3
EtgSiO N-x H0 10 11 35 DK 168539 B1 5
Opfindelsen beskrives nærmere i detaljer, idet der henvises til det foranstående i reaktionsskema.
Omdannelsen af cholensyre til esteren (1) kan udføres ved 5 allerede kendte metoder, hvilket er velkendt af fagman den.
25.26.27- Trinorcholesta-l,4,6-trien-3-on-24-syremethyl-ester (2) 10
En opløsning af esteren (1) (110 g, 0,28 mol) og dichlor-dicyanobenzoquinon (212 g, 3,3 ækv. ) i dioxan (850 ml) opvarmedes 14 timer med tilbagesvaling under nitrogen. Efter afkøling frafiltreredes det fremkomne bundfald og 15 vaskedes med flere portioner CH2C12. Filtratet inddampedes til tørhed, og remanensen chromatograferedes på aluminiumoxid (2 kg). Eluering med benzen-AcOEt (50:1) gav trienonen (2) (60 g, 55%), smp.: 134-136 °C (fra methanol); [ et]30/D = -42,5° (C=l, CHC10); UV (EtOH), λ v 299
g lltoX
20 (s 13.000), 258 (e 9.200); 223 nm (ae 12.000); IR
(CHClg), 1730, 1655 cm-1; 1H-NMR, δ 0,80 (3H, s, 18-Hg), 0,93 (3H, d, J = 6 Hz, 21-H3), 1,2 (3H, s, 19-H3), 3,68 (3H, s, -C02Me), 5,90-6,30 (4H, m, 2-, 4-, 6-, og 7-H), 7,05 (IH, d, J=10 Hz, 1-H), (fundet; M+, 382,2494, 25 CH25H3^03 kræver M, 382,2505).
25.26.27- Trinor-lg,2g-epoxycholesta-4,6-dien-3-on-24-sy-remethylester (3) 30 En opløsning af trienonen (2) (30 g, 0,0785 mol) i methanol (550 ml) sattes til en blanding af 5% NaOH-MeOH (15 ml) og 30% H202 (42 ml). Reaktionsblandingen henstod 18 timer ved stuetemperatur og ekstraheredes med AcOEt; og ekstrakten vaskedes med saltopløsning, tørredes over 35 Na2S0^ og inddampedes. Chromatografi på silieagel (400 g) og eluering med benzen-AcOEt (100:1) gav epoxidet (3) (24,8 g, 80%) med smp.: 166-168 °C (fra methanol); DK 168539 B1 6 [ct]27/D = +187,3° (C=l, CHC10 ) ; UV (EtOH), 290 nm (e o max 22.000), IR (CHC13), 1730, 1660 cm ; H-NMR, 0,78 (3H, s, 18-H), 0,95 (3H, d, J = 6 Hz, 21-H3), 1,18 (3H, s, 19-H3), 3,42 (IH, dd, J-4 og 1,5 Hz, 1-H), 3,58 (IH, d, J=4 5 Hz; 20-H), 3,67 (3H, s, -C02Me); 5,61 (IH, d, J-1,5 Hz, 4-H), 6,04 (2H, br, 6- og 7-H), (fundet; C75,27, H 8,61, ^H25H34®3 ^ræver c 75,34; H 8,60).
25,26,27-Trinorcholest-5-en-lg,30,24-triol (4) 10
En firehalset kolbe udstyredes med en forseglet mekanisk omrøring, en tildrypningstragt, en kold finger fyldt med tøris og en tilledning forbundet med en vandfri ammoniakkilde. Nitrogen skylledes gennem systemet, og herefter 15 blev vandfrit ammoniak (1000 ml) indelukket i kolben under afkøling (tøris-methanol). Lithiumtråd (30,5 g) blev udskåret i korte stykker og tilsat i løbet af 30 minutter. Efter 1 times omrøring tildryppedes epoxidet (3) (21,7 g, 0,054 mol) i tør THF (1000 ml) i løbet af 1,5 20 time. Herefter tilsattes vandfrit NH^Cl (350 g), og blandingen blev hvid og pastaagtig. Afkølingsbadet fjernedes og det meste af ammoniakken fjernedes i en strøm af nitrogen. Vand sattes forsigtigt til, og blandingen ekstra-heredes med AcOEt. Ekstrakten vaskedes med fortyndet HC1, 25 mættet NaHCOg og saltopløsning, tørredes over Na2S04 og inddampedes til tørhed. Chromatografi på silicagel (350 g), der elueredes med benzén-acetone (3:1) gav forbindelsen (13,9 g, 65%) med smp.: 210-211 °C (fra methanol-acetone); [et]26/D = -17,4° (C,l, methanol); IR (KBR) 3400 30 cm"1; 1H-NMR (py-dg CDC13, 1:1), δ 0,67 (3H, s, 18-Hg), 1,02 (3H, s, 21-H3), 3,69 (2H, m, 24-H2), 3,95 (IH, m, la-H), 4,40 (IH, m, 3-H), 5,50 (IH, m, 6-H), (fundet; M+, 376,2956, CH24H3C)03 kræver M, 376,2974).
35 DK 168539 B1 7 25,26,27-Trinorcholest-5-en-lg,3fl, 24-triol-l, 3-diacetat (5)
En opløsning af triolen (4) (1,0 g) og tritylchlorid (2,2 5 g) i pyridin (10 ml) omrørtes natten over ved stuetemperatur. Til reaktionsblandingen sattes eddikesyreanhydrid (2 ml) og en katalytisk mængde dimethylaminopyridin, og blandingen omrørtes i 4 timer ved 40 °C. Almindelig oparbejdning gav la,30-diacetoxychol-5-en-24-yl-tritylat.
10
Den rå tritylether behandledes med vandig dioxan (50 ml) indeholdende en katalytisk mængde p-TsoH ved 90-100 °C i 3 timer. Efter sædvanlig oparbejdning under anvendelse af AcOEt til ekstraktion chromatograferedes den urensede 15 forbindelse på silicagel (50 g). Den fraktion, der elue-rede med benzen-AcOEt (10:1) gav det ønskede diacetat (5) (880 mg) i form af et amorft pulver; [a]26/D = -16,4° (C 1,05); NMR, δ 0,68 (3H, s, 13-Me), 0,92 (3H, d, J=6 Hz, 20-Me), 1,10 (3H, s, 10-Me), 2,02, 2,06 (6H, hvert s, 20 acetyl) 3,59 (2H, t, J=6 Hz, 24-H2), 4,90 (IH, m, 3a-H), 5,04 (IH, m, 10-H), 5,51 (IH, m, 6H); λ (CHC10), 3450,
« IDdX O
1730 og 1250 cm ; (fundet: M -2AcOH, 340,2765, C^H^O kræver M, 340,2765).
25 25,26,27-Trinorcholest-24-brom-5-en-lg,30-diol-diacetat (6)
Til en opløsning af (5) (177 mg) i pyridin (3 ml) sattes tosylchlorid (96,8 mg) ved 0 °C, og blandingen omrørtes 30 natten over ved 0 °C. Adskillige stykker is tilsattes, og hele blandingen omrørtes 1 time. Almindelig oparbejdning under anvendelse af AcOEt til ekstraktion gav en farveløs olie af tosylatet (149 mg). Til en opløsning af tosylatet (149 mg) i DMF (5 ml) sattes LiBr (42,4 mg), og blandin-35 gen opvarmedes under tilbagesvaling i 2 timer i en argonatmosfære. Reaktionsblandingen afkøledes, vand og AcOEt tilsattes, og den organiske fase vaskedes først med 2N
DK 168539 B1 8 HC1, derefter med fortyndet NaHCO^ og med mættet NaCl og tørredes (MgSO^). Den ved afdampning af opløsningsmidlet tilbageblevne remanens rensedes ved hjælp af søjlechroma-tografi på silicagel (4 g). Eluering med benzen gav bro-5 midet (6) (107 mg) med et smp.: 127-129 “C (fra hexan); [a]26/D = -16,9° (C 1,00).
25,26,27-Trinor-lfl,30-diacetoxycholest-5-en-24-yl-phenyl-sulfon (7) 10
Til en opløsning af bromidet (6) (164 mg) i DMF (8 ml) sattes PhSO^Na (260 mg), og suspensionen omrørtes ved 70-80 °C i 4 timer. Reaktionsblandingen afkøledes, og der ekstraheredes med ether. Den organiske fase vaskedes med 15 2N HC1, fortyndet NaHCO^ og saltopløsning, og der tørredes over MgSO^. Den tilbageblevne remanens chromatografe-redes efter afdampning af opløsningsmidlet på silicagel (20 g). Eluering med benzen gav sulfonen (7) (169 mg) som et amorft pulver; [a]28/D = -16,9° (C 0,66); NMR, δ 0,64 20 (3H, s, 13-Me), 0,86 (3H, d, J=6 Hz, 20-Me), 1,08 (3H, s, 10-Me), 2,02, 2,05 (6H, hvert s, acetyl), 3,04 (2H, t, J=7 Hz, 24-H2), 4,91 (IH, m, 3«-H), 5,04 (IH, m, la-H), 5,50 (IH, m, 6H), 7,50 (5H, Ar-).
25 25,26,27-Trinorcholest-la,30-diol-5-enyl-phenylsulfon (8)
En opløsning af diacetatet (7) (42,8 mg) i 5% KOH-MeOH (3 ml) og THF (2 ml) omrørtes ved stuetemperatur i 18 timer. Efter sædvanlig oparbejdning rensedes forbindelsen ved 30 søjlechromatografi på silicagel (8 g). Eluering med he-xan-AcOEt (1:1) gav den ønskede diol (8) (31,2 mg) med en smp.: 110-111 °C (-hexan).
35 DK 168539 B1 9 25, 26,27-Trinor-la,3)3--bistriethylsiloxycholesteryl-phe-nylsulfon (9)
Efter omsætning af 75 mg (150 mol) af (8) med triethylsi-5 lylchlorid (0,3 ml) og triethylamin (0,5 ml) i pyridin (3 ml) i 15 timer ved stuetemperatur, udhældtes reaktions-blandingen i isvand og ekstraheredes med ether. Det organiske lag vaskedes først med 0,5 N-HC1, saltopløsning og dernæst tørredes over MgSO^. Ekstrakterne søjlechromato-10 graferedes (Si02), hvorved der opnåedes 61,8 mg (85 mol, 57%) af (9) som en olie; MS m/e 728, 596 (M+ - HOSiEt^), 567, 464, 401; NMR, δ (CDClg) 0,44-0,7Q (15H, m, C-18 og SiCH2CH3), 3 07 (2H, t, J=7Hz, C_24), 3,83 (IH, m, C_l), 4,00 (IH, m/ C-3), 5,50 (IH, m, C-6), 7,50-7,80 (3H, m) 15 7,95-8,10 (2H, m).
1,25-Dihydroxy-26,26,26,27,27,27-hexafluorcholesteryl-24-phenylsulfon-1,3-ditriethylsilylether (10) 20 Til en opløsning af diisopropylamin (28 liter, 200 mol) i THF (2 ml) sattes ved -78 °C under en argonatmosfære n-BuLi (190 mol), og den fremstillede opløsning omrørtes i 5 minutter. Til denne LDA-opløsning sattes (9) (58 mg; 80 mol) i THF (3 ml), og reaktionsblandingen omrørtes 20 mi-25 nutter ved 0 °C. Der afkøledes atter til -78 °C (tøris-acetonebad) og behandledes med et overskud af hexafluor-acetonegas i 3 minutter ved denne temperatur. Reaktionsblandingen bratkøledes ved tilsætning af NH^Cl-opløsning og ekstraheredes med ether. Det organiske lag vaskedes 30 med saltopløsning, tørredes over MgSO^ og rensedes ved silicagelchromatografi. Den fraktion, der eluerede med benzenen, gav 53 mg (74%) af additionsproduktet (10) som en stereoisomer blanding; NMR, 6 (CDCl^), 3,53 (IH, m, C- 24), 3,81 (IH, m, C-l), 3,98 (IH, m, C-3), 5,47 (IH, m, 35 C-6), 6,80 (IH, bred, 25-OH), 7,67-7,87 (3H, m), 8,00- 8,13 (2H, m); 19F-NMR (CDClg) 6 +7,8 og +1,08 ppm.
DK 168539 B1 10 la,25-Dihydroxy-26,26,26,27,27,27-hexafluorcholesterol (11)
En opløsning af 45 rag (10) i en blanding af dimethoxy- 5 ethan (1 ml), MeOH (1 ml) og 1N-HC1 (1 ml) omrørtes 1 time ved stuetemperatur. Reaktionsblandingen fortyndedes med saltopløsning og ekstraheredes med ethylacetat. Efter at de organiske ekstrakter var koncentreret i vakuum chromatograferedes remanensen på silicagel (C^C^-AcOEt 10 2:3 v/v), hvorved der opnåedes 34,0 mg (100%) af triolen; NMR, δ (CDC13), 0,60 (s, C-18), 0,77 (d, J=6 Hz, C-21), 1,00 (s, C-19), 1,70 (1-OH og 3-OH), 3,50 (IH, m, C-24), 3,83 (IH, m, C-l), 4,00 (IH, m, C-3), 5,60 (IH, m, C-6), 6,77 (IH, bred, 25-0H), 7,43-7,87 (3H, m), 8,00-8,10 (2H, 19 15 m); F-NMR (CDCl^), δ +7,7 og +10,8 ppm.
Til en blanding af 31 mg af triolen og 50 mg Na2HP0^ i THF (2 ml) og MeOH (2 ml) sattes 800 mg 5%-Na-(Hg), og den samlede masse omrørtes 45 minutter ved stuetempera-20 tur. Herefter tilsattes yderligere 300 mg 5% Na(Hg), og blandingen omrørtes i 9,5 timer ved stuetemperatur. Reaktionsblandingen fortyndedes med saltopløsning og ekstraheredes med AcOEt. Ekstrakterne chromatograferedes på silicagel (Of^C^-AcOEt 1:2), hvorved der opnåedes 17,6 mg 25 (72%) af det ønskede hexafluorid (11) med et smeltepunkt 201-202 °C (fra CHCl^). Spektraldata (NMR og massespektrum) af (11) var identisk med resultaterne fra en autentisk prøve.
30 26,26,26,27,27,27-Hexafluor-ΐα,25-dihydroxycholesterol kan omdannes til 26,26,26,27,27,27-hexafluor-la,25-dihy-droxycholecalciferol således som beskrevet i DK ansøgning nr. 1576/83.
35
Claims (12)
1. Fremgangsmåde til fremstilling af 26,26,26,27,27,27-5 hexafluor-1«,25-dihydroxycholesterol, kendeteg net ved, at man behandler et arylsulfonylderivat med formlen SO-Ar alk^ S i 0 2 15 alk^ SiO hvori alk betegner en alkylgruppe, og Ar betegner en phe-20 nylgruppe, med hexafluoracetone, hydrolyserer den frem stillede 25-hydroxy-26,26,26,27,27,27-hexafluorforbindel-se og reducerer den fremstillede triol med natriumamalgam, således at phenylsulfonylgruppen fjernes.
2. Fremgangsmåde ifølge krav 1, kendetegnet ved, at alk betegner en ethylgruppe.
3. Fremgangsmåde ifølge et vilkårligt af de foregående krav, kendetegnet ved, at phenyl sul f ony Ideri-30 vatet er opnået ved silylering af hydroxyforbindelsen 35 DK 168539 B1 T ao^Ar oh HO hvori Ar betegner phenyl. 10
4. Fremgangsmåde ifølge krav 3, kendetegnet ved, at silyleringen er udført med triethylsilylchlorid og triethylamin. 15
5. Fremgangsmåde ifølge krav 3 eller 4, kendetegnet ved, at hydroxy for bi ndel s en er fremstillet ved at omsætte bromidet med formlen
20 Vvv yv I sr AcO ysj/v AcO 30 hvori Ac betegner acetyl, med en phenylsulfonylnatrium og hydrolyse af det fremstillede diacyloxy-phenylsulfo-nyIderivat.
6. Fremgangsmåde ifølge krav 5, kendetegnet 35 ved, at bromidet er fremstillet ved acylering af triolen med formlen DK 168539 B1 OH OH HO 10 og bromering af det fremstillede la, 3i3-diacylat efter to-sylering af 24-OH gruppen.
7. Fremgangsmåde ifølge krav 6, kendetegnet ved, at triolen er fremstillet ved reduktion af epoxidet med formlen ^ cooch3 25 o
8. Fremgangsmåde ifølge krav 7, kendetegnet ved, at epoxidet er opnået ved behandling af trienonen 30 med formlen 35 DK 168539 B1 COOCH3 10 med alkalisk hydrogenperoxid.
9. Fremgangsmåde ifølge krav 8, kendetegnet 15 ved, at trienonen er opnået ved oxidering af en ester med formlen C00CH3 20 Γτ"! XCr
25 S0 med dichlordicyanobenzoquinon.
10. Forbindelser med formlen Vy/s/^SO-Ar /\ιΛ <W3S10~\/*V DK 168539 B1 hvor Ar betegner phenyl.
11. 25,26,27-trinor-la,2Æ-epoxy-cholesta-4,6-dien-3-on- 24-syremethylester. 5
12. Forbindelser med formlen S°2Ar (c 7h )3sio vs. , 10 /Yn ^ ^C2H5^3Si0 15 hvori Ar betegner phenyl. 20 25 30 35
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US38205582 | 1982-05-26 | ||
| US06/382,055 US4411833A (en) | 1982-05-26 | 1982-05-26 | Method for preparing 26,26,26,27,27,27-hexafluoro-1α,25-dihydroxycholesterol |
| PCT/US1983/000577 WO1983004256A1 (en) | 1982-05-26 | 1983-04-18 | METHOD FOR PREPARING 26,26,26,27,27,27-HEXAFLUORO-1alpha,25-DIHYDROXYCHOLESTEROL |
| US8300577 | 1983-04-18 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK32684D0 DK32684D0 (da) | 1984-01-25 |
| DK32684A DK32684A (da) | 1984-01-25 |
| DK168539B1 true DK168539B1 (da) | 1994-04-18 |
Family
ID=23507359
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK032684A DK168539B1 (da) | 1982-05-26 | 1984-01-25 | Speciel fremgangsmåde til fremstilling af 26,26,26,27,27,27-hexafluor-1alfa,25-dihydroxycholesterol og mellemprodukter til brug herved |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US4411833A (da) |
| JP (2) | JPH0742305B2 (da) |
| AU (1) | AU561182B2 (da) |
| BE (1) | BE896830A (da) |
| CH (2) | CH663212A5 (da) |
| DE (1) | DE3390016C2 (da) |
| DK (1) | DK168539B1 (da) |
| FR (2) | FR2527615B1 (da) |
| GB (2) | GB2121044B (da) |
| IE (1) | IE55022B1 (da) |
| IL (1) | IL68537A (da) |
| IT (1) | IT1203706B (da) |
| NL (1) | NL8320153A (da) |
| WO (1) | WO1983004256A1 (da) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4613594A (en) * | 1984-11-16 | 1986-09-23 | Hoffmann-La Roche Inc. | Fluorinated vitamin D3 compounds |
| US4749710A (en) * | 1985-05-01 | 1988-06-07 | Hoffmann-La Roche Inc. | Immunosuppressive agents |
| US4619920A (en) * | 1985-09-16 | 1986-10-28 | Wisconsin Alumni Research Foundation | 26,26,26,27,27-pentafluoro-1α-hydroxy-27-methoxyvitamin D3 |
| JPH0764804B2 (ja) * | 1986-04-25 | 1995-07-12 | 住友製薬株式会社 | 活性型ビタミンｄ３のフッ素誘導体 |
| WO1990009179A1 (en) * | 1989-02-16 | 1990-08-23 | University Of Georgia Research Foundation, Inc. | Treatment of tibial dyschondroplasia |
| US5366736A (en) * | 1989-02-16 | 1994-11-22 | University Of Georgia Research Foundation, Inc. | Vitamin D derivative feed compositions and methods of use |
| US5316770A (en) * | 1989-02-16 | 1994-05-31 | University Of Georgia Research Foundation, Inc. | Vitamin D derivative feed compositions and methods of use |
| AU6247194A (en) * | 1993-02-19 | 1994-09-14 | Wisconsin Alumni Research Foundation | Use of 26,26,26,27,27,27-hexafluoro-1alpha,25-dihydroxycholecalcife rol for the treatment of calcium metabolism disorders |
| JP2009532458A (ja) * | 2006-04-06 | 2009-09-10 | ウイスコンシン アラムニ リサーチ ファンデーション | ２−メチレン−１α−ヒドロキシ−１９，２１−ジノルビタミンＤ３類縁体およびその使用 |
| NZ570712A (en) * | 2006-04-06 | 2011-11-25 | Wisconsin Alumni Res Found | 2-methylene-1alpha-hydroxy-18,19,21-trinorvitamin D3 analogs and uses thereof |
| AU2007291005A1 (en) * | 2006-04-06 | 2008-03-06 | Wisconsin Alumni Research Foundation | 19-nor-vitamin D analogs with 1,2,or 3,2 heterocyclic ring |
| CA2639585A1 (en) * | 2006-04-06 | 2007-10-06 | Wisconsin Alumni Research Foundation | 2-methylene-1.alpha., 25-dihydroxy-18, 19, 21-trinorvitamin d3 and uses thereof |
| US8404666B2 (en) | 2006-04-06 | 2013-03-26 | Wisconsin Alumni Research Foundation | 2-substituted-1α,25-dihydroxy-19,26,27-trinor vitamin D analogs and uses thereof |
| MX2008012912A (es) * | 2006-04-06 | 2008-11-26 | Wisconsin Alumni Res Found | Analogos de 2-metilen-1a,25-dihidroxi-19,21-dinorvitamina d3 y sus usos. |
| NZ570816A (en) * | 2006-04-10 | 2011-07-29 | Wisconsin Alumni Res Found | 1alpha-hydroxy-2-(3'-hydroxypropylidene)-19-nor-vitamin D compounds with a 1,1-dimethylpropyl side chain |
| AU2010208323B2 (en) | 2009-01-27 | 2016-03-10 | Berg Llc | Vitamin D3 and analogs thereof for alleviating side effects associated with chemotherapy |
| EP2464357B1 (en) | 2009-08-14 | 2019-05-22 | Berg LLC | Vitamin d3 and analogs thereof for treating alopecia |
| SG10201709894RA (en) | 2013-05-29 | 2018-01-30 | Berg Llc | Preventing or mitigating chemotherapy induced alopecia using vitamin d |
| CN113968888B (zh) * | 2020-07-24 | 2023-06-27 | 上海医药工业研究院 | 一种胆甾衍生物的制备方法、其中间体及应用 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4183852A (en) * | 1977-07-18 | 1980-01-15 | Kaiser Emil T | Process for preparing 25-hydroxycholesterol |
| LU80545A1 (de) * | 1978-11-17 | 1980-06-05 | Hoffmann La Roche | Verfahren zur herstellung von 1a,3s-dihydroxy->5-steroiden |
| US4217279A (en) * | 1978-12-18 | 1980-08-12 | Kaiser Emil T | Synthesis of steroids |
| JPS5598199A (en) * | 1979-01-17 | 1980-07-25 | Eisai Co Ltd | Preparation of 25-hydroxy cholesta-1,4,6-trien-3-one |
| US4269777A (en) * | 1979-05-21 | 1981-05-26 | Wisconsin Alumni Research Foundation | Isotopically labeled vitamin D derivatives and processes for preparing same |
| IL60270A0 (en) * | 1979-06-14 | 1980-09-16 | Diamond Shamrock Corp | Preparation of 25-ydroxycholesterol |
| US4248791A (en) * | 1980-02-04 | 1981-02-03 | Wisconsin Alumni Research Foundation | 25-Hydroxy-26,26,26,27,27,27-hexafluorocholecalciferol |
| US4360470A (en) * | 1980-10-22 | 1982-11-23 | Hoffmann-La Roche Inc. | Process and intermediates for the synthesis of Vitamin D3 metabolites and chenodeoxycholic acid |
| US4358406A (en) * | 1981-07-27 | 1982-11-09 | Wisconsin Alumni Research Foundation | 26,26,26,27,27,27-Hexafluoro-1α,25-dihydroxycholecalciferol and process for preparing same |
-
1982
- 1982-05-26 US US06/382,055 patent/US4411833A/en not_active Expired - Lifetime
-
1983
- 1983-04-18 WO PCT/US1983/000577 patent/WO1983004256A1/en not_active Ceased
- 1983-04-18 CH CH341/84A patent/CH663212A5/de not_active IP Right Cessation
- 1983-04-18 AU AU15542/83A patent/AU561182B2/en not_active Ceased
- 1983-04-18 DE DE19833390016 patent/DE3390016C2/de not_active Expired
- 1983-04-18 CH CH4413/86A patent/CH662572A5/de not_active IP Right Cessation
- 1983-04-18 NL NL8320153A patent/NL8320153A/nl not_active Application Discontinuation
- 1983-04-29 IL IL68537A patent/IL68537A/xx not_active IP Right Cessation
- 1983-05-24 IT IT21261/83A patent/IT1203706B/it active
- 1983-05-24 IE IE1226/83A patent/IE55022B1/en not_active IP Right Cessation
- 1983-05-25 FR FR8308650A patent/FR2527615B1/fr not_active Expired
- 1983-05-25 BE BE0/210839A patent/BE896830A/fr not_active IP Right Cessation
- 1983-05-26 GB GB08314612A patent/GB2121044B/en not_active Expired
- 1983-11-04 FR FR8317598A patent/FR2533929B1/fr not_active Expired
-
1984
- 1984-01-25 DK DK032684A patent/DK168539B1/da active IP Right Grant
- 1984-06-19 GB GB08415630A patent/GB2140016B/en not_active Expired
-
1992
- 1992-01-23 JP JP4032644A patent/JPH0742305B2/ja not_active Expired - Lifetime
- 1992-01-23 JP JP4032645A patent/JPH0742306B2/ja not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| IL68537A0 (en) | 1983-07-31 |
| GB2121044B (en) | 1986-01-02 |
| DK32684D0 (da) | 1984-01-25 |
| BE896830A (fr) | 1983-09-16 |
| DK32684A (da) | 1984-01-25 |
| GB2121044A (en) | 1983-12-14 |
| US4411833A (en) | 1983-10-25 |
| WO1983004256A1 (en) | 1983-12-08 |
| FR2533929B1 (fr) | 1986-10-31 |
| FR2527615B1 (fr) | 1986-05-23 |
| IL68537A (en) | 1986-07-31 |
| IT1203706B (it) | 1989-02-15 |
| IE55022B1 (en) | 1990-04-25 |
| AU1554283A (en) | 1983-12-16 |
| NL8320153A (nl) | 1984-04-02 |
| JPH0742305B2 (ja) | 1995-05-10 |
| DE3390016C2 (de) | 1989-08-10 |
| IT8321261A0 (it) | 1983-05-24 |
| DE3390016T1 (de) | 1984-05-17 |
| AU561182B2 (en) | 1987-04-30 |
| JPH0742306B2 (ja) | 1995-05-10 |
| CH663212A5 (de) | 1987-11-30 |
| GB8314612D0 (en) | 1983-06-29 |
| GB2140016A (en) | 1984-11-21 |
| IE831226L (en) | 1983-11-26 |
| JPH0578388A (ja) | 1993-03-30 |
| CH662572A5 (de) | 1987-10-15 |
| GB8415630D0 (en) | 1984-07-25 |
| JPH0578387A (ja) | 1993-03-30 |
| FR2533929A1 (fr) | 1984-04-06 |
| GB2140016B (en) | 1986-01-02 |
| FR2527615A1 (fr) | 1983-12-02 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) |