AU605007B2 - Steroidal compounds and process for lengthening the side-chain of certain steroids - Google Patents
Steroidal compounds and process for lengthening the side-chain of certain steroids Download PDFInfo
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- AU605007B2 AU605007B2 AU27614/88A AU2761488A AU605007B2 AU 605007 B2 AU605007 B2 AU 605007B2 AU 27614/88 A AU27614/88 A AU 27614/88A AU 2761488 A AU2761488 A AU 2761488A AU 605007 B2 AU605007 B2 AU 605007B2
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- Prior art keywords
- compound according
- carbon
- gave
- ethyl acetate
- hydrogen
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- 150000001875 compounds Chemical class 0.000 title claims description 20
- 238000000034 method Methods 0.000 title claims description 11
- 150000003431 steroids Chemical class 0.000 title claims description 6
- 230000003637 steroidlike Effects 0.000 title description 4
- 150000002148 esters Chemical group 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- -1 methyl magnesium halide Chemical class 0.000 claims description 6
- NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 125000002252 acyl group Chemical group 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- 239000003643 water by type Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical group [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 239000012043 crude product Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 238000010626 work up procedure Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 9
- 238000010828 elution Methods 0.000 description 8
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 6
- 150000003710 vitamin D derivatives Chemical class 0.000 description 6
- 229930003316 Vitamin D Natural products 0.000 description 5
- 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 5
- 235000019166 vitamin D Nutrition 0.000 description 5
- 239000011710 vitamin D Substances 0.000 description 5
- 229940046008 vitamin d Drugs 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 239000011541 reaction mixture Substances 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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 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
- JWUBBDSIWDLEOM-DCHLRESJSA-N 25-Hydroxyvitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C/C=C1\C[C@@H](O)CCC1=C JWUBBDSIWDLEOM-DCHLRESJSA-N 0.000 description 1
- JWUBBDSIWDLEOM-NQZHSCJISA-N 25-hydroxy-3 epi cholecalciferol Chemical compound C1([C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=CC=C1C[C@H](O)CCC1=C JWUBBDSIWDLEOM-NQZHSCJISA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 102000020897 Formins Human genes 0.000 description 1
- 108091022623 Formins Proteins 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 240000007049 Juglans regia Species 0.000 description 1
- 235000009496 Juglans regia Nutrition 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010031240 Osteodystrophy Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 235000012012 Paullinia yoco Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000000746 allylic group Chemical group 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
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033558 biomineral tissue development Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- PHBAAFDKJNNRNJ-UHFFFAOYSA-N dimethoxymethoxy(dimethoxy)methane Chemical compound COC(OC)OC(OC)OC PHBAAFDKJNNRNJ-UHFFFAOYSA-N 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- CIXSDMKDSYXUMJ-UHFFFAOYSA-N n,n-diethylcyclohexanamine Chemical compound CCN(CC)C1CCCCC1 CIXSDMKDSYXUMJ-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 208000005368 osteomalacia Diseases 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- IOIHFHNPXJFODN-UHFFFAOYSA-M tetrakis(hydroxymethyl)phosphanium;hydroxide Chemical compound [OH-].OC[P+](CO)(CO)CO IOIHFHNPXJFODN-UHFFFAOYSA-M 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000020234 walnut Nutrition 0.000 description 1
- 238000005406 washing Methods 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
- C07J9/005—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 containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
-
- 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
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- 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
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Obesity (AREA)
- Life Sciences & Earth Sciences (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Hematology (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nutrition Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Signa- (3) ture. of Applicant (8) or Beal of Company and Signatures of its Officers as prescribed by its Articles of Assoclation.
by D. B. Mischlewski Form COMMONWEALTH r0- AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPEC IFICATION
(ORIGINAL)
Class Int. Class Application Number: Lodged: b05007 Complete Specification Lodged: Accepted: Published: Prority: ,Related Art: o c Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: WISCONSIN ALUMNI RESEARCH FOUNDATION 614 North Walnut Street, Madison, Wisconsin 53705, United States of America HECTOR F. DeLUCA, NOBUO IKEKAWA and YOKO TANAKA EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.
Complete Specification for the invention entitled: STEROIDAL COMPOUNDS AND PROCESS FOR LENGTHENING THE SIDE- CHAIN OF CERTAIN STEROIDS The following statement is a full description of this invention, including the best method of performing it known to us i i -L Sipiun of dedr ant(s) (s o anntatson qumred) Note: b.Atw II sIteratio Edward Waters Son, S- O. u001pn, f trpi P M& P I rne .30.f ir- Vni i N7 1 STEROIDAL COMPOUNDS AND PROCESS FOR LENGTHENING THE SIDE-CHAIN OF CERTAIN STEROIDS This invention relates to novel steroidal compounds useful for preparing vitamin D derivatives, especially 24-homovitamin D derivatives, as well as a process fo- lengthening the side chain of certain steroids.
Vitamin D is known to regulate calcium and phosphorus metabolism in animals and humans and it has now been firmly established that the biological efficiency of vitamin D depends upon its metabolic conversion, in vivo, to hydroxylated derivatives. Thus vitamin D 3 is hvdroxylated in vivo to 25-hydroxyvitamin D 3 in the liver which in turn is converted into lo',25-dihydroxyvitamin D 3 in the kidneys. It is the latter compound which is now recognised as being the circulating hormonal form of Sfit Vitamin D.
Because of their biological activity in promoting calcium and phosphorus transport in the intestine and the mobilization and mineralization of bone these forms of vitamin D are important pharmaceutical products which are eminently suitable for use in the treatment of various bone disorders.
New derivatives of vitamin D 3 have now been found which express excellent vitamin D-like activity and which, therefore, could readily serve as a substitute for vitamin
D
3 in known applications, such as the treatment of various disease states manifesting calcium and phosphorus imbalance such as bypoparathyroidism, osteodystrophy, osteomalacia and osteoporosis.
These derivatives are 24-homovitamins, particularly 1p,25-dihydroxy-22E(orZ)-dehydro-24homovitamin D 3 and l,25-dihydroxy-24-homovitamin D 3 These derivatives are described and claimed in our Application No. 47761/85.
I I 4i I 2 These compounds can be represented by the formula: S
OR
3
(RR
R,
where R 1
R
2 and R 3 are each independently hydrogen, acyl having from 1 to 4 carbon atoms or benzoyl and R 4 and R each represent hydrogen atoms or taken together form a carbon to carbon bond.
SThe compounds can be prepared in accordance with the following schematic and detailed description where like numbers identify like compounds.
The intermediates of formulae 7 to 10 and 13 are novel and form the subject of the present invention.
Accordingly the present invention provides compounds having the formulae: i wherein each R is independently hydrogen, acyl having from 1 to 4 carbon atoms, benzoyl or methoxymethyl, and Rg 1 wherein R 1
R
2 and R 3 are each independently hydrogen, acl having from 1 to 4 carbon atoms or benzoyl and R 4 and R 5 represent hydrogen atoms or taken together form a carbon to carbon bond
K
OOH
0- Nor* 2. R=THP 3 k:1m 0004 0 C 0 1, 00 4 0 0 o oo 00 0 0004 00 O 0 o 400 00 0 0 00 0 04 00 0 4 00 0 04 0 0 0 0 00 00 0 0 00 0 04 o 0" 0 ,k4 0 0 0440 0 q 0 00 0 00 0 0 0 0 0 40 f1 DA4 7R=A;~ ~1
I
4 4 In accordance with the prces's' ei t-s inventiel.
Bisnorcholenic acid acetate was reduced with lithium aluinum hydride and subsequently oxidized with dichlorodicyanobenzcclinone to afford the 1,4 ,6-triene-3-one in 47% yield. 22-7T--ether of b was treated with alkaline hydrogen peroxide to give the lcx,2a-epoxide in 41% yield.
Reduction of with lithiumi and a-mnrriurn chloride in licuid aflroru-a-tetrahydrofuran at and subseqient treatrPnt with chlorarethyl rethyl ether provided the direthyoxymethyl ether (MOW) in 38% yield. Removal of the fliP group, fol1ou-- by Sw r-n oxidation gave the a-ldehyd3e in 81% yield. This was reacted with vinylxagnesium braride to provi--de the allylalcohol in 94% yield. This alcohol was heated in refluxed j xylene with triethyl ortho acetate and a catalytic amrount of 215 prcpionic acid, to afford the ester in 93% yield. Then, the ester w;as reacted with rrethyii-iagnesin braaide to pro~vide the alcohol in 93% yield. Rez-ovaa of 101~ group, follomad byacylation, e.g. acetylation gave (22E)-1-9,38-diaoetoxy- 25-hydroxy-24-.hcm-cholesta-5,22-cliene in 73% yield.
Allylic bra-,inatin of with 14rr~sciirie I It folloqed by treat-,ent with tetra-n-butyla.7miurn brom~ide and than with tetra-n-butylarrmonium, fluoride gave the 5,7,22triene (10) as a r-ain product in 24% yield. The 5,7-diene was irradiated with a rrediurn pressure mrercury la~ in bnerzene-ethanl for 5 min, subsequently refluxed for 1 hr, and then hydrolyzed to afford (22E) -la, 25-d:iydroxy-22-dehydro-24hc-,ovitam'in D(11) in 22% yield by analogous methods well 'k:awn in the art other acylates or benzoates can be prepared which would be equally useful in the succeeding prcess steps.
a 4 44 1 44 9 4 t44 4 tIIt4 4I a The 5, 22-d-iene was selectively hydrogenated, e.g. using tetra n-b.atylamxoniun fluoride, to provide the 5--ene (12) in 92% yield. This caTpound was converted to 1, z5-dihydroxy-24-hcovitanin D(14) via the 5,7-diene (13) as described above in 12% ovecr--.ll 5 yield.
In the following detailed description melting points were deterT-dned with a hot-stage mnicroscope and were -ancorrected.
1 H-NR spectra were taken
I
with a Hitachi R-24A (60 M-1z) in CX1I with Me 4Si as an intern'al standard, unless otherwise noted. Mass spectra were obtained with a Shirradzu OP-iCCO mass spectrcn-eter at 70 eVI.
UV spectra were obtained in ethanol solution with a Shiinadzu UV-200 double beam spectrophotcreter. Column Chromatcgraphy was effected using silica gel Merck, Kieselgel 60, 70-230 mresh). Preparative thin laye~r chromatography was carried out on precoated plates of silica gel Merck, Kieselgel F 2 54 0.25 mmr thickness). The usual. work-up 1refers to dilution with water, extraction with an organic solvent indicated in parenthesis, washing the extract to neutrality, drying over anhydrous iragnesium sulphate, filtration, and 40*4,removal of the solvent under reduced pressure. The follair:, abbreviations are used; THP tetrahydropyranyl; THF tetrahydrofuran; ether diethyl ether, MjeCH methanol, I4CM trethoxyirethyl. Teroperatures are in centigrade.
22-Hydroxy-23 ,24-dinorchola-l, 4, 6-triene-3-one (b) To a solution of 3 A-acetoxydinorcholenic r' 0 g, 18.04 nmmle) in THF (20 mL,) lithium aluminum hydride (3.0 g, a 20 78.95 nmole) was added. This mixture was stirred at 60"C for 14 h. To this reaction inixiaire water and ethyl acetate were go 0 64carefully added. Filtration and removal of the solvent gave 4 the residue (5.2 g) This in dioxane (140 o.L) was treated 4 with dich" Llocdicyanobenzoquinone (11.7 g, 51.54 niwole) under 0 t 25 reflux for 14 i'h. After cooling to room terrperature the react-ion mix.-ture was filtered and -the filtrate was evaporated to leave the residue, which was applied to a column of alumina (200 g) Elution with dichloroirethane provided the trienone (2.8 g, 47%) rip 156-l57* (ether) UVtj~OH rn 299 (13u0), 252 (9200) 224 (12000) 1 H-NM (CDCI 3 0.80 (3H, s, 18-H 3 1.04 (3H, d, !16 Hiz, 21-H 3 1.21 (3H, s, 19-H 3 3.10-3.80 (311, ri, 22-H 2and OH), 5.90-6.40 (4H, m, 2-H, 4-H,6-H, and 7.05 (111, d, J=10 Hz, 1-H)U, I-IS mhz: 326 311, 308, 293, 267, 112.
lt, 2a-Epoky-22-tetrahvdro2pvranyloxy-23 ,24-dinorchola-4, 6-dirn- 1 4 t 4 04 t 4 1 4 449 4o 4 4 4 4 4 4444 3-one (1) The alcohol (2.7 g, 8.28 rmole) in dichlororrmethane miL) was treated with dihydropyrane (1.5 nmL, 16.42 nrrmole) and ptoluenesulfonic acid (50 mg) at roam terperature for 1 h. The usual work-up (ethyl acetate for etraction) gave a crude product. To a solution of this product in MeOH (70 rrmL), H 202 (4.8 miL) and 10% NaOH/MeH (0.74 it) were added and this mixture 9as stirred at rocmn temperature for 14 h. The usual work-up (ethyl acetate for extraction) gave a crude product, which was applied to a column of silica gel (50 g).
Elution with benzene-ethyl acetate (1CO 1) provided the EtOH eoxide (1.45 g, 41%):'mp 113-115 (hexane) UVX m rmax 290 (22000), 'H-NMR (C1 3 8: 0.80 (3H, 5, 18-H 3 1.07 (3H, d, J=6 Hz, 21-H3), L.18 (3H, s, 19-H 3 3.38 dd, J=4 and 15 1.5 Hz, 3.55 (1H, d, J=4 Hz, 3.30-4.10 (4H, m, 22-H 2 and THP), 4.!0 m, THP), 5.58 (1H, d, J=1.5 Hz, 6.02 (2H, s, 6-H and MS m/z: 342 (M -DHP), 324 (M THPOH), 309, 283, 1la,3 -Dimethox-vmethoxy-23, .24-dinorchol-5-en-22-tetra- 20 hydropyranyl ether (2) Lithium C00 g) was added in small portion to liquid arronia (2CO ml) at -780 under argon atrcsphere during 30 min.
After stirring for 1 hr at -780, la, 2a-epoxy-22-tetrapyranyloxy-23,24-dinorchola-4,6-diene-3-ne (2.00 g, 4.69 m rol) in dry THF (150 ml) was added dropwise at -780 during 30 min, and this mixture was stirred for 1 hr at To this reaction mixture, anhydrous NH 4 C1 (60 g) was added in small portion at -780 during 1 hr. After 1.5 hr the cooling bath was rerroved and monst of the anronia was rexoved by bubbling argon. The usual twork-up (ether was used as a solvent) gave a crude product. This was treated with chloro-rethyl mrethyl ether (2.0 ml, 26.34 i nol) and N,N-diethylcyclohexylamine (4.6 ml, 24.93 mn mol) in dioxane (20 ml) at 450 for *24 hr.
The usual work-up (ethyl acetate) gave a crude product, which was applied to a 'column of silica gel (40 Elution with hexane-ethyl acetate (5 1) provided the dimethoxymethyl ether (922 img, 38%) as an oil. 'H-NMR 8 0.70 (3H, s, 18-H 3 1.02 (3H, s, 19-H 3 1.04 (3H, d, J=6 Hz, 21-H 3 3.34 (3H, s, -O-CH 3 3.37(3H, s, -O-CH 3 ),4.63 (2H, ABq, J=7 Hz, LAB=ll Hz, cl-O-CH 2 4.64 (2H, s, 3-0O-CH 2 and 5.50 (1H, m, 6-H).
la, 3 -Dimethoxyrrthoxy-23,24-dinorchol-5-en-22-ol (3) The TEP ether (922 mg, 1.77 rmol) in T~F (8 ml) ard (8 ml) was treated with 2M HC1 (1 ml) at room temperature for 2 h. The usual work-up (ethyl acetate) gave a crude product, which was applied to a column of silica gel (40 g).
SElution with hexane-ethyl acetate (2 1) gave the alcohol (3) (678 mg, 88%) as an amorphous solid. 1 H-NMR 6 0.70 (3H, s, 18-H 3 1.02(3H,s,19-H 3 1.04 (3H, d, J=6 Hz, 21-H 3 3.34 (3H, s, -0-CH 3 3.38 (3H, s, -0-CH 3 4.65 (2H, ABq, J=7 Hz, L d AB 11 Hz, la-O-CH 2 4.66 (2H,s,3A-O-CH 2 5.53 S(lH,m,6-H).
la, 3 B-Dimethoxymethoxy-23,24-dinorchol-5-en-22-al (4) To a solution of oxalyl chloride (0.27 ml, 3.09 rnml) in dichloromethane (8 ml) dimethyl sulphoxide (0.44 ml, 6.21 rmtl) was added at -78 0 C under argon. The mixture was stirred at -78 0 C for 10 min. To the solutioh the alcohol (660 mg, 1.51 mnl) in dichloramethane (5 ml) was added at -78 0
C.
After stirring for 15 min, triethylamine (1.89 ml, 13.6 rmol) was added. The mixture was stirred at -78 0 C under argon for min, and warmed up to room temperature. The usual work-up (ether) gave a crude product, which was applied to a column of silica gel (30 Elution with hexane-ethyl acetate (4 1) gave the aldehyde (607 g, 92%) as a crystal. mp 71-72 0
C
(hexane;, H-NN*R 8 0.74 (3H, s, 18-H 3 1.04 (3H, s, 19-H 3 1.12 (3H, d, J=6 Hz, 21-H 3 3.35 (3H, s, -O-CH 3 3.39 (3H, s, -0-CH 3 3.7 (IH, m, 10-H), 4.65 (2H, ABq, J=7 Hz, AB 11, Hz, loa-O-CH 2 4.66 (2H, s, 3A-0-CH-O-), 5.52 (1H, m, 6-H), and 9.61 (1H, d, J=3 H2, -CHO), Anal. Calcd for C 26
H
42 0 5
C,
71:85; H, 9.74. Found: C, 71.71; H, 9.68.
8 23-dien-22-ol To magnesium (70 mg, 2.92 rrml) in 'IF (3 ml) solution of vinyl brcnide in THF (0.42 ml, 2.98 mrol) was added. The mixture was stirred at room temperature under argon for 30 min. To the resulting Grignard reagent the aldehyde (595 mg, 1.37 Txmol) in THF (6 ml) was added at roan temperature. The mixture was stirred at roam temperature for 1 h. The usual work-up (ether) gave a crude product, which was applied to a column of silica gel (30 Elution with hexane-ethyl acetate (3 1) gave the allylic alcohol (595 mg, 94%) as an amorphous solid. B-NMR 6: 0.70 (3H, s, 18-H 3 1.02 (3H, s, 19-H 3 3.35 (3H, s, -0-CH 3 3.38 (3H, s, CH 3 3.69 (1H, m, 1A-H), 4.20 (1H, m, 22-H), 4.64 (2H, SABq, J=7 Hz, AAB 11 Hz, la-O-CH2 4.65 (2H, s, 3-0-CH 5.52 m, 4.90-6.0 (3H, m, 23-H and 24-H (22E) 3B-Dirmthoxyrrethoxy-27-norcholesta-5 22-dien-26oic acid ethyl ester (6) A solution of the allylic alcohol (590 mg, 1.28 rmol), triethyl orthoacetate (1.0 ml, 5.46 mtol) propionic acid (4 drops), and xylene (8 ml) was refluxed under argon for 2 h. Removal of the solvent under reduced pressure gave the residue, which was applied to a column of silica gel (30 g).
Elution with hexane-ethyl acetate (4 1) gave the ester (6) (630 mg, 93%) as an oil. 1 H-NR 8: 0.68 (3H, s, 18-H3), 0.97 (3H, d, J=6 Hz, 21-H 3 1.03 (3H, s, 19-H3). 1.24 (311, t, J=7 Hz, -CO2 CH23) 3.35 (3H, s, -O-CH3 3.39 (3H, 7, -O-CH3), 3.70 (1H, m, 1B-H), 4.11 (2H, q, J=7 Hz, -COH 2 C 3 4.64 (2H, ABq, J=7 Hz, LAB 11 Hz, la-0-CH 2 4.65 (2H, s, 3 -0-CH 2 5.29 mn, 22-H and 23-H), 5.52 (1H, m, 6-H).
If desired the 22E stereo isaer, carompound can bs readily converted to the 22Z stereo isomrer by treatment with iodine. Thus, treatment of compound in ether with a catalytic amount of iodine of the amount of while under diffuse daylight for 1 hr. results in a trans to cis i isw.reri'zation which, after HPLC purification, (Zorba-A-Sil coluri, 4.6 3, 25 cm, 6% 2-propanol/hex- ane) yielded the 22Z stereo isomer.
(22E) -lc4,3 0-Diietho yrretoxy-2 4-hc.-cholesta-5,22-diene-25-ol (7) To a solution of the ester (605 iwg, 1. 14 itxrl) in THF (6 ml) IM solution of nrethylwagnesiui bromide in THF (4.5 ml, nxto1) was added at roan. temp~erature. The mixture was stirred at roa, teirlperature for 1 h. 'The usual work-=n (ether) gave a crude product. which was applied to a column of silica gel (30 g) Elution- with hexane-ethvl acetate (3 :1) gave the alcohol ()(548 rtg, 93%) as an oil. 1 -H-NM b: 0.68 (311, s, 18-H 3 0.97 (3H1, d, J=6 Hz, 21-H 3 1.01 (3H1, s, 19-H 3 1. 21 (6H1, s, 26-H3 and 27-H 3 3.33 (3H1, s, -0-CU 3 715 3.38 (3Hi, s, -0-CH) 3.70 (1H, m, lp-H), 4.64 (2H1, ABq, 7 in2-H and 23-) ,a taed w5 ih 6Hl(l) at 0 product, which was applied to a colturm of silicz gel (20 g) 11t 04 Elution with hexazne-ethyl acetate (1 1) gave the triol (8) (428 mg, 95%) as a crystal. mp9 164-1661C (hexane-et-hyl acetate), 3 11-M 5: 0.68 (3H1, s, 18-H3), 0.95 (3H1, s, J=6 Hz, 21-H 3 1.00 (3H1, s, 19-H 3 1. 20 (6H1, s, 26-H and 27H 3.80 m, 2. 3.92 (1H1, m, cc--H) 5.30 (211, mn, 22-H and 23-H) and 5.53 (1H1, m, 6-H).
(22t) -laL, 3 P-DiacetSxL 2-hdoy24hncolsa572-in (9) A solution of the triol (395 mg, 0.919 frol) in pyridine (2 ml) was treated with acetic anhydride (1 ml) at rocm temperature for 16 h. The usual work-up (ethyl acetate) gave a crude product, which was applied to a colmn of silica gel (20 Elution -with hexane-ethyl acetate (2 gave the diacetate (361 rrg 77%) as an oil. 1 H-NM 8: 0.67 (3H, s, 18-H 3 0. 97 (3H, d, J=6 Hz, 1. 07 (3H, s, 19-H), 1. 21 (6H, s, 26-H,3 and 27-H 3 2.01 O3H, s, acetyl), 2.04 (3H, s, acetyl) 4.98 (1H, m, 3(X-H) 5.05 m, lp-H) 5. 31 (2H1, m, 22-H and 23-H) and 5.52 (1H, m, 6-H) (22E) -la, 3 g-Diacetoxy-25-hydox-24-hanocholesta-5, 7, 22-triene A solution of the 5-ene (51 mg, 0,0992 inrol) and N-brnr-succinimide (21 mng, 0.118 nml) in carbontetrachioride (3 ml) was ref luxed under argon for 20 min. After the mixture had been cooled to 0 0 C, -the cesulting precipitate was filtered off. The filtrate was concentrated below 40 0 C to leave the residue. This in THF (5 ml) wias treated with a catalytic amtunt of tetra-n-butyla~niun brcmide at room temrperature 15 for 50 min. Then, the mixture was treated with a solution of 04 0 4 tetra-n-butyammni.m fluoride in ThE' (3.5 ml, 3.5 mrol) at room tem.perature for 30 min. The usual work-up (ethyl acetate) gave a crude product, which was submitted to preparative thin layer chrcxTatography (hexane-ethyl acetate, 4 1, developed five time~s) The band of RE value 0.48 was scraped cff and eluted with ethyl acetate. Renoval of the solvent provided the 5,7-diene (10) 12.5 mgz, UXEC Max: 293, 282, and 271.
104* ia, ?9-D.ydox-22E-dehydro-24-hcrrovitamin D 3 (11I) A solution of the 5,7-diene (10) (7.3 nrq, 0.0143 'mml) in 4tbenzene (90 ml) and ethanol (40 mrl) was irradiated with with a mredium pressure n'ercury lamp through a Vycol filter at 0 0
C
under argon for 5 m The reaction mixture was refluxed under argon for 1 h. Removal of the solvent under reduced pressure gave a crude product, which was submitted to preparative thin layer chrocatography (hexane-ethyl acetate,4 1, developed five tinres). The band of Rf value 0.38 was srraped off and el.uted with ethyl acetate. Peroval of the solvent gave the vitamiun D 3 diacetate 1.8 irq, ,The band /2 11 of Rf value 0.43 was scraped off and eluted with ethyl acetate. Removal of the solvent recovered the 5,7-diene (2.1 mg, 29%).
The vitamin D diacetate (1.8 mg, 2.15 Imol) in THF (4 ml) was treated with 5% KOH/MeOH (1 ml) at room tenperature for 20 min. The usual work-up (ethyl acetate) gave a crude product, which was submitted to preparative thin layer chromatography (hexane-ethyl acetate, 1 2, developed three times). The band of Rf value 0.43 was scraped off and eluted with ethyl acetate. Renoval of the solvent gave the vitamin D3 analogue (11) mg, The purity of the product (11) was determined as 100% by high performance liquid chrcaTatography (a Shimadzu C-3A; column, Zorbax ZI normal phase, 4.6 rm I.i. x 15 cm; solvent, MeOH-CHI 2 C12, 1 49; floi rate, 3 -7l/min; retention time, 11.5 min). The vitamin D 3 EtOH analogue (11) had the following spectral data; UVX 265 EH- May.
nm, l-tO 228 nm, MS m/z: 428 (N 410, 392 (base peak), 374, 287, 269, 251, 152, 134, 123, 59, H-Rd (360 MHz) 6: 0.55 (3H, s, 18-H 3 1.02 (3H, d, J=6.6 Hz, 21-H 3 1.22 (6H, s, 26-H 3 and 27-H 2.32 (1H, dd, J=13.2 and 6.7 Hz), 2.60 (1H, dd, J=13.0 and, 3.0 Hz), 2.83 (1H, dd, J=12.0 and 3.0 Hz), 4.23 n, 4 Hz, 3a-H), 4.43 (1H, m, 16.9 Hz, l-H) 5.00 bs, W/2 3.2 Hz, 19-H) 5.30 (1L, ad, 1/2 J=15.0 and 7.1 Hz, 22-H or 23-H), 5.33 (1H, bs, W1 3.2 Hz, 19-H), 5.37 (11r, dd, J=15.0 and 5.8 Hz, 22-H or 23-H), 6.01 (1H, d, J=11.0 Hz, 6.32 (1II, d, J=11.0 Az, 6-H).
la, 3 -Diaetoxv-24-hoocholest-5-en-25-ol (12) A mixture of the 5,22-diene (40 mg, 0.0778 nmrol) and Pd-C (4 mg) in etlyl acetate (2 ml) was stirred at room tenmerature under hydrogen for 3 h. The Pd catalyst was filtered off and the filtrate was concentrated to leave the residue, which was applied to a column of silica gel (5 g).
Elttion with hexane-ethyl acetate (4 1) gave th -L sne (12) (37 N, 92%) as an oil. 1 H-NMR 8: 0.66 (3H, s, lI 'A 3 1.08 (3H, s, 19-H 3 1.20 (6H, s, 26-H 3 and 27-H 3 2.02 (ZH, s, L -12acetyl), 2.05 (3H, s, acetyl) 4.97 (II, mn, 3a-H) 5.07 (1Hi, mn, 10-H), 5.53 (LE, m, 6-H) lot, 35- )aeo~y-4h ~oet-, 7-dien-25-ol (13) The 5-e (12) (19 mg, 0.037 rniL-.l) was converted, as described for (10) to the 5, 7-diene (:132I 8 mg, 31%).
EtCH 293, 282, 271 rim.
la, 25-Dihydrcxy-24-hcn-ovitarnin D 3 (14) The 5,7-diene 413) (5.8 rng, 0.0113 =mrl) was converted, as described for (21) to the vita=i D 3 analogue (14) (890 The retention tirm of. (14) under t.7-, ahcve-described EPLC corditi"Lon w-as 11.0 mnin. UVXEtOH 265 X 228 rim. M~S m/z 430 412, 394 (base r-eak, mnun 376, 287, 269, 251, 152, 134, 59.
4If desired, the compounds of this inventLjn can be readilyobtained in crystalline form by crsalzto frcrni atsuitable solvents, eg. hexane, ehr, alcoholis, or mixtures thereof as will be apparent to those skilled in the art.
The present invent.ion thus also provides a process for converting a al OR side chain of a steroid nucleus to a
OH
s.'.de chain which comprises reacting trie starting matercial with triethyl orthoacetate to provide the ester side chain and reacting the ester with a methyl magnesium halide.
L
Claims (13)
1. A compound having the formula Ro wherein each R is independently hydrogen, acyl having from 1 to 4 carbon atoms, benzoyl or methoxymethyl. 5
2. A compound according to claim 1 wherein each R is methoxymethyl.
3. A compound according to claim 1 wherein each R is hydrogen.
4. A compound according to claim 1 wherein each R is acetyl. A compound having the formula 0 4 4 I0 I wherein R 1 R 2 and R 3 are eac independently hydrogen, acyl having from 1 to 4 carbon atoms or benzoyl and R4 and R 5 represent hydrogen atoms or taken together form a carbon to carbon bond. L3 i i i; II i.
L-~ i li'._il 14
6. A compound according to claim 5 wherein R I and R 2 are each independently acyl having from 1 to 4 carbon atoms or benzoyl.
7. A compound according to claim 5 wherein R 1 and R 2 are both acetyl and R 3 is hydrogen.
8. A compound according to any one of claims to 7 wherein R4 and R 5 together form a carbon to carbon bond.
9. A compound according to any one of claims to 7 wherein R 4 and R 5 represent hydrogen atoms.
Process for converting a 1 OH side chain of a steroid nucleus to a A a 4 4 OH j4 dii side chain which comprises reacting the starting material with triethyl orthoacetate to provide the ester side chain WCO 2 t E and reacting the ester with a methyl magnesium halide.,
11. Process according to claim 10 wheerein the I. 1 I 0 15 halide is methylmagnesium bromid'e.
12. Process according to claim 10 or 11 wherein the reaction with triethyl orthoacetate is carried out in the presence of propionic acid, as catalyst.
13. Process according to claim 10 substantially as hereinbefore described. DATED this 29th day of December 1988. WISCONSIN ALUMNI RESEARCH FOUNDATION EDWD. WATERS SONS PATENT ATTORNEYS QUEEN STREET MELBOURNE. VIC. 3000. L
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| US4927815A (en) * | 1988-04-29 | 1990-05-22 | Wisconsin Alumni Research Foundation | Compounds effective in inducing cell differentiation and process for preparing same |
| NL8920392A (en) * | 1988-04-29 | 1990-04-02 | Wisconsin Alumni Res Found | 1FA-HYDROXYVITAMINE D-HOMOLOGISTS WITH UNSATURATED SIDE CHAIN. |
| US5063221A (en) * | 1989-04-05 | 1991-11-05 | Chugai Seiyaku Kabushiki Kaisha | Treatment for hyperparathyroidism with use of vitamin d derivatives |
| DE3933034A1 (en) * | 1989-10-02 | 1991-04-11 | Schering Ag | 24-HOMO-VITAMIN-D DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF |
| US5030772A (en) * | 1990-02-14 | 1991-07-09 | Deluca Hector F | Process for preparing vitamin D2 compounds and the corresponding 1 α-hydroxylated derivatives |
| US5260290A (en) * | 1990-02-14 | 1993-11-09 | Wisconsin Alumni Research Foundation | Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives |
| US5891865A (en) * | 1996-10-04 | 1999-04-06 | Wisconsin Alumni Research Foundation | Treatment of arthritic disease induced by infectious agents |
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| US3833622A (en) * | 1969-03-17 | 1974-09-03 | Upjohn Co | Crystalline 25-hydroxycholecalciferol hydrate and structurally related compounds |
| US3880894A (en) * | 1974-05-24 | 1975-04-29 | Wisconsin Alumni Res Found | 1,25-Dihydroxyergocalciferol |
| US4226770A (en) | 1978-02-10 | 1980-10-07 | Kaiser Emil T | Synthesis of steroids |
| US4163744A (en) | 1978-02-10 | 1979-08-07 | Kaiser Emil T | Synthesis of steroids |
| US4225596A (en) * | 1978-10-13 | 1980-09-30 | Wisconsin Alumni Research Foundation | Method for treating calcium imbalance and improving calcium absorption in mammals |
| US4448721A (en) * | 1982-09-20 | 1984-05-15 | Wisconsin Alumni Research Foundation | Hydroxyvitamin D2 compounds and process for preparing same |
| US4508651A (en) * | 1983-03-21 | 1985-04-02 | Hoffmann-La Roche Inc. | Synthesis of 1α,25-dihydroxyergocalciferol |
| CH665834A5 (en) * | 1983-05-09 | 1988-06-15 | Wisconsin Alumni Res Found | METHOD FOR PRODUCING 1ALPHA, 25-DIHYDROXYLATED VITAMIN D (2) AND RELATED COMPOUNDS. |
-
1985
- 1985-08-19 DE DE3590488A patent/DE3590488C2/de not_active Expired - Lifetime
- 1985-08-19 CH CH2351/86A patent/CH672920A5/de not_active IP Right Cessation
- 1985-08-19 NL NL8520265A patent/NL8520265A/en unknown
- 1985-08-19 EP EP85904336A patent/EP0197949A1/en not_active Withdrawn
- 1985-08-19 WO PCT/US1985/001571 patent/WO1986002078A1/en not_active Ceased
- 1985-08-19 AU AU47761/85A patent/AU582789B2/en not_active Ceased
- 1985-08-19 DE DE19853590488 patent/DE3590488T/en active Pending
- 1985-08-19 JP JP60503924A patent/JPS62500301A/en active Granted
- 1985-10-04 FR FR8514758A patent/FR2571369B1/en not_active Expired
- 1985-10-04 IT IT22359/85A patent/IT1190401B/en active
- 1985-10-04 GB GB08524479A patent/GB2167070B/en not_active Expired
- 1985-10-04 BE BE0/215682A patent/BE903376A/en not_active IP Right Cessation
- 1985-10-04 IE IE244385A patent/IE58104B1/en not_active IP Right Cessation
-
1986
- 1986-06-03 DK DK260086A patent/DK154290C/en active
-
1987
- 1987-04-23 GB GB08709579A patent/GB2188932B/en not_active Expired
-
1988
- 1988-03-02 DK DK111188A patent/DK159389C/en active
- 1988-12-29 AU AU27614/88A patent/AU605007B2/en not_active Ceased
-
1989
- 1989-04-13 DK DK177489A patent/DK158989C/en active
-
1990
- 1990-01-19 DK DK015390A patent/DK158991C/en active
- 1990-01-19 DK DK015290A patent/DK158990C/en active
-
1992
- 1992-05-19 JP JP4150044A patent/JPH0635475B2/en not_active Expired - Lifetime
- 1992-05-19 JP JP4150045A patent/JPH0689022B2/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU3843478A (en) * | 1978-07-27 | 1978-12-21 | Research Institute For Medicine And Chemistry Inc. | Chemical process |
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