JP2016531159A - エステトロールの製造プロセス - Google Patents
エステトロールの製造プロセス Download PDFInfo
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- JP2016531159A JP2016531159A JP2016543386A JP2016543386A JP2016531159A JP 2016531159 A JP2016531159 A JP 2016531159A JP 2016543386 A JP2016543386 A JP 2016543386A JP 2016543386 A JP2016543386 A JP 2016543386A JP 2016531159 A JP2016531159 A JP 2016531159A
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- Prior art keywords
- ether
- compound
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- group
- ethers
- Prior art date
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- AJIPIJNNOJSSQC-NYLIRDPKSA-N estetrol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)[C@@H]4O)O)[C@@H]4[C@@H]3CCC2=C1 AJIPIJNNOJSSQC-NYLIRDPKSA-N 0.000 title claims abstract description 56
- 229950009589 estetrol Drugs 0.000 title claims abstract description 55
- 238000004519 manufacturing process Methods 0.000 title claims description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 115
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 64
- 238000000034 method Methods 0.000 claims abstract description 56
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 239000012453 solvate Substances 0.000 claims abstract description 28
- 150000002170 ethers Chemical group 0.000 claims abstract description 20
- 150000002148 esters Chemical group 0.000 claims abstract description 17
- 229910000489 osmium tetroxide Inorganic materials 0.000 claims abstract description 13
- 239000007800 oxidant agent Substances 0.000 claims abstract description 13
- 239000012285 osmium tetroxide Substances 0.000 claims abstract description 9
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000004657 carbamic acid derivatives Chemical group 0.000 claims abstract description 6
- 150000004649 carbonic acid derivatives Chemical group 0.000 claims abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 122
- -1 phenylthiomethyl Chemical group 0.000 claims description 75
- 125000000217 alkyl group Chemical group 0.000 claims description 63
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 28
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- GVHVFVYYNDTEJJ-UHFFFAOYSA-N 1-[1-(1-butoxyethoxy)ethoxy]butane Chemical compound CCCCOC(C)OC(C)OCCCC GVHVFVYYNDTEJJ-UHFFFAOYSA-N 0.000 claims description 11
- UYPYRKYUKCHHIB-UHFFFAOYSA-N trimethylamine N-oxide Chemical compound C[N+](C)(C)[O-] UYPYRKYUKCHHIB-UHFFFAOYSA-N 0.000 claims description 8
- 230000001590 oxidative effect Effects 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 3
- 229920003228 poly(4-vinyl pyridine) Polymers 0.000 claims description 3
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims 1
- 229910052707 ruthenium Inorganic materials 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 34
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 34
- 239000000203 mixture Substances 0.000 description 33
- 125000006239 protecting group Chemical group 0.000 description 27
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- 125000003118 aryl group Chemical group 0.000 description 23
- 150000002009 diols Chemical class 0.000 description 23
- 230000015572 biosynthetic process Effects 0.000 description 21
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 229960005309 estradiol Drugs 0.000 description 18
- 229910052739 hydrogen Inorganic materials 0.000 description 16
- 239000001257 hydrogen Substances 0.000 description 16
- 229960003399 estrone Drugs 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 125000000753 cycloalkyl group Chemical group 0.000 description 14
- 238000007254 oxidation reaction Methods 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- 230000003647 oxidation Effects 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000007792 addition Methods 0.000 description 11
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 10
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 10
- 125000003710 aryl alkyl group Chemical group 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 229960001359 estradiol 3-benzoate Drugs 0.000 description 9
- 125000001153 fluoro group Chemical group F* 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 235000012970 cakes Nutrition 0.000 description 7
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- JIWAALDUIFCBLV-UHFFFAOYSA-N oxoosmium Chemical compound [Os]=O JIWAALDUIFCBLV-UHFFFAOYSA-N 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 150000003431 steroids Chemical class 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 235000021463 dry cake Nutrition 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 239000013641 positive control Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 229910052717 sulfur Chemical group 0.000 description 5
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 5
- UZKWTJUDCOPSNM-UHFFFAOYSA-N 1-ethenoxybutane Chemical compound CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 238000005833 cis-dihydroxylation reaction Methods 0.000 description 4
- 238000007269 dehydrobromination reaction Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- IHUHXSNGMLUYES-UHFFFAOYSA-J osmium(iv) chloride Chemical compound Cl[Os](Cl)(Cl)Cl IHUHXSNGMLUYES-UHFFFAOYSA-J 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- HKUKRSLIEVXDMS-UHFFFAOYSA-N (13-methyl-17-oxo-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-3-yl) benzoate Chemical compound O=C1CCC2C1(C)CCC(C1=CC=3)C2CCC1=CC=3OC(=O)C1=CC=CC=C1 HKUKRSLIEVXDMS-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 3
- 229940011871 estrogen Drugs 0.000 description 3
- 239000000262 estrogen Substances 0.000 description 3
- 150000002167 estrones Chemical class 0.000 description 3
- 125000001033 ether group Chemical group 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- 229910052751 metal Chemical class 0.000 description 3
- 239000002184 metal Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000012286 potassium permanganate Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical group C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 2
- YUCBLVFHJWOYDN-HVLQGHBFSA-N 1,4-bis[(s)-[(2r,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]phthalazine Chemical compound C1=C(OC)C=C2C([C@H](OC=3C4=CC=CC=C4C(O[C@H]([C@@H]4N5CC[C@H]([C@H](C5)CC)C4)C=4C5=CC(OC)=CC=C5N=CC=4)=NN=3)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 YUCBLVFHJWOYDN-HVLQGHBFSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 2
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-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 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000005695 dehalogenation reaction Methods 0.000 description 2
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 2
- 150000004683 dihydrates Chemical class 0.000 description 2
- LJOQGZACKSYWCH-UHFFFAOYSA-N dihydro quinine Natural products C1=C(OC)C=C2C(C(O)C3CC4CCN3CC4CC)=CC=NC2=C1 LJOQGZACKSYWCH-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000003687 estradiol congener Substances 0.000 description 2
- 229940106582 estrogenic substances Drugs 0.000 description 2
- JKKFKPJIXZFSSB-CBZIJGRNSA-N estrone 3-sulfate Chemical compound OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKKFKPJIXZFSSB-CBZIJGRNSA-N 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 238000002657 hormone replacement therapy Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- DEDOPGXGGQYYMW-UHFFFAOYSA-N molinate Chemical compound CCSC(=O)N1CCCCCC1 DEDOPGXGGQYYMW-UHFFFAOYSA-N 0.000 description 2
- 229910052762 osmium Inorganic materials 0.000 description 2
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 2
- 229910000487 osmium oxide Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- IMSSROKUHAOUJS-MJCUULBUSA-N mestranol Chemical compound C1C[C@]2(C)[C@@](C#C)(O)CC[C@H]2[C@@H]2CCC3=CC(OC)=CC=C3[C@H]21 IMSSROKUHAOUJS-MJCUULBUSA-N 0.000 description 1
- 229960001390 mestranol Drugs 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- CPZBTYRIGVOOMI-UHFFFAOYSA-N methylsulfanyl(methylsulfanylmethoxy)methane Chemical compound CSCOCSC CPZBTYRIGVOOMI-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- LFMTUFVYMCDPGY-UHFFFAOYSA-N n,n-diethylethanamine oxide Chemical compound CC[N+]([O-])(CC)CC LFMTUFVYMCDPGY-UHFFFAOYSA-N 0.000 description 1
- UJZXIGKNPLTUOZ-UHFFFAOYSA-N n,n-dimethyl-1-phenylmethanamine oxide Chemical compound C[N+](C)([O-])CC1=CC=CC=C1 UJZXIGKNPLTUOZ-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- TYZYRCHEVXXLSJ-UHFFFAOYSA-N phenylmethoxymethoxymethoxymethylbenzene Chemical compound C=1C=CC=CC=1COCOCOCC1=CC=CC=C1 TYZYRCHEVXXLSJ-UHFFFAOYSA-N 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- CKVRJOBUMGJKDE-UHFFFAOYSA-N phenylsulfanylmethoxymethylsulfanylbenzene Chemical compound C=1C=CC=CC=1SCOCSC1=CC=CC=C1 CKVRJOBUMGJKDE-UHFFFAOYSA-N 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
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- AFGAERUSIXWDRP-UHFFFAOYSA-N potassium osmium(6+) Chemical compound [K+].[Os+6] AFGAERUSIXWDRP-UHFFFAOYSA-N 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- XKXIQBVKMABYQJ-UHFFFAOYSA-M tert-butyl carbonate Chemical compound CC(C)(C)OC([O-])=O XKXIQBVKMABYQJ-UHFFFAOYSA-M 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- KJTULOVPMGUBJS-UHFFFAOYSA-N tert-butyl-[tert-butyl(diphenyl)silyl]oxy-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C(C)(C)C)O[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 KJTULOVPMGUBJS-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- LGSAOJLQTXCYHF-UHFFFAOYSA-N tri(propan-2-yl)-tri(propan-2-yl)silyloxysilane Chemical compound CC(C)[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)C(C)C LGSAOJLQTXCYHF-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- WILBTFWIBAOWLN-UHFFFAOYSA-N triethyl(triethylsilyloxy)silane Chemical compound CC[Si](CC)(CC)O[Si](CC)(CC)CC WILBTFWIBAOWLN-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- IVZTVZJLMIHPEY-UHFFFAOYSA-N triphenyl(triphenylsilyloxy)silane Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C=1C=CC=CC=1)O[Si](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 IVZTVZJLMIHPEY-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- 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
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
-
- 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
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
- C07J1/0077—Ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
Description
1)エストロン(7)の、3−A−オキシ−エストラ−1,3,5(10),15−テトラエン−17−オン(6)への変換、ここで、Aは保護基であり、この工程は続いての5つのサブ工程を含む;
2)3−A−オキシ−エストラ−1,3,5(10),15−テトラエン−17−オン(6)の17−ケト基の3−A−オキシ−エストラ−1,3,5(10),15−テトラエン−17β−オール(5)への還元;
3)3−A−オキシ−エストラ−1,3,5(10),15−テトラエン−17β−オール(5)の17−OH基の保護による3−A−オキシ−17−C−オキシ−エストラ−1,3,5(10),15−テトラエン(4)の生成、ここで、Cは保護基である;
4)3−A−オキシ−17−C−オキシ−エストラ−1,3,5(10),15−テトラエン(4)の環Dの炭素−炭素二重結合の酸化による保護エステトロール(3)の生成;および
5)保護基の除去、ここで、好ましくは、まず、保護基Aが17−OC保護エステトロール(2)から除去され、次に、保護基Cが除去されてエステトロール(1)が生成される;
を含んでなり、
ここで、保護基Aは、C1−C5アルキル基またはC7−C12ベンジル基から選択され、保護基Cは、一官能性脂肪族ヒドロキシル保護基から選択される。
(1)エストロン(II)の、17−B−オキシ−3−A−オキシ−エストラ−1,3,5(10),16−テトラエン(Ill)への変換、ここで、Aは保護基であり、Bは−Si(R2)3である;
(2)17−B−オキシ−3−A−オキシ−エストラ−1,3,5(10),16−テトラエン(III)の、3−A−オキシ−エストラ−1,3,5(10),15−テトラエン−17−オン(IV)への変換、ここで、Aは保護基である;
(3)3−A−オキシ−エストラ−1,3,5(10),15−テトラエン−17−オン(IV)の17−ケト基の還元による3−A−オキシ−エストラ−1,3,5(10),15−テトラエン−17β−オール(V)の生成、ここで、Aは保護基である;
(4)3−A−オキシ−エストラ−1,3,5(10),15−テトラエン−17β−オールVの17−OH基の保護による3−A−オキシ−17−C−オキシ−エストラ−1,3,5(10),15−テトラエン(VI)の生成、ここで、AおよびCは保護基である;
(5)3−A−オキシ−17−C−オキシ−エストラ−1,3,5(10),15−テトラエン(VI)の環Dの炭素−炭素二重結合の酸化による保護エステトロール(VII)の生成、ここで、AおよびCは保護基である;および
(6)保護基AおよびCの除去によるエステトロール(I)の生成
を含んでなり、ここで、
Aは、C1−C5アルキル基、C7−C12ベンジル基および−Si(R1)3基からなる群から選択される保護基であり、ここで、R1は、C1−C6アルキル基およびC6−C12アリール基からなる群から独立に選択され;
Bは、−Si(R2)3であり、ここで、R2は、C1−C6アルキル基およびC6−C12アリール基からなる群から独立に選択され;かつ
Cは、一官能性脂肪族ヒドロキシル保護基からなる群から選択される保護基である。
a)式(IV)
R1は、シリルエーテル、エーテル、エステル、カルバメートおよびカーボネートから選択されるヒドロキシル保護基であり、かつ、
R2は、エーテルから選択されるヒドロキシル保護基である]
の化合物またはその塩もしくは溶媒和物を、OsO4または四酸化オスミウム源から選択される酸化剤と反応させて、エステトロールまたは式(II)
の化合物またはその塩もしくは溶媒和物を生成すること;および
b)工程a)で式(II)の化合物が得られる場合には、前記化合物を脱保護してエステトロールを生成すること
を含んでなる。
R1は、シリルエーテル、エーテル、エステル、カルバメートおよびカーボネートから選択されるヒドロキシル保護基であり、かつ
R2は、エーテルから選択されるヒドロキシル保護基であり、
ただし、R1がメチルである場合、R2は2−プロピニル基でも2−テトラヒドロピラニル基でもない]
の化合物またはその塩もしくは溶媒和物に関する。
本発明に関して、以下の用語は以下に詳細に示す意味を有する。
・単純エーテル[−R’]、ここで、Rは、アルキル、シクロアルキル、アリールおよびアリールアルキルから選択することができる。エーテルの例としては、メチルエーテル、tert−ブチルエーテル、ベンジルエーテル、p−メトキシベンジルエーテル、3,4−ジメトキシベンジルエーテル、トリチルエーテル、アリルエーテルが挙げられる;
・アルコキシおよびアリールオキシアルキルエーテル、例えば、アルコキシおよびアリールオキシメチルエーテル、およびアルコキシおよびアリールオキシエチルエーテル、ならびにアルキルおよびアリールチオアルキルエーテル、例えば、アルキルおよびアリールチオメチルエーテルおよびアルキルおよびアリールチオアルキルエーテルを含む、ヘテロ原子置換アルキルエーテル:
・カルバメート[−CON(R’)2]、ここで、各R’は、アルキル、シクロアルキル、アリールおよびアリールアルキルから独立に選択することができる;および
・カーボネート[−COOR’]、ここで、R’は、アルキル、シクロアルキル、アリールおよびアリールアルキルから選択することができる。カーボネートの例としては、ベンジルカーボネート、p−ニトロベンジルカーボネート、tert−ブチルカーボネート、2,2,2−トリクロロエチルカーボネート、2−(トリメチルシリル)エチルカーボネート、アリルカーボネートが挙げられる。
a)式(IV)
R1は、シリルエーテル、エーテル、エステル、カルバメートおよびカーボネートから選択されるヒドロキシル保護基であり、かつ、
R2は、エーテルから選択されるヒドロキシル保護基である]
の化合物またはその塩もしくは溶媒和物をOsO4または四酸化オスミウム源と反応させて、エステトロールまたは式(II)
の化合物またはその塩もしくは溶媒和物を生成すること;および
b)工程a)で式(II)の化合物が得られる場合には、前記化合物を脱保護してエステトロールを生成すること
を含んでなる。
の化合物またはその塩もしくは溶媒和物を生成すること;および
式(IV)の化合物またはその塩もしくは溶媒和物をOsO4または四酸化オスミウム源と反応させてエステトロールを生成すること
を含んでなる。
R1およびR2は上記で定義される通りであり、ただし、R1がメチルで場合、R2は2−プロピニル基でも2−テトラヒドロピラニル基でもない。
工程1: エストラ−1,3,5(10),15−テトラエン−3,17β−ジオールビス(ジメチル−tert−ブチルシリル)エーテル
工程1
NMR-H1: 8.08 (2H); 7.71 (1H); 7.56 (2H); 7.30 (1H); 6.98 (1H); 6.93 (1H); 6.03 (1H); 5.72 (1H); 4.74 (1H); 4.26 (1H); 3.56-3.33 (2H); 2.83 (2 H); 2.33-1.89 (3H); 1.55-1.26 (4H); 1.21 (3 H), 0.84( 3 H); 0.77 (3H).
NMR-C13: 164.6; 148.3; 137.8; 137.7; 137.5; 133.9; 133.2; 130.9; 129.6; 129.0; 128.9; 126.1; 121.5; 118.8; 98.9; 88.1; 87.1; 64.1; 55.9; 54.8; 50.8; 43.9; 39.9; 35.4; 31.4; 30.3; 28.7; 26.7; 25.5; 20.5; 19.7; 18.9; 13.6; 12.9.
NMR-H1: 7.15 (1H); 6.76 (1H); 6.71 (1H); 6.05 (1H); 5.76 (1H); 5.13 (2H, OCH2O); 4.65 (2H, OCH2O); 4.18 (1H); 3.48 (OCH3); 3.29 (OCH3); 2.83 (2H); 2.29-2.17 (2H); 2.07-1.89 (3H); 1.75-1.68 (2H); 1.51-1.34 (4 H); 0.80 (3H).
NMR-C13: 154.6; 137.3; 133.1; 131.2; 125.9; 115.9; 113.6; 95.7; 93.7; 90.1; 67.0; 55.9; 55.3; 54.6; 50.5; 44.1; 35.6; 34.4; 28.9; 26.9; 25.6; 25.1; 12.9.
NMR-H1: 7.19 (1H); 6.84 (1H); 6.80 (1H); 5.97 (1H); 5.79 (1H); 5.39 (1H); 4.74 (1H); 4.37 (1H); 3.93 (2H); 3.58 (2H); 2.88 (2H); 2.27 (2H); 2.15-1.35 (19H); 0.89 (3H).
Claims (15)
- エステトロールまたはその塩もしくは溶媒和物の製造方法であって、
a)式(IV)
R1は、シリルエーテル、エーテル、エステル、カルバメートおよびカーボネートから選択されるヒドロキシル保護基であり、かつ、
R2は、エーテルから選択されるヒドロキシル保護基である]
の化合物またはその塩もしくは溶媒和物を、OsO4または四酸化オスミウム源から選択される酸化剤と反応させて、エステトロールまたは式(II)
の化合物またはその塩もしくは溶媒和物を生成すること;および
b)工程a)で式(II)の化合物が得られる場合には、前記化合物を脱保護してエステトロールを生成すること
を含んでなる、方法。 - 酸化剤が支持される、請求項1に記載の方法。
- 酸化剤がOsO4−PVP(ポリ(4−ビニル−ピリジン))である、請求項1または2に記載の方法。
- 補助酸化剤がさらに添加される、請求項1〜3のいずれか一項に記載の方法。
- トリメチルアミン−N−オキシドが補助酸化剤として添加される、請求項1〜4のいずれか一項に記載の方法。
- 15β,16β−ジオール異性体が、15β,16β−ジオールと15α,16α−ジオールの合計に対して≦3%の量で得られる、請求項1〜5のいずれか一項に記載の方法。
- 式(IV)の化合物のC17位のヒドロキシル基が、(1−ブトキシエチル)エーテル、テトラヒドロピラニル(THP)エーテル、フェニルチオメチル(PTM)エーテル、およびメトキシメチル(MOM)エーテルから選択されるエーテルにより保護される、請求項1〜6のいずれか一項に記載の方法。
- 式(IV)の化合物のC3位のヒドロキシル基がエステルにより保護される、請求項1〜7のいずれか一項に記載の方法。
- 式(IV)の化合物のC3位のヒドロキシル基がベンゾイルエステルにより保護される、請求項1〜8のいずれか一項に記載の方法。
- 式(IV)の化合物のC3位のヒドロキシル基がベンゾイルエステルより保護され、かつ、C17のヒドロキシル基が(1−ブトキシエチル)エーテルにより保護される、請求項1〜9のいずれか一項に記載の方法。
- 式(IV)の化合物のC3位のヒドロキシル基がエーテルにより保護される、請求項1〜7のいずれか一項に記載の方法。
- 式(IV)の化合物のC3位のヒドロキシル基が、(1−ブトキシエチル)エーテル、テトラヒドロピラニル(THP)エーテル、フェニルチオメチル(PTM)エーテル、およびメトキシメチル(MOM)エーテルから選択されるエーテルにより保護される、請求項11に記載の方法。
- C3位およびC17位のヒドロキシル基が、アルコキシまたはアリールオキシアルキルエーテルまたはアルキルまたはアリールチオアルキルエーテルから独立に選択されるエーテルにより保護され、好ましくは、それらの両方がメトキシメチル(MOM)エーテルまたはテトラヒドロピラニル(THP)エーテルとして保護される、請求項11に記載のプロセス。
- 式(IV)の化合物またはその塩もしくは溶媒和物:
R1は、シリルエーテル、エーテル、エステル、カルバメートおよびカーボネートから選択されるヒドロキシル保護基であり、かつ
R2は、エーテルから選択されるヒドロキシル保護基であり、
ただし、R1がメチルである場合、R2は2−プロピニル基でも2−テトラヒドロピラニル基でもない]。 -
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IT201900017414A1 (it) | 2019-09-27 | 2021-03-27 | Ind Chimica Srl | Processo per la preparazione di (15α,16α,17β)-estra-1,3,5(10)-triene-3,15,16,17-tetrolo (Estetrolo) ed intermedi di detto processo |
IT201900021879A1 (it) | 2019-11-22 | 2021-05-22 | Ind Chimica Srl | PROCESSO PER LA PREPARAZIONE DI (15α,16α,17β)-ESTRA-1,3,5(10)-TRIENE-3,15,16,17-TETROLO (ESTETROLO) ED INTERMEDI DI DETTO PROCESSO |
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