JPS623840B2 - - Google Patents
Info
- Publication number
- JPS623840B2 JPS623840B2 JP54015420A JP1542079A JPS623840B2 JP S623840 B2 JPS623840 B2 JP S623840B2 JP 54015420 A JP54015420 A JP 54015420A JP 1542079 A JP1542079 A JP 1542079A JP S623840 B2 JPS623840 B2 JP S623840B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- oxocholesterol
- hydroxy
- hydroxyl group
- carbon
- 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.)
- Expired
Links
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 31
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- CMNWLRQKTRKSQO-QWMOJLDXSA-N (6r)-2-hydroxy-6-[(3s,8s,9s,10r,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylheptan-3-one Chemical class C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC(=O)C(C)(C)O)C)[C@@]1(C)CC2 CMNWLRQKTRKSQO-QWMOJLDXSA-N 0.000 claims description 20
- 125000006239 protecting group Chemical group 0.000 claims description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 10
- PGLNLCWHYQYRGQ-ZHHJOTBYSA-N 24-oxocholest-5-en-3beta-ol Chemical class C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCC(=O)C(C)C)[C@@]1(C)CC2 PGLNLCWHYQYRGQ-ZHHJOTBYSA-N 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 150000007514 bases Chemical class 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 3
- -1 compound 25-hydroxy-24-oxocholesterol derivative Chemical class 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000000704 physical effect Effects 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 4
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 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 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000001340 alkali metals Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 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)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- BUWXUSLQPDDDSD-UHFFFAOYSA-N 2-methyl-2-(2-methylbutan-2-yloxy)butane Chemical compound CCC(C)(C)OC(C)(C)CC BUWXUSLQPDDDSD-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000005456 alcohol based solvent Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- QVQLCTNNEUAWMS-UHFFFAOYSA-N barium oxide Chemical compound [Ba]=O QVQLCTNNEUAWMS-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 239000011647 vitamin D3 Substances 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- WDCYWAQPCXBPJA-UHFFFAOYSA-N 1,3-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC([N+]([O-])=O)=C1 WDCYWAQPCXBPJA-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- DDZHNKIBJQESJA-AHMPPUFCSA-N 25-hydroxy-24-oxocalciol 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 DDZHNKIBJQESJA-AHMPPUFCSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- WBGSHQQDUAYVCG-LVHBRSFRSA-N O=C(CC[C@H]([C@H]1C(C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)O)C)C(C)C Chemical class O=C(CC[C@H]([C@H]1C(C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)O)C)C(C)C WBGSHQQDUAYVCG-LVHBRSFRSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical group OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 150000001841 cholesterols Chemical class 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002633 crown compound Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 150000004292 cyclic ethers Chemical group 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- LJSQFQKUNVCTIA-UHFFFAOYSA-N diethyl sulfide Chemical compound CCSCC LJSQFQKUNVCTIA-UHFFFAOYSA-N 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 239000010446 mirabilite Substances 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 150000004707 phenolate Chemical class 0.000 description 1
- ZGJADVGJIVEEGF-UHFFFAOYSA-M potassium;phenoxide Chemical compound [K+].[O-]C1=CC=CC=C1 ZGJADVGJIVEEGF-UHFFFAOYSA-M 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- NESLWCLHZZISNB-UHFFFAOYSA-M sodium phenolate Chemical compound [Na+].[O-]C1=CC=CC=C1 NESLWCLHZZISNB-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
Description
本発明は新規化合物である25−ヒドロキシ−24
−オキソコレステロール誘導体及びその製造法に
関する。更に詳細には種々の活性型ビタミンD3
製造中間体として極めて有用な新規化合物、25−
ヒドロキシ−24−オキソコレステロール誘導体及
びその製造法に関する。
本発明で提供される25−ヒドロキシ−24−オキ
ソコレステロール誘導体及びその製造法は、従来
知られていない。
本発明の25−ヒドロキシ−24−オキソコレステ
ロール誘導体は、下記式〔〕
〔式中、R1及びR5は水素原子又は水酸基の保護
基、R2は水素原子、水酸基又は保護された水酸
基、R3及びR4は水素原子又はR3とR4が一緒にな
つて炭素−炭素結合を表わす。〕
で表わされる。
特開昭50−140436号公報には、下記式〔〕
で表わされるコレステロール誘導体と２・３−ジ
クロル−５・６−ジシアノベンゾキノンとを反応
せしめてコレスタ−１・４・６−トリエン−３−
オン誘導体を製造する方法が記載されており、そ
して上記式〔〕で表わされるコレステロール誘
導体の１つとして、24−ケト−25−ヒドロキシコ
レステロールの名称が開示されている。
しかしながら上記公報には24−ケト−25−ヒド
ロキシコレステロールを具体的に製造する方法あ
るいはこの化合物を用いる実施例、、またその物
性値等が記載されていない。従つて本発明によつ
て提供される上記式〔〕で表わされる25−ヒド
ロキシ−24−オキソコレステロール誘導体は本発
明者らによつて初めて製造された、新規化合物で
ある。
本発明により提供される上記式〔〕で表わさ
れる新規化合物25−ヒドロキシ−24−オキソコレ
ステロール誘導体におけるR1は水素原子又は水
酸基の保護基である。かかる水酸基の保護基とし
ては例えば、アセチル基、プロパノイル基、ブタ
ノイル基、ピバロイル基、ペンタノイル基、シク
ロヘキサノイル基、クロロアセチル基、ブロモア
セチル基、ベンゾイル基、ｐ−ブロモベンゾイル
基、ｐ−ニトロベンゾイル基、エチルベンゾイル
基、トルイル基等の炭素数１〜12の脂肪族もしく
は芳香族カルボン酸残基もしくはそれらのニト
ロ、ハロゲン、アルコキシ置換誘導体、又はトリ
メチルシリル基、ジメチル−ｔ−ブチルシリル基
等のトリアルキルシリル基又は２−テトラヒドロ
ピラニル基、２−テトラヒドロフラニル基等の２
−環状エーテル基等を挙げることができる。R2
は水素原子、水酸基又は保護された水酸基を表わ
す。かかる保護された水酸基は前述した如き保護
基で保護された水酸基が挙げられる。
R3及びR4は水素原子又はR3とR4が一緒になつ
て炭素−炭素結合を表わす。
従つて本発明によれば、R2、R3及びR4が水素
原子である25−ヒドロキシ−24−オキソコレステ
ロール類、R2が水酸基又は保護された水酸基、
R3及びR4が水素原子である１α・３β・25−ト
リヒドロキシ−24−オキソコレスト−５−エン
類、R2が水素原子、R3とR4が一緒になつて炭素
−炭素結合である３β・25−ジヒドロキシ−24−
オキソコレスタ−５・７−ジエン類、R2が水酸
基又は保護された水酸基、R3とR4が一緒になつ
て炭素−炭素結合である１α・３β−25−トリヒ
ドロキシ−24−オキソコレスタ−５・７−ジエン
類等の25−ヒドロキシ−24−オキソコレステロー
ル誘導体が提供される。
この様な25−ヒドロキシ−24−オキソコレステ
ロール誘導体としては例えば以下に挙げるものが
ある。
すなわち例えば、
(1) ３β・25−ジヒドロキシ−24−オキソコレス
ト−５−エン
(2) ３β・25−ジヒドロキシ−24−オキソコレス
ト−５−エン−３−アセテート
(3) ３β・25−ジヒドロキシ−24−オキソコレス
ト−５−エン−３−ベンゾエート
(4) 25−ヒドロキシ−24−オキソコレスト−５−
エン−３・2′−テトラヒドロピラニルエーテル
(5) 25−ヒドロキシ−24−オキソコレスト−５−
エン−３−トリメチルシリルエーテル
(6) ３β・25−ジヒドロキシ−24−オキソコレス
ト−５−エン−３−ｐ−トルエンスルホネート
などの25−ヒドロキシ−24−オキソコレステロー
ル類、
(7) １α、・３β・25−トリヒドロキシ−24−オ
キソコレスト−５−エン
(8) １α・３β・25−トリヒドロキシ−24−オキ
ソコレスト−５−エン−１・３−ジアセテート
(9) １α・３β・25−トリヒドロキシ−24−オキ
ソコレスト−５−エン−１・３−ジベンゾエー
ト
(10) 25−ヒドロキシ−24−オキソコレスト−５−
エン−１・2′・３・2′−ジテトラヒドロピラニ
ルエーテル
などの１α・３β・25−トリヒドロキシ−24−オ
キソコレスト−５−エン類、
(11) ３β・25−ジヒドロキシ−24−オキソコレス
タ−５・７−ジエン
(12) ３β・25−ジヒドロキシ−24−オキソコレス
タ−５・７−ジエン−３−アセテート
などの３β・25−ジヒドロキシ−24−オキソコレ
スタ−５・７−ジエン類、
(13) １α・３β・25−トリヒドロキシ−24−オ
キソコレスタ−５・７−ジエン
(14) １α・３β・25−トリヒドロキシ−24−オ
キソコレスタ−５・７−ジエン−１・３−ジア
セテート
などの１α・３β・25−トリヒドロキシ−24−オ
キソコレスタ−５・７−ジエン類等が挙げられ
る。
しかして、本発明によれば、上記式〔〕で表
わされる新規な25−ヒドロキシ−24−オキソコレ
ステロール誘導体を製造する方法が同様に提供さ
れる。すなわち下記式〔〕
〔式中、R1は水素原子又は水酸基の保護基、R2は
水素原子、水酸基又は保護された水酸基、R3及
びR4は水素原子又はR3とR4が一緒になつて炭素
−炭素結合を表わす。〕
で表わされる24−オキソコレステロール誘導体を
塩基性化合物の存在下で、酸素酸化反応に付し、
次いで必要に応じて保護基を除去せしめるか、又
は水酸基を保護することにより上記式〔〕で表
わされる25−ヒドロキシ−24−オキソコレステロ
ール誘導体を製造する方法である。
上記式〔〕におけるR1、R2、R3及びR4は前
記式〔〕における場合と同じである。従つて、
24−オキソコレステロール誘導体としては24−オ
キソコレステロール類、１α・３β−ジヒドロキ
シ−24オキソコレスタ−５−エン類、３β−ヒド
ロキシ−24−オキソコレスタ−５・７−ジエン
類、１α・３β−ジヒドロキシ−24−オキソコレ
スタ−５・７−ジエン類などの24−オキソコレス
テロール誘導体が挙げられる。
本発明においては、上記式〔〕で表わされる
24−オキソコレステロール誘導体を塩基性化合物
の存在下で、酸素酸化反応に付すことにより、先
ず下記式〔〕
〔式中、R1、R2、R3及びR4は上記式〔〕の定義
に同じ。〕
で表わされる25−パーオキシ−24−オキソコレス
テロール誘導体が生成し、次いで該誘導体から本
発明の上記式〔〕で表わされる25−ヒドロキシ
−24−オキソコレステロール誘導体が製造される
ものと考えられる。
ここで使用される塩基性化合物としては例えば
リチウム、ナトリウム、カリウム等のアルカリ金
属もしくはアルカリ土類金属、酸化バリウム、酸
化銀等の金属酸化物、水酸化ナトリウム、水酸化
カルシウム、炭酸ナトリウム、炭酸水素ナトリウ
ム等のアルカリ金属もしくはアルカリ土類金属の
水酸化物、炭酸塩、重炭酸塩、ナトリウムメトキ
シド、カリウム−ｔ−ブトキシド、ナトリウム−
ｔ−ペンチルオキシド等の低級アルキルアルコキ
シド、カリウムフエノラート、ナトリウムフエノ
ラート等のフエノラート、トリエチルアミン、ｓ
−コリジン等のアミン類、グライム類、クラウン
化合物と云われる環状グライム類とアルカリ金属
との反応化合物の錯化合物、ベンジルトリメチル
アンモニウムハイドロオキサイド等の四級塩基な
どが挙げられる。
なかでもナトリウム−ｔ−ブトキシド、カリウ
ム−ｔ−ブトキシド、ナトリウム−ｔ−ペンチル
オキシド等の低級アルキルアルコキサイドが好ま
しい。
かかる塩基性化合物の使用量は上記式〔〕で
表わされる24−オキソコレステロール誘導体１モ
ルに対して0.1〜100モルの範囲が好ましく特に１
〜10モルの範囲が好ましい。
反応せしめるに際し、有機液状溶媒を溶剤とし
て使用するのが有利であり、かかる有機液状媒体
としては、ヘキサン、ヘプタン等の脂肪族炭化水
素、シクロペンタン、シクロヘキサン等の脂環式
炭化水素、ベンゼン、トルエン、キシレン等の芳
香族炭化水素、クロルベンゼン、四塩化炭素等の
ハロゲン化炭化水素、メタノール、エタノール、
プロパノール、ｔ−ブタノール等のアルコール系
溶剤、ジエチルエーテル、テトラヒドロフラン、
ジオキサン、ジグライム等のエーテル類、メチル
アセテート、エチルアセテート等のエステル系溶
剤、ジエチルチオエーテル、ジメチルスルホキシ
ド等の硫黄含有化合物、トリエチルアミン、ピリ
ジン等のアミン類、ニトロベンゼン、ジニトロベ
ンゼン等のニトロ化合物、アセトニトリル等のシ
アノ化合物、ジメチルホルムアミド、テトラメチ
ル尿素、Ｎ−メチルピロリドン等のアミド類が挙
げられる。なかでも特にベンゼン、トルエン、キ
シレン等の芳香族炭化水素、ジオキサン、ジグラ
イム等のエーテル類、プロパノール、ｔ−ブタノ
ール等のアルコール系溶剤及びこれらの組合せに
よる混合溶剤が好ましい。
かかる溶媒中にて、前記塩基性化合物の存在下
に酸素酸化せしめるに際しては、反応液を密閉系
中で撹拌しながら酸素を上記式〔〕で表わされ
る24−オキソコレステロール誘導体１モルに対し
0.5〜２モル吸収させることによつて達成でき
る。
反応温度は−40゜〜100℃の範囲が好ましく、
特に−20゜〜20℃の範囲が好ましい。
反応時間は使用する化合物、溶媒、反応温度等
により異なるが通常30分〜10時間であり、反応時
間は酸素吸収量で決めるのが好ましい。
反応混合物から目的化合物を単離精製するには
通常の方法が任意に用いられる。すなわち、抽
出、カラムクロマトグラフイー、高速液体クロマ
トグラフイー、再結晶法が用いられる。
目的化合物中に保護基が存在する場合には、す
なわち前記式〔〕で表わされる25−ヒドロキシ
−24−オキソコレステロール誘導体における
OR1、R2の少なくとも１つが保護された水酸基で
ある場合には、保護基を前記反応に引き続いて、
もしくは単離精製の後に脱離せしめてもよい。こ
の保護基の脱離反応はそれ自体公知の反応であ
り、例えば保護基がアシル基の場合には酸又はア
ルカリと接触せしめることにより容易に除去する
ことができる。また例えば保護基が水酸基の酸素
原子と結合してエーテル基を形成している場合
は、還元的にあるいは酸又はアルカリと接触せし
めることにより容易に除去することができる。
また目的化合物中に水酸基の保護基を導入する
場合には、前記反応に引き続いて、もしくは単離
精製の後に水酸基を保護せしめることができる。
この水酸基の保護反応はそれ自体公知の反応であ
り、例えば保護基がアシル基の場合には酸ハロゲ
ン化物もしくは酸無水物とピリジンとを反応せし
めることにより容易に保護基を導入することがで
きる。また保護基がトリアルキルシリル基の場合
にはトリアルキルシリルハロゲン化物とイミダゾ
ールとを反応せしめることにより容易に保護基を
導入することができる。
以上に詳述した如く、本発明によれば上記式
〔〕で表わされる。25−ヒドロキシ−24−オキ
ソコレステロール誘導体が得られる。これらの化
合物で、R3とR4が一緒になつて炭素−炭素結合
を表わす化合物はそのまま、R3及びR4が水素原
子を表わす化合物は通常の方法、例えば臭化水素
酸等により７位をハロゲン化し、次いで脱ハロゲ
ン化水素反応に付して、R3とR4が一緒になつて
炭素−炭素結合を表わす化合物とした後、それ自
体公知の光照射、熱異性化反応に付して24−オキ
ソ−25−ヒドロキシビタミンD3等の活性型ビタ
ミンD3に導くことができる。従つて本発明の化
合物は活性型ビタミンD3の製造中間体として極
めて有用なものである。
以下に本発明を実施例によつて更に詳細に説明
する。
実施例 １
３β−〔（テトラヒドロ−2H−ピラン−２−イ
ル）オキシ〕−コレスト−５−エン−24−オン
1452mg（３ｍmol）及びポタシウム−ｔ−ブトキ
シド504.5mg（4.5ｍmol）をｔ−ブタノールとジ
グライム（１：１）の混合溶液に加え、バス温40
℃で加熱撹拌し溶解させた。
得られた溶液を20℃にコントロールしながら撹
拌下酸素を72c.c.吸収させ反応を完了した。反応終
了後、適量の水及びエーテルを加え、分液し、水
溶液をエーテル抽出した。エーテル分液とエーテ
ル抽出液を合わせ、希塩酸、飽和食塩水で洗浄
後、無水硫酸ナトリウムで乾燥し、過後濃縮し
た。濃縮残渣をシリカゲルを充填したカラムクロ
マトグラフイーに付す（溶媒：ベンゼン−酢エチ
系）ことによつて25−ヒドロキシ−３β−〔（テト
ラヒドロ−2H−ピラン−２−イル）オキシ〕−コ
レスト−５−エン−24−オン291.5mgを得た。こ
のものの物性値は次の通りであつた。
融点；146〜148℃（ｎ−ヘキサン）
IR（KBr；cm-1）；
3450、2940、1708、1060、1030
NMR（CDCl3；δppm）；
0.68（3H、ｓ、Ｃ−18−CH3）、1.01（3H、
3H、ｓ、Ｃ−19−CH3）
1.38（6H、ｓ、Ｃ−26＆27−CH3×２）
3.78（1H、ｓ、Ｃ−25−OH）、3.92（1H、
bm、Ｃ−３−Ｈ）
4.70（1H、bm、Ｃ−2′−Ｈ）、5.32（1H、bd、
Ｃ−６−Ｈ）
実施例 ２
24−オキソコレステロール−３−アセテート
1702mg（3.85ｍmol）及びポタシウム−ｔ−ブト
キシド647mg（5.77ｍmol）をｔ−ブタノールとジ
グライム（１：１）の混合溶液に加え、バス温40
℃で加熱撹拌し溶解させた。
得られた溶液を20℃にコントロールしながら撹
拌下酸素を88c.c.吸収させ反応を完了した。反応終
了後、、適量の水及びエーテルを加え、分液し、
水溶液をエーテル抽出した。エーテル分液とエー
テル抽出液を合わせ希塩酸、飽和食塩水で洗浄
後、無水硫酸ナトリウムで乾燥し、過後濃縮し
た。濃縮残渣をシリカゲルを充填したカラムクロ
マトグラフイーに付す（溶媒ベンゼン−酢エチ
系）ことによつて25−ヒドロキシ−24−オキソコ
レステロール−３−アセテート72mg及び25−ヒド
ロキシ−24−オキソコレステロール299mgを得
た。このものの物性値は次の通りであつた。
：25−ヒドロキシ−24−オキソコレステロール−
３−アセテート
融点；141〜143℃（ｎ−ヘキサン：針状晶）
IR（KBr；cm-1）；
3430、2940、1730、1710、1465、1365、1248、
1035
NMR（CDCl3；δppm）；
0.68（3H、ｓ、Ｃ−18−CH3）
1.01（3H、ｓ、Ｃ−19−CH3）
1.38（6H、ｓ、Ｃ−26＆27−CH3×２）
2.02（3H、ｓ、
The present invention provides a novel compound, 25-hydroxy-24
-Relating to oxocholesterol derivatives and methods for producing the same. More specifically, various active forms of vitamin D 3
A novel compound extremely useful as a manufacturing intermediate, 25-
The present invention relates to a hydroxy-24-oxocholesterol derivative and a method for producing the same. The 25-hydroxy-24-oxocholesterol derivative provided by the present invention and the method for producing the same have not been previously known. The 25-hydroxy-24-oxocholesterol derivative of the present invention has the following formula [] [In the formula, R 1 and R 5 are hydrogen atoms or hydroxyl group protecting groups, R 2 is hydrogen atoms, hydroxyl groups, or protected hydroxyl groups, R 3 and R 4 are hydrogen atoms, or R 3 and R 4 are combined Represents a carbon-carbon bond. ] It is expressed as . In Japanese Patent Application Laid-open No. 50-140436, the following formula [] Cholesta-1,4,6-triene-3-
A method for producing one derivatives is described, and the name 24-keto-25-hydroxycholesterol is disclosed as one of the cholesterol derivatives represented by the above formula []. However, the above-mentioned publication does not describe a specific method for producing 24-keto-25-hydroxycholesterol, examples using this compound, or its physical properties. Therefore, the 25-hydroxy-24-oxocholesterol derivative represented by the above formula [] provided by the present invention is a novel compound produced for the first time by the present inventors. R 1 in the novel compound 25-hydroxy-24-oxocholesterol derivative represented by the above formula [] provided by the present invention is a hydrogen atom or a hydroxyl group-protecting group. Examples of such hydroxyl protecting groups include acetyl group, propanoyl group, butanoyl group, pivaloyl group, pentanoyl group, cyclohexanoyl group, chloroacetyl group, bromoacetyl group, benzoyl group, p-bromobenzoyl group, p-nitrobenzoyl group. aliphatic or aromatic carboxylic acid residues having 1 to 12 carbon atoms, such as ethylbenzoyl group, toluyl group, or their nitro-, halogen-, or alkoxy-substituted derivatives, or trialkyl group, such as trimethylsilyl group, dimethyl-t-butylsilyl group, etc. 2 such as silyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, etc.
- A cyclic ether group, etc. can be mentioned. R2
represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group. Examples of such protected hydroxyl groups include hydroxyl groups protected with the above-mentioned protecting groups. R 3 and R 4 represent a hydrogen atom or R 3 and R 4 together represent a carbon-carbon bond. Therefore, according to the present invention, 25-hydroxy-24-oxocholesterols in which R 2 , R 3 and R 4 are hydrogen atoms, R 2 is a hydroxyl group or a protected hydroxyl group,
1α・3β・25-trihydroxy-24-oxocholest-5-enes in which R 3 and R 4 are hydrogen atoms, R 2 is a hydrogen atom, and R 3 and R 4 together form a carbon-carbon bond 3β・25-dihydroxy-24-
Oxocholesta-5,7-dienes, 1α,3β-25-trihydroxy-24-oxocholesta-5, where R 2 is a hydroxyl group or a protected hydroxyl group, and R 3 and R 4 together form a carbon-carbon bond. 25-hydroxy-24-oxocholesterol derivatives such as 7-dienes are provided. Examples of such 25-hydroxy-24-oxocholesterol derivatives include the following. That is, for example, (1) 3β·25-dihydroxy-24-oxocholest-5-ene (2) 3β·25-dihydroxy-24-oxocholest-5-ene-3-acetate (3) 3β·25-dihydroxy-24- Oxocholest-5-ene-3-benzoate (4) 25-hydroxy-24-oxocholest-5-
En-3,2'-tetrahydropyranyl ether (5) 25-hydroxy-24-oxocholest-5-
En-3-trimethylsilyl ether (6) 25-hydroxy-24-oxocholesterols such as 3β・25-dihydroxy-24-oxocholest-5-ene-3-p-toluenesulfonate, (7) 1α,・3β・25 -Trihydroxy-24-oxocholest-5-ene (8) 1α, 3β, 25-trihydroxy-24-oxocholest-5-ene-1, 3-diacetate (9) 1α, 3β, 25-trihydroxy-24 -Oxocholest-5-ene-1,3-dibenzoate (10) 25-hydroxy-24-oxocholest-5-
1α, 3β, 25-trihydroxy-24-oxocholest-5-enes such as ene-1, 2', 3, 2'-ditetrahydropyranyl ether, (11) 3β, 25-dihydroxy-24-oxocholest-5・7-Diene (12) 3β・25-dihydroxy-24-oxocholesta-5,7-dienes such as 3β・25-dihydroxy-24-oxocholesta-5,7-diene-3-acetate, (13) 1α・3β·25-trihydroxy-24-oxocholesta-5,7-diene (14) 1α·3β· such as 1α·3β·25-trihydroxy-24-oxocholesta-5·7-diene-1·3-diacetate Examples include 25-trihydroxy-24-oxocholester-5,7-dienes. Therefore, according to the present invention, a method for producing a novel 25-hydroxy-24-oxocholesterol derivative represented by the above formula [] is also provided. In other words, the following formula [] [In the formula, R 1 is a hydrogen atom or a protecting group for a hydroxyl group, R 2 is a hydrogen atom, a hydroxyl group, or a protected hydroxyl group, R 3 and R 4 are hydrogen atoms, or R 3 and R 4 taken together form a carbon-carbon Represents a bond. ] A 24-oxocholesterol derivative represented by is subjected to an oxygen oxidation reaction in the presence of a basic compound,
This is a method for producing a 25-hydroxy-24-oxocholesterol derivative represented by the above formula [] by removing the protecting group or protecting the hydroxyl group, if necessary. R 1 , R 2 , R 3 and R 4 in the above formula [] are the same as in the above formula []. Therefore,
Examples of 24-oxocholesterol derivatives include 24-oxocholesterols, 1α/3β-dihydroxy-24oxocholest-5-enes, 3β-hydroxy-24-oxocholest-5,7-dienes, 1α/3β-dihydroxy-24- Examples include 24-oxocholesterol derivatives such as oxocholesta-5,7-dienes. In the present invention, represented by the above formula []
By subjecting a 24-oxocholesterol derivative to an oxygen oxidation reaction in the presence of a basic compound, the following formula [] [In the formula, R 1 , R 2 , R 3 and R 4 are the same as defined in the above formula []. It is believed that a 25-peroxy-24-oxocholesterol derivative represented by the following is produced, and then a 25-hydroxy-24-oxocholesterol derivative of the present invention represented by the above formula [] is produced from the derivative. Examples of basic compounds used here include alkali metals or alkaline earth metals such as lithium, sodium, and potassium, metal oxides such as barium oxide and silver oxide, sodium hydroxide, calcium hydroxide, sodium carbonate, and hydrogen carbonate. Hydroxides, carbonates, bicarbonates of alkali metals or alkaline earth metals such as sodium, sodium methoxide, potassium t-butoxide, sodium-
Lower alkyl alkoxides such as t-pentyl oxide, phenolates such as potassium phenolate and sodium phenolate, triethylamine, s
Examples include amines such as collidine, glymes, complex compounds of reaction compounds of cyclic glymes and alkali metals called crown compounds, and quaternary bases such as benzyltrimethylammonium hydroxide. Among these, lower alkyl alkoxides such as sodium t-butoxide, potassium t-butoxide, and sodium t-pentyl oxide are preferred. The amount of the basic compound to be used is preferably in the range of 0.1 to 100 mol per 1 mol of the 24-oxocholesterol derivative represented by the above formula [].
A range of ~10 moles is preferred. In carrying out the reaction, it is advantageous to use an organic liquid solvent as a solvent, such as aliphatic hydrocarbons such as hexane and heptane, alicyclic hydrocarbons such as cyclopentane and cyclohexane, benzene and toluene. , aromatic hydrocarbons such as xylene, halogenated hydrocarbons such as chlorobenzene and carbon tetrachloride, methanol, ethanol,
Alcohol solvents such as propanol and t-butanol, diethyl ether, tetrahydrofuran,
Ethers such as dioxane and diglyme, ester solvents such as methyl acetate and ethyl acetate, sulfur-containing compounds such as diethylthioether and dimethyl sulfoxide, amines such as triethylamine and pyridine, nitro compounds such as nitrobenzene and dinitrobenzene, and acetonitrile. Examples include amides such as cyano compounds, dimethylformamide, tetramethylurea, and N-methylpyrrolidone. Among these, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane and diglyme, alcohol solvents such as propanol and t-butanol, and mixed solvents of combinations thereof are particularly preferred. When performing oxygen oxidation in such a solvent in the presence of the basic compound, oxygen is added per mole of the 24-oxocholesterol derivative represented by the above formula [] while stirring the reaction solution in a closed system.
This can be achieved by absorbing 0.5 to 2 moles. The reaction temperature is preferably in the range of -40° to 100°C,
Particularly preferred is a temperature range of -20° to 20°C. The reaction time varies depending on the compound used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 10 hours, and the reaction time is preferably determined by the amount of oxygen absorbed. Any conventional method can be used to isolate and purify the target compound from the reaction mixture. That is, extraction, column chromatography, high performance liquid chromatography, and recrystallization methods are used. When a protecting group exists in the target compound, that is, in the 25-hydroxy-24-oxocholesterol derivative represented by the above formula [],
When at least one of OR 1 and R 2 is a protected hydroxyl group, the protecting group is added following the reaction,
Alternatively, it may be removed after isolation and purification. This elimination reaction of the protecting group is a known reaction per se. For example, when the protecting group is an acyl group, it can be easily removed by bringing it into contact with an acid or an alkali. Further, for example, when the protecting group is bonded to the oxygen atom of the hydroxyl group to form an ether group, it can be easily removed reductively or by contacting with an acid or an alkali. Furthermore, when a hydroxyl-protecting group is introduced into the target compound, the hydroxyl group can be protected subsequent to the reaction or after isolation and purification.
This hydroxyl group protection reaction is a known reaction per se. For example, when the protecting group is an acyl group, the protecting group can be easily introduced by reacting an acid halide or acid anhydride with pyridine. Further, when the protecting group is a trialkylsilyl group, the protecting group can be easily introduced by reacting a trialkylsilyl halide with imidazole. As detailed above, according to the present invention, it is represented by the above formula []. A 25-hydroxy-24-oxocholesterol derivative is obtained. Among these compounds, compounds in which R 3 and R 4 together represent a carbon-carbon bond are left as is, while compounds in which R 3 and R 4 represent a hydrogen atom are removed at the 7-position using a conventional method such as hydrobromic acid. is halogenated, then subjected to dehydrohalogenation reaction to form a compound in which R 3 and R 4 together represent a carbon-carbon bond, and then subjected to photoirradiation and thermal isomerization reactions known per se. can lead to active vitamin D3 such as 24-oxo-25-hydroxyvitamin D3 . Therefore, the compounds of the present invention are extremely useful as intermediates for the production of active vitamin D3 . The present invention will be explained in more detail below using examples. Example 1 3β-[(tetrahydro-2H-pyran-2-yl)oxy]-cholest-5-en-24-one
1452 mg (3 mmol) and 504.5 mg (4.5 mmol) of potassium t-butoxide were added to a mixed solution of t-butanol and diglyme (1:1), and the bath temperature was 40°C.
The mixture was heated and stirred at ℃ to dissolve it. While controlling the temperature of the resulting solution at 20°C, 72 c.c. of oxygen was absorbed while stirring to complete the reaction. After the reaction was completed, appropriate amounts of water and ether were added to separate the layers, and the aqueous solution was extracted with ether. The ether separation and ether extract were combined, washed with dilute hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was subjected to column chromatography packed with silica gel (solvent: benzene-ethyl acetate system) to obtain 25-hydroxy-3β-[(tetrahydro-2H-pyran-2-yl)oxy]-cholesto-5. 291.5 mg of -en-24-one was obtained. The physical properties of this product were as follows. Melting point: 146-148°C (n-hexane) IR (KBr; cm -1 ); 3450, 2940, 1708, 1060, 1030 NMR (CDCl 3 ; δppm); 0.68 (3H, s, C-18-CH 3 ) , 1.01 (3H,
3H, s, C-19-CH 3 ) 1.38 (6H, s, C-26 & 27-CH 3 ×2) 3.78 (1H, s, C-25-OH), 3.92 (1H,
bm, C-3-H) 4.70 (1H, bm, C-2'-H), 5.32 (1H, bd,
C-6-H) Example 2 24-oxocholesterol-3-acetate
Add 1702 mg (3.85 mmol) and 647 mg (5.77 mmol) of potassium t-butoxide to a mixed solution of t-butanol and diglyme (1:1), and leave the bath at a temperature of 40°C.
The mixture was heated and stirred at ℃ to dissolve it. While controlling the temperature of the obtained solution at 20°C, 88 c.c. of oxygen was absorbed while stirring to complete the reaction. After the reaction is complete, add an appropriate amount of water and ether, separate the liquid,
The aqueous solution was extracted with ether. The ether separation and ether extract were combined, washed with dilute hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was subjected to column chromatography packed with silica gel (solvent benzene-ethyl acetate system) to obtain 72 mg of 25-hydroxy-24-oxocholesterol-3-acetate and 299 mg of 25-hydroxy-24-oxocholesterol. Ta. The physical properties of this product were as follows. :25-hydroxy-24-oxocholesterol-
3-acetate melting point; 141-143°C (n-hexane: needle crystals) IR (KBr; cm -1 ); 3430, 2940, 1730, 1710, 1465, 1365, 1248,
1035 NMR ( CDCl3 ; δppm); 0.68 (3H, s, C-18- CH3 ) 1.01 (3H, s, C-19- CH3 ) 1.38 (6H, s, C-26&27-CH3 x 2 ) 2.02 (3H, s,
【式】）
4.60（1H、bm、Ｃ−３−Ｈ）
5.36（1H、bd、Ｃ−６−Ｈ）
高分解能マススペクトル（IV＝75eV）；
M+−AcOH 398.3182（C27H42O2）
：25−ヒドロキシ−24−オキソコレステロール
融点；168〜170℃（ベンゼン）
IR（KBr；cm-1）；
3425、2925、1708、1460、1370、1050
NMR（CDCl3；δppm）；
0.68（3H、ｓ、Ｃ−18−CH3）
1.01（3H、ｓ−Ｃ−19−CH3）
1.38（6H、ｓ、Ｃ−26＆27−CH3×２）
3.60（1H、bm、Ｃ−３−Ｈ）
5.34（1H、bd、Ｃ−６−Ｈ）
高分解能マススペクトル（IV＝75eV）；
M+ 416.3380（C27H44O3）
なお実施例１、２で用いた原料化合物、24−オ
キソコレステロール類と同時に、原料化合物とし
て１α・３β−ジヒドロキシ−24−オキソコレス
ト−５−エン類、３β−ヒドロキシ−24−オキソ
コレスタ−５・７−ジエン類、１α・３β−ジヒ
ドロキシ−24−オキソコレスタ−５・７−ジエン
類等を用いた場合にも、25位にヒドロキシル基が
導入された25−ヒドロキシ−24−オキソコレステ
ロール誘導体が製造される。
実施例 ３
３β−ヒドロキシ−24−オキソコレスタ−５・
７−ジエン290mg（0.73ｍＭ）及びｔ−ブトキシ
カリ122.5mg（1.1ｍＭ）を、ｔ−ブタノールとジ
グライム（１：１）の混合溶媒20mlに加え、バス
温40℃で加熱撹拌溶解させた。
得られた溶液を０℃にコントロールしながら撹
拌下酸素を８c.c.吸収させ反応を完了した。
反応終了後、適量の水を加え酢酸エチルで抽出
した。抽出液を水、希塩酸及び飽和炭酸水素ナト
リウム水溶液で洗浄後芒硝で乾燥した。濾過後濃
縮することにより得られた濃縮残渣をベンゼン５
mlに溶解しトリフエニルホスフイン48mgを加え、
室温で30分撹拌した。
濃縮することにより得られた濃縮残渣をシリカ
ゲル薄層クロマトグラフイーにより精製し（溶
媒：ベンゼン−酢エチ系）85mgの３β・25−ジヒ
ドロキシ−24−オキソコレスタ−５・７−ジエン
を得た。
このものの物性値は次の通りであつた。
融点：150〜152℃（酢酸エチル）
IR（KBr、cm-1）：
3400、2940、1710、1460、1375、1060、1035
NMR（CDCl3：δppm）
0.63（3H、ｓ）、0.95（3H、ｓ）、1.38（6H、
ｓ）、3.4〜3.7（1H、brm）、5.3〜5.66（2H、
brm）
UV（EtOH：λmax ｎｍ）
294（ε＝6470）、282（ε＝11270）
271（ε＝10760）、
262（sh、ε＝7840）
高分解能マススペクトル（IV＝75eV）
M+：414.3201（C27H42O3）
実施例 ４
１α・３β−ジエトキシカルボニルオキシ−24
−オキソコレスタ−５・７−ジエン1.425ｇ
（2.55ｍＭ）及びｔ−ブトキシカリ2.86ｇ（25.5ｍ
Ｍ）に40mlのｔ−ブタノールとジグライム（１：
１）の混合溶媒を加え窒素気流下40℃で30分撹拌
した。
次に−20℃に冷却後酸素で置換しほぼ理論量の
酸素（60ml）を吸収するまで撹拌を続けた。トリ
フエニルホスフインを加え、更に酢酸エチル、
1N−HClを加えPH〜７とした後抽出した。1N−
HCl、飽和炭酸水素ナトリウム水溶液、飽和食塩
水で順次洗浄後、芒硝で乾燥した。濾過濃縮後得
られた粗成生物を、シリカゲルカラムで精製し１
α・３β・25−トリヒドロキシ−24−オキソコレ
スタ−５・７−ジエン325mg（収率30.1％）を得
た。
このものの物性値は次の通りであつた。
IR（KBr、cm-1）：
3400、2945、1710
NMR（CDCl3：δppm）
0.629（3H、ｓ）、0.947（3H、ｓ）、1.386
（6H、ｓ）
3.65〜4.25（2H、brm）、5.44（1H、ｍ）、
5.78（1H、ｍ）
UV（EtOH：λmax ｎｍ）
294、282、271、262
MS：430（M+）、412、394、371、251
実施例 ５
10ｇの24−オキソ−25−ヒドロキシコレステロ
ール（24ｍＭ）を122.6ｇの無水酢酸（1.2M）お
よび171.0ｇのピリジン（2.2M）の混合物と共に
90℃で24間加熱撹拌した。無水酢酸を減圧下濃縮
し、酢酸エチル11を加え抽出した。1N−HCl200
mlで３回、飽和炭酸水素ナトリウム水溶液200ml
で２回、飽和食塩水２回洗浄し、無水硫酸ナトリ
ウムで乾燥後濃縮した。得られた粗生成物をシリ
カゲル200ｇを用いたカラムクロマトグラフイー
に付し、ベンゼン−酢酸エチル系で溶出し7.5ｇ
の24−、オキソ−３β・25−ジアセトキシコレス
ト−５−エンを得た。
IR（KBr、cm-1）
1725、1740
NMR（CDCl3：δppm）
0.70（3H、ｓ）、1.05（3H、ｓ）、1.50（6H、
ｓ）、2.05（3H、ｓ）、2.12（3H、ｓ）、4.6
（1H、ｍ）、5.4（1H、ｍ）[Formula]) 4.60 (1H, bm, C-3-H) 5.36 (1H, bd, C-6-H) High resolution mass spectrum (IV = 75eV); M + -AcOH 398.3182 (C 27 H 42 O 2 ): 25-hydroxy-24-oxocholesterol Melting point; 168-170°C (benzene) IR (KBr; cm -1 ); 3425, 2925, 1708, 1460, 1370, 1050 NMR (CDCl 3 ; δppm); 0.68 (3H , s, C-18-CH 3 ) 1.01 (3H, s-C-19-CH 3 ) 1.38 (6H, s, C-26 & 27-CH 3 ×2) 3.60 (1H, bm, C-3-H) 5.34 (1H, bd, C-6-H) High resolution mass spectrum (IV = 75eV); M + 416.3380 (C 27 H 44 O 3 ) Raw material compounds used in Examples 1 and 2, 24-oxocholesterols At the same time, 1α, 3β-dihydroxy-24-oxocholest-5-enes, 3β-hydroxy-24-oxocholest-5, 7-dienes, 1α, 3β-dihydroxy-24-oxocholesta-5, 7- are used as raw material compounds. Even when dienes or the like are used, a 25-hydroxy-24-oxocholesterol derivative having a hydroxyl group introduced at the 25th position is produced. Example 3 3β-hydroxy-24-oxocholesta-5.
290 mg (0.73 mM) of 7-diene and 122.5 mg (1.1 mM) of t-butoxypotassium were added to 20 ml of a mixed solvent of t-butanol and diglyme (1:1), and dissolved with stirring at a bath temperature of 40°C. The reaction was completed by absorbing 8 c.c. of oxygen while stirring the resulting solution while controlling the temperature to 0°C. After the reaction was completed, an appropriate amount of water was added and the mixture was extracted with ethyl acetate. The extract was washed with water, dilute hydrochloric acid, and a saturated aqueous sodium bicarbonate solution, and then dried over Glauber's salt. The concentrated residue obtained by concentrating after filtration was mixed with benzene 5
ml and add 48mg of triphenylphosphine,
Stirred at room temperature for 30 minutes. The concentrated residue obtained by concentration was purified by silica gel thin layer chromatography (solvent: benzene-ethyl acetate system) to obtain 85 mg of 3β.25-dihydroxy-24-oxocholester-5.7-diene. The physical properties of this product were as follows. Melting point: 150-152℃ (ethyl acetate) IR (KBr, cm -1 ): 3400, 2940, 1710, 1460, 1375, 1060, 1035 NMR (CDCl 3 : δppm) 0.63 (3H, s), 0.95 (3H, s), 1.38 (6H,
s), 3.4-3.7 (1H, brm), 5.3-5.66 (2H,
brm) UV (EtOH: λmax nm) 294 (ε=6470), 282 (ε=11270) 271 (ε=10760), 262 (sh, ε=7840) High resolution mass spectrum (IV=75eV) M + :414.3201 (C 27 H 42 O 3 ) Example 4 1α・3β-diethoxycarbonyloxy-24
-Oxocholesta-5,7-diene 1.425g
(2.55mM) and t-butoxypotassium 2.86g (25.5mM
M) with 40ml of t-butanol and diglyme (1:
The mixed solvent of 1) was added, and the mixture was stirred at 40°C for 30 minutes under a nitrogen stream. Next, after cooling to -20°C, the mixture was replaced with oxygen and stirring was continued until almost the theoretical amount of oxygen (60 ml) was absorbed. Add triphenylphosphine, then ethyl acetate,
1N-HCl was added to adjust the pH to ~7, followed by extraction. 1N−
After sequentially washing with HCl, saturated aqueous sodium bicarbonate solution, and saturated brine, it was dried with sodium sulfate. The crude product obtained after filtration and concentration was purified using a silica gel column.
325 mg (yield 30.1%) of α·3β·25-trihydroxy-24-oxocholesta-5·7-diene was obtained. The physical properties of this product were as follows. IR (KBr, cm -1 ): 3400, 2945, 1710 NMR (CDCl 3 : δppm) 0.629 (3H, s), 0.947 (3H, s), 1.386
(6H, s) 3.65-4.25 (2H, brm), 5.44 (1H, m), 5.78 (1H, m) UV (EtOH: λmax nm) 294, 282, 271, 262 MS: 430 (M + ), 412 , 394, 371, 251 Example 5 10 g of 24-oxo-25-hydroxycholesterol (24 mM) with a mixture of 122.6 g of acetic anhydride (1.2 M) and 171.0 g of pyridine (2.2 M)
The mixture was heated and stirred at 90°C for 24 hours. Acetic anhydride was concentrated under reduced pressure, and ethyl acetate 11 was added for extraction. 1N−HCl200
ml 3 times, 200 ml of saturated sodium bicarbonate aqueous solution
The mixture was washed twice with brine and twice with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The obtained crude product was subjected to column chromatography using 200 g of silica gel, and 7.5 g was eluted with benzene-ethyl acetate system.
24-,oxo-3β·25-diacetoxycholest-5-ene was obtained. IR (KBr, cm -1 ) 1725, 1740 NMR (CDCl 3 : δppm) 0.70 (3H, s), 1.05 (3H, s), 1.50 (6H,
s), 2.05 (3H, s), 2.12 (3H, s), 4.6
(1H, m), 5.4 (1H, m)
Claims (1)
基、R2は水素原子、水酸基又は保護された水酸
基、R3及びR4は水素原子又はR3とR4が一緒にな
つて炭素−炭素結合を表わす。〕 で表わされる25−ヒドロキシ−24−オキソコレス
テロール誘導体。 ２ 下記式〔〕 〔式中、R1は水素原子又は水酸基の保護基、R2は
水素原子、水酸基又は保護された水酸基、R3及
びR4は水素原子又はR3とR4が一緒になつて炭素
−炭素結合を表わす。〕 で表わされる24−オキソコレステロール誘導体を
塩基性化合物の存在下で、酸素酸化反応に付する
ことを特徴とする下記式〔′〕 〔式中、R1は水素原子又は水酸基の保護基、R2は
水素原子、水酸基又は保護された水酸基、R3及
びR4は水素原子又はR3とR4が一緒になつて炭素
−炭素結合を表わす。〕 で表わされる25−ヒドロキシ−24−オキソコレス
テロール誘導体の製造法。[Claims] 1. The following formula [] [In the formula, R 1 and R 5 are hydrogen atoms or hydroxyl group protecting groups, R 2 is hydrogen atoms, hydroxyl groups, or protected hydroxyl groups, R 3 and R 4 are hydrogen atoms, or R 3 and R 4 are combined Represents a carbon-carbon bond. ] A 25-hydroxy-24-oxocholesterol derivative represented by: 2 The following formula [] [In the formula, R 1 is a hydrogen atom or a protecting group for a hydroxyl group, R 2 is a hydrogen atom, a hydroxyl group, or a protected hydroxyl group, R 3 and R 4 are hydrogen atoms, or R 3 and R 4 together form a carbon-carbon Represents a bond. ] The following formula [′] is characterized in that the 24-oxocholesterol derivative represented by is subjected to an oxygen oxidation reaction in the presence of a basic compound. [In the formula, R 1 is a hydrogen atom or a protecting group for a hydroxyl group, R 2 is a hydrogen atom, a hydroxyl group, or a protected hydroxyl group, R 3 and R 4 are hydrogen atoms, or R 3 and R 4 together form a carbon-carbon Represents a bond. ] A method for producing a 25-hydroxy-24-oxocholesterol derivative represented by:
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1542079A JPS55108898A (en) | 1979-02-15 | 1979-02-15 | 25-hydroxy-24-oxocholesterol derivative and its preparation |
| EP80300426A EP0015122B1 (en) | 1979-02-15 | 1980-02-14 | New 25-hydroxy-24-oxocholestane derivatives and preparation thereof |
| CA000345624A CA1138859A (en) | 1979-02-15 | 1980-02-14 | 25-hydroxy-24-oxocholestane derivatives and preparation thereof |
| DE8282200223T DE3069391D1 (en) | 1979-02-15 | 1980-02-14 | Vitamin d3 |
| DE8080300426T DE3064789D1 (en) | 1979-02-15 | 1980-02-14 | New 25-hydroxy-24-oxocholestane derivatives and preparation thereof |
| EP82200223A EP0055999B1 (en) | 1979-02-15 | 1980-02-14 | Vitamin d3 |
| DK063080A DK162648C (en) | 1979-02-15 | 1980-02-14 | 3BETA, 25-DIHYDROXY-24-OXOCHOLEST-5-ONE DERIVATIVES AND PROCEDURES FOR PREPARING IT |
| US06/121,857 US4292249A (en) | 1979-02-15 | 1980-02-15 | 25-Hydroxy-24-oxocholestane derivatives and preparation thereof |
| DK233585A DK233585D0 (en) | 1979-02-15 | 1985-05-24 | ANALOGY PROCEDURE FOR PREPARING 25-HYDROXY-24-OXOCHOLECALCIFEROLS AND INTERMEDIATES FOR USE |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1542079A JPS55108898A (en) | 1979-02-15 | 1979-02-15 | 25-hydroxy-24-oxocholesterol derivative and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS55108898A JPS55108898A (en) | 1980-08-21 |
| JPS623840B2 true JPS623840B2 (en) | 1987-01-27 |
Family
ID=11888262
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1542079A Granted JPS55108898A (en) | 1979-02-15 | 1979-02-15 | 25-hydroxy-24-oxocholesterol derivative and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS55108898A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55172290U (en) * | 1979-05-28 | 1980-12-10 | ||
| JPS5612141U (en) * | 1979-07-10 | 1981-02-02 | ||
| WO1995014032A1 (en) * | 1993-11-19 | 1995-05-26 | Chugai Seiyaku Kabushiki Kaisha | Process for producing 25-hydroxylated cholesterol |
-
1979
- 1979-02-15 JP JP1542079A patent/JPS55108898A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS55108898A (en) | 1980-08-21 |
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