WO1995033716A1 - Derive de la vitamine d3 et son procede de production - Google Patents
Derive de la vitamine d3 et son procede de production Download PDFInfo
- Publication number
- WO1995033716A1 WO1995033716A1 PCT/JP1995/001145 JP9501145W WO9533716A1 WO 1995033716 A1 WO1995033716 A1 WO 1995033716A1 JP 9501145 W JP9501145 W JP 9501145W WO 9533716 A1 WO9533716 A1 WO 9533716A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- indene
- group
- configuration
- formula
- Prior art date
Links
- 150000003704 vitamin D3 derivatives Chemical class 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims description 15
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 28
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims abstract description 26
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 18
- 125000002252 acyl group Chemical group 0.000 claims abstract description 16
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 141
- -1 lactone compound Chemical class 0.000 claims description 121
- RHDGNLCLDBVESU-UHFFFAOYSA-N but-3-en-4-olide Chemical group O=C1CC=CO1 RHDGNLCLDBVESU-UHFFFAOYSA-N 0.000 claims description 63
- 238000004519 manufacturing process Methods 0.000 claims description 52
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 38
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 229930195733 hydrocarbon Natural products 0.000 claims description 28
- 150000002430 hydrocarbons Chemical class 0.000 claims description 28
- 239000004215 Carbon black (E152) Substances 0.000 claims description 27
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical class CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims description 24
- 239000003054 catalyst Substances 0.000 claims description 21
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 19
- 229910052763 palladium Inorganic materials 0.000 claims description 18
- 150000002596 lactones Chemical group 0.000 claims description 16
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 10
- 229910052740 iodine Inorganic materials 0.000 claims description 10
- 238000010511 deprotection reaction Methods 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- 229930003316 Vitamin D Natural products 0.000 claims 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 claims description 5
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 5
- OUUQCZGPVNCOIJ-UHFFFAOYSA-N hydroperoxyl Chemical group O[O] OUUQCZGPVNCOIJ-UHFFFAOYSA-N 0.000 claims description 5
- 235000019166 vitamin D Nutrition 0.000 claims description 5
- 239000011710 vitamin D Substances 0.000 claims description 5
- 229940046008 vitamin d Drugs 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003844 furanonyl group Chemical group 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims 1
- LYINKTVZUSKQEQ-UHFFFAOYSA-N furan-3-one Chemical class O=C1COC=C1 LYINKTVZUSKQEQ-UHFFFAOYSA-N 0.000 claims 1
- 238000005469 granulation Methods 0.000 claims 1
- 230000003179 granulation Effects 0.000 claims 1
- 239000007787 solid Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 11
- 239000001257 hydrogen Substances 0.000 abstract description 11
- 125000000217 alkyl group Chemical group 0.000 abstract description 8
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 abstract description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 1
- 125000000686 lactone group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 176
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 174
- 239000000203 mixture Substances 0.000 description 114
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 93
- 239000000243 solution Substances 0.000 description 85
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 81
- 238000006243 chemical reaction Methods 0.000 description 79
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 71
- 239000002904 solvent Substances 0.000 description 65
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 61
- 230000002829 reductive effect Effects 0.000 description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 47
- 238000001816 cooling Methods 0.000 description 47
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 46
- 239000000741 silica gel Substances 0.000 description 46
- 229910002027 silica gel Inorganic materials 0.000 description 46
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 43
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 42
- 238000005481 NMR spectroscopy Methods 0.000 description 41
- 239000012043 crude product Substances 0.000 description 41
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 41
- 239000012044 organic layer Substances 0.000 description 39
- 239000002274 desiccant Substances 0.000 description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- 238000001914 filtration Methods 0.000 description 32
- 229920006395 saturated elastomer Polymers 0.000 description 32
- 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 32
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 25
- 238000003756 stirring Methods 0.000 description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- 239000000047 product Substances 0.000 description 20
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentenylidene Natural products C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 19
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 19
- HWYHDWGGACRVEH-UHFFFAOYSA-N n-methyl-n-(4-pyrrolidin-1-ylbut-2-ynyl)acetamide Chemical compound CC(=O)N(C)CC#CCN1CCCC1 HWYHDWGGACRVEH-UHFFFAOYSA-N 0.000 description 19
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N 1-Heptene Chemical compound CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 18
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 18
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 235000002597 Solanum melongena Nutrition 0.000 description 16
- 239000010410 layer Substances 0.000 description 16
- CXOZQHPXKPDQGT-UHFFFAOYSA-N 3-Methylcyclopentene Chemical compound CC1CCC=C1 CXOZQHPXKPDQGT-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 239000007983 Tris buffer Substances 0.000 description 14
- REOJLIXKJWXUGB-UHFFFAOYSA-N mofebutazone Chemical group O=C1C(CCCC)C(=O)NN1C1=CC=CC=C1 REOJLIXKJWXUGB-UHFFFAOYSA-N 0.000 description 13
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 241000243251 Hydra Species 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000499 gel Substances 0.000 description 12
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 11
- 229910052705 radium Inorganic materials 0.000 description 11
- HCWPIIXVSYCSAN-UHFFFAOYSA-N radium atom Chemical compound [Ra] HCWPIIXVSYCSAN-UHFFFAOYSA-N 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 150000001941 cyclopentenes Chemical class 0.000 description 10
- 239000012046 mixed solvent Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 8
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 8
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical class 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 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical compound C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- WMKGGPCROCCUDY-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one Chemical compound C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 WMKGGPCROCCUDY-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 102000008186 Collagen Human genes 0.000 description 6
- 108010035532 Collagen Proteins 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- FUZYFWJHBYRPIP-UHFFFAOYSA-N methyl 2-methylheptanoate Chemical compound CCCCCC(C)C(=O)OC FUZYFWJHBYRPIP-UHFFFAOYSA-N 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- QMMOXUPEWRXHJS-UHFFFAOYSA-N pentene-2 Natural products CCC=CC QMMOXUPEWRXHJS-UHFFFAOYSA-N 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- SEPPVOUBHWNCAW-FNORWQNLSA-N (E)-4-oxonon-2-enal Chemical compound CCCCCC(=O)\C=C\C=O SEPPVOUBHWNCAW-FNORWQNLSA-N 0.000 description 5
- LLBZPESJRQGYMB-UHFFFAOYSA-N 4-one Natural products O1C(C(=O)CC)CC(C)C11C2(C)CCC(C3(C)C(C(C)(CO)C(OC4C(C(O)C(O)C(COC5C(C(O)C(O)CO5)OC5C(C(OC6C(C(O)C(O)C(CO)O6)O)C(O)C(CO)O5)OC5C(C(O)C(O)C(C)O5)O)O4)O)CC3)CC3)=C3C2(C)CC1 LLBZPESJRQGYMB-UHFFFAOYSA-N 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 5
- NKBWMBRPILTCRD-UHFFFAOYSA-N alpha-methylheptanoic acid Natural products CCCCCC(C)C(O)=O NKBWMBRPILTCRD-UHFFFAOYSA-N 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 229920001436 collagen Polymers 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 5
- 150000002941 palladium compounds Chemical class 0.000 description 5
- YWAKXRMUMFPDSH-UHFFFAOYSA-N pentene Chemical compound CCCC=C YWAKXRMUMFPDSH-UHFFFAOYSA-N 0.000 description 5
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 4
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N 1,4-Benzenediol Natural products OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 4
- NNEAKBWZBQOQDH-UHFFFAOYSA-N 3-(1h-inden-2-yl)pyridine Chemical compound C=1C2=CC=CC=C2CC=1C1=CC=CN=C1 NNEAKBWZBQOQDH-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 102000007591 Tartrate-Resistant Acid Phosphatase Human genes 0.000 description 4
- 108010032050 Tartrate-Resistant Acid Phosphatase Proteins 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000004210 ether based solvent Substances 0.000 description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 4
- 150000002241 furanones Chemical class 0.000 description 4
- 230000036571 hydration Effects 0.000 description 4
- 238000006703 hydration reaction Methods 0.000 description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XGCDBGRZEKYHNV-UHFFFAOYSA-N 1,1-bis(diphenylphosphino)methane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CP(C=1C=CC=CC=1)C1=CC=CC=C1 XGCDBGRZEKYHNV-UHFFFAOYSA-N 0.000 description 3
- LRTOHSLOFCWHRF-UHFFFAOYSA-N 1-methyl-1h-indene Chemical compound C1=CC=C2C(C)C=CC2=C1 LRTOHSLOFCWHRF-UHFFFAOYSA-N 0.000 description 3
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 3
- UCYQBFGYQFAGSO-UHFFFAOYSA-N 3-hydroxy-3h-furan-2-one Chemical compound OC1C=COC1=O UCYQBFGYQFAGSO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- XXICBPSJGZAFBO-UHFFFAOYSA-N [6-(bromomethylidene)cyclohexa-2,4-dien-1-yl]-diphenylphosphanium;bromide Chemical compound [Br-].BrC=C1C=CC=CC1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 XXICBPSJGZAFBO-UHFFFAOYSA-N 0.000 description 3
- 125000004036 acetal group Chemical group 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
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- JGNKTUBXSLYNDP-UHFFFAOYSA-N [Ra+2].[O-][Cr]([O-])(=O)=O Chemical group [Ra+2].[O-][Cr]([O-])(=O)=O JGNKTUBXSLYNDP-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
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- 150000001602 bicycloalkyls Chemical group 0.000 description 1
- 102000023732 binding proteins Human genes 0.000 description 1
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- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- DLIJPAHLBJIQHE-UHFFFAOYSA-N butylphosphane Chemical compound CCCCP DLIJPAHLBJIQHE-UHFFFAOYSA-N 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
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- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 description 1
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- POCFBDFTJMJWLG-UHFFFAOYSA-N dihydrosinapic acid methyl ester Natural products COC(=O)CCC1=CC(OC)=C(O)C(OC)=C1 POCFBDFTJMJWLG-UHFFFAOYSA-N 0.000 description 1
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- RXPRRQLKFXBCSJ-UHFFFAOYSA-N dl-Vincamin Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-UHFFFAOYSA-N 0.000 description 1
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- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
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- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 1
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- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
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- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
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- ARYZCSRUUPFYMY-UHFFFAOYSA-N methoxysilane Chemical compound CO[SiH3] ARYZCSRUUPFYMY-UHFFFAOYSA-N 0.000 description 1
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- MOVBJUGHBJJKOW-UHFFFAOYSA-N methyl 2-amino-5-methoxybenzoate Chemical compound COC(=O)C1=CC(OC)=CC=C1N MOVBJUGHBJJKOW-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- DWCZIOOZPIDHAB-UHFFFAOYSA-L methyl green Chemical compound [Cl-].[Cl-].C1=CC(N(C)C)=CC=C1C(C=1C=CC(=CC=1)[N+](C)(C)C)=C1C=CC(=[N+](C)C)C=C1 DWCZIOOZPIDHAB-UHFFFAOYSA-L 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
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- SLRFIGRURFZMHI-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine;toluene Chemical compound CC1=CC=CC=C1.CCN(C(C)C)C(C)C SLRFIGRURFZMHI-UHFFFAOYSA-N 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- BTSIZIIPFNVMHF-UHFFFAOYSA-N nor-leaf alcohol Natural products CCC=CCO BTSIZIIPFNVMHF-UHFFFAOYSA-N 0.000 description 1
- BMJSZITYLSLWNW-UHFFFAOYSA-N oct-4-en-1-yne Chemical compound CCCC=CCC#C BMJSZITYLSLWNW-UHFFFAOYSA-N 0.000 description 1
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- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 150000003018 phosphorus compounds Chemical class 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920000470 poly(p-phenylene terephthalate) polymer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
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- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
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- YXCSPMRGMHOTBN-UHFFFAOYSA-N pyridin-2-yl 4-methylbenzenesulfonate Chemical group C1=CC(C)=CC=C1S(=O)(=O)OC1=CC=CC=N1 YXCSPMRGMHOTBN-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- JWHOQZUREKYPBY-UHFFFAOYSA-N rubonic acid Natural products CC1(C)CCC2(CCC3(C)C(=CCC4C5(C)CCC(=O)C(C)(C)C5CC(=O)C34C)C2C1)C(=O)O JWHOQZUREKYPBY-UHFFFAOYSA-N 0.000 description 1
- PPAXFJNSJJMILV-UHFFFAOYSA-N ruthenium dihydride Chemical compound [RuH2] PPAXFJNSJJMILV-UHFFFAOYSA-N 0.000 description 1
- 229940119265 sepp Drugs 0.000 description 1
- FZHAPNGMFPVSLP-UHFFFAOYSA-N silanamine Chemical compound [SiH3]N FZHAPNGMFPVSLP-UHFFFAOYSA-N 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 239000013076 target substance Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000002303 tibia Anatomy 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 1
- 239000005544 vitamin D3 metabolite Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/675—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids of saturated hydroxy-carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/716—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D317/34—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Definitions
- the present invention relates to Vita Mi emissions D 3 derivatives useful as a pharmaceutical. More specifically, 1-hydroxyhydroxymin D3 derivatives useful as pharmaceuticals such as bone formation promoters, tumor cell growth inhibitors, hypercalcemia agents, immunosuppressants, etc. Regarding intermediates. Background art
- This compound has a serum calcium lowering effect (JP-A-58-118516), a tumor cell growth inhibitory effect (JP-A-58-210011), a bone formation promoting effect (JP-A-60-118). No. 185715). Disclosure of the invention
- An object of the present invention is a child provide novel Vita Mi emissions D 3 derivative conductor and manufacturing method and a manufacturing intermediate thereof having osteogenic activity.
- R is each independently an hydrogen atom, a tri (C, -C 7 hydrocarbon) silyl group, a C 2 -C 8 acyl group or an acetal bond with an oxygen atom of a hydroxyl group. Represents a group that forms
- R ' is here represents a methyl group or methylene down group
- R 1 is a methylene emissions groups binding to the 3-position of R 1 and la click tons ring represents a double bond
- R 2 represents a hydrogen atom or a C, -C 3 alkyl group
- R 3 is either a hydrogen atom, even properly will represent one methylene group but it may also be substituted R 2 and R 3 together May be indicated by
- 1 and 2 are drawings showing the results of collagen synthesis and non-collagen protein synthesis in the following examples, respectively.
- the configuration of the asymmetric center at the C-11 and C-14 positions of the cyclopentene ring may be any of the (R) configuration and the (S) configuration. . Further, the present invention includes a mixture of these four stereoisomers in any ratio. Among them, the C-11 chiral center has the (R) configuration, and the C-14 chiral center has the (S) configuration, and C— It is preferable that the asymmetric center at the 1-position has the (S) configuration and the asymmetric center at the C-4 position has the (S) configuration.
- bimin D3 derivatives included in the first embodiment of the present invention are as follows. 1) 23, 24, 25, 26, 27—Pentano 1 1 Hydroxy 22 — [(1-Hydroxy 1—11 Methyl) 1—2—Cyclopentene 1—4—Ill D 3
- R is a hydrogen atom, Application Benefits (C, -C 7 hydrocarbon) silyl group.
- X represents a bromine atom or an iodine atom, and represents a C 2 to C 7 acyl group or a group that forms an acyl bond with a hydroxyl oxygen atom.
- R ⁇ R? Is a hydrogen atom, Application Benefits (CC 7 hydrocarbon) Shi Li group, a C 2 ⁇ C 7 Ashiru group or a hydroxyl group to form a ⁇ cell evening Lumpur bond with an oxygen atom, Express)
- the above formula is the starting material '(1 one 2) represented by the consequent Ropenten derivatives consequent Ropenten ring at C-1 position and C one 4th chirality center
- the configuration may be either (R) configuration or (S) configuration. It may be a mixture of these stereoisomers in any ratio.
- the above formula (111) wherein the C-11 chiral center of the cyclopentene ring has the (S) configuration and the C-4 chiral center has the (S) configuration ) Vita Mi emissions D 3 derivative represented by is obtained.
- R;, R] may represent Application Benefits (C, -C 7 hydrocarbon) silyl group, as a specific example thereof, for example, Application Benefits Mechirushiri Le, preparative Ryechirushiri Honoré, t - butyl Jimechirushi Li Le based on such bets Li of (C -! C 4 alkyl) silyl group, t - heptyl Ziff you when Ziff-et-two Le (C, - C 4 alkyl) of enyl silyl groups like the silyl group, etc. It can be mentioned as a new thing.
- R if R ⁇ , or represents a Ashiru group d ⁇ C 7, and the specific examples, for example Asechi Le, pro Pioniru, n- butyl Li Le, pivaloyl, Benzoiru, main butoxycarbonyl, Ethoxycarbonyl, benzyloxycarbonyl and the like can be mentioned as preferred.
- R;, R ⁇ or represents a group that forms an acetal bond with the oxygen atom of the hydroxyl group
- specific examples thereof include, for example, methoxymethyl, (2- (Methoxyethoxy) Methyl, 2-methoxy-2-propyl, 2-tetrahydrofuranyl, 2-tetrahydrovinylyl group and the like can be mentioned as preferred.
- the production of the vitamin D 3 derivative represented by the above formula (114) is carried out by preparing a cyclopentene derivative represented by the above formula (112) and an enyne derivative represented by the above formula (113) in palladium.
- the reaction is carried out in the presence of a catalyst.
- the palladium catalyst used here is a zero-valent or divalent organic palladium compound. Examples of such a palladium compound include tetrakis (triphenylphosphine) 'radium or tris (dibenzylideneaceton) and radium, tris (dibenzylideneacetate). ) ,.
- a mixture of radium chloroform, palladium acetate and the like with a phosphorus compound such as triphenylphosphine and tributylphosphine (molar ratio 1: 1 to 1:10) can be mentioned.
- palladium catalysts include tris (dibenzylidene acetate) radium and triphenyl phosphine (1: 1-1: 1: 10) or tris (dibenzylidene acetate), '
- a combination of radium-cloth form and triphenylphosphine (1: 1 to 1:10) is preferred.
- the cyclopentene derivative represented by the above formula (1-2) and the enein derivative represented by the above formula (1-3) perform an equimolar reaction stoichiometrically. It is desirable to use a small excess.
- the radium catalyst is used in an amount of 0.1100 mol%, preferably 120 mol%, based on the cyclopentene derivative represented by the above formula (112).
- Reaction solvents used in this reaction include hydrocarbon solvents such as hexane and toluene, getyl ether, tetrahydrofuran, and dioxane.
- reaction temperature a range from room temperature to the boiling point of the solvent is used.
- the reaction time depends on the reaction temperature, and is usually represented by the cyclopentene derivative represented by the above formula (1-2) or the above formula (1-3) by using an analytical means such as thin layer chromatography. It is advisable to do this until one of the Yen In derivatives disappears.
- a salt group such as, for example, triethylamine or diisopropylethylamine to cause the reaction.
- the base is preferably used in an amount of 1 equivalent or more based on the cyclopentene derivative represented by the above formula (1-2), and may be used also as a solvent.
- Ku to bi evening Mi emissions D 3 derivative represented by the above formula (1 one 4) will be produced in the reaction system, by deprotection reaction allowed if necessary, represented by Formula (1 one 1) bi evening can the child and Mi emissions D 3 derivatives.
- a deprotection reaction for example, when a silyl group is deprotected, it can be performed according to a known method (for example, Calveley, MJ, Tetrahedron, 20, 4609-4619, 1987).
- the deprotecting agent include tetrabutylammonium fluoride and pyridinumum p-toluenesulfonate.
- the compound represented by the formula (112) used as a raw material in the method of the present invention can be synthesized, for example, according to the following scheme.
- R;, R, and R; 2 are a hydrogen atom, a tri (C, to C 7 hydrocarbon) silyl group, a C 2 to C 7 acyl group, or an oxygen atom of a hydroxyl group. And a group capable of forming an acetal bond.
- R;, R, and R; 2 are a hydrogen atom, a tri (C, to C 7 hydrocarbon) silyl group, a C 2 to C 7 acyl group, or an oxygen atom of a hydroxyl group. And a group capable of forming an acetal bond.
- R are a hydrogen atom, a tri (C, to C 7 hydrocarbon) silyl group, a C 2 to C 7 acyl group, or an oxygen atom of a hydroxyl group. And a group capable of forming an acetal bond.
- R and R may be the same or different and each represents a hydrogen atom, a tri (C, to C 7 hydrocarbon) silyl group, a C, to C 7 acyl group, or It represents an acetal group together with the oxygen atom of the hydroxyl group.
- Preferred specific examples of the cyclopentene derivative of the present invention represented by the above formula (115) are as follows.
- C, ⁇ (: represents an acetyl group together with a 7-acyl group or a hydroxyl group oxygen atom).
- in the above formula (2-1), may be either a methyl group or a methylene group.
- R represents a methylene group
- the bond between R and the 3-position of the lactone ring represents a double bond (the same shall apply hereinafter).
- the configuration at the 3-position asymmetric center of the lactone ring is (S) configuration
- the configuration at the 5-position asymmetric center is (S), (R) It may be in any arrangement, and may be a mixture of (S) and (R) in any ratio.
- the configuration at the asymmetric center at the 5-position of the lactone ring may be either (S) or (R), and (S), It may be a mixture of (R) in any proportion. Among them, those in which the asymmetric center at the 5-position has the (S) configuration are preferred.
- R ⁇ and R ⁇ are the same or different and represent a hydrogen atom, a tri (C, to C 7 hydrocarbon) silyl group, or a C 2 to C 8 acyl group.
- R and R ⁇ represent a tri (C, to C 7 hydrocarbon) silyl group
- specific examples thereof include, for example, trimethyl silyl, triethyl silyl, t Tris such as butyldimethylsilyl (C, ⁇ (: 4 Alkyl) a diphenyl (C, to C4 alkyl) silyl group such as a silyl group, a t-butyldiphenylsilyl group, a tribenzylsilyl group, and the like can be mentioned as preferred.
- a dimethyl (2,4,6-tri-tert-butylphenoxy) silyl group can be used.
- R ⁇ and RI represent a C 2 to C 8 acyl group
- examples thereof include acetyl, propionyl, n-butylyl, is 0-butylinole, and n-phenyl.
- examples thereof include linole, is0-yl, propyl, enanthryl, benzoyl, methoxycarbonyl, ethoxyquincarbonyl, and benzyloxycarbonyl group.
- C 2 -C sacyl groups such as n-butylyl, is0-butyryl, methoxycarbonyl, ethoxycarbonyl, and benbenzyl are preferred.
- the present invention also provides a vitamin D 3 derivative represented by the above formula (2-1).
- the manufacturing method of the conductor is included, that is, the following formula (2-2)
- X 2 represents a bromine atom or an iodine atom
- R represents a methyl group or a methylene group.
- R ⁇ and R 3 2 are as defined above
- the (S) configuration is used, but the fifth position may be any of the (S) and (R) configurations, and may be an arbitrary mixture thereof.
- the configuration of these sites is preserved during the reaction, and the chiral position at position 3 of the lactone ring is the (S) configuration and the chiral position at position 5 is the strong (S) configuration.
- a lactone compound represented by the above formula (2-1) is obtained.
- a compound represented by the above formula (2-2) in which the asymmetric center at the 3-position of the lactone ring has the (S) configuration and the asymmetric center at the 5-position has the (R) configuration.
- the asymmetric center at the 3-position of the lactone ring has the (S) configuration and the asymmetric center at the 5-position has the (R) configuration, and is represented by the above formula (2-1).
- a lactone compound is obtained.
- the vitamin D 3 derivative represented by the above formula (2-11) is produced by combining the lactone compound represented by the above formula (2-2) with an enyne represented by the above formula (2-10).
- the reaction is performed by reacting the compound with a palladium catalyst.
- the palladium catalyst is, for example, a zero-valent or divalent organic palladium. Examples of such palladium compounds include tetrakis (triphenylphosphine).
- Examples thereof include a mixture with a phosphorus compound such as butylphosphine (molar ratio 1: 11: 1: 10).
- palladium catalysts include tris (dibenzylidene acetate) radium and triphenylphosphine (1: 11: 1: 10)
- the lactone compound represented by the above formula (2-2) and the enyne compound represented by the above formula (2-10) perform an equimolar reaction stoichiometrically. To ensure completeness, it is desirable to use one or the other, which is usually easily available, in small excess.
- the radius catalyst is used in an amount of 1100 mol%, preferably 530 mol%, based on the lactone compound represented by the above formula (2-2).
- organic solvent used in the present production method examples include hydrocarbon solvents such as hexane and toluene, ether solvents such as tetrahydrofuran and dioxane, N, N-dimethylformamide, and the like.
- examples thereof include water-soluble solvents such as acetonitrile and the like, and a mixed solvent thereof. It is important to use each of them after sufficiently degassing.
- the reaction temperature generally ranges from room temperature to the boiling point of the solvent.
- the reaction time varies depending on the reaction solvent and the reaction temperature used.
- the lactone compound represented by the above formula (2-2) is analyzed using an analytical means such as thin-layer chromatography.
- reaction is preferably carried out in the presence of a base such as, for example, triethylamine or diisopropylethylamine.
- the amount of the base is preferably at least 1 equivalent to the lactone compound represented by the above formula (2-2), and may be used also as a solvent if necessary.
- vitamin D 3 derivative represented by the above formula (2-1) of the present invention is deprotected if necessary, so that the derivative represented by the above formula (2-11) is obtained.
- Mi emissions D 3 can be derivatized and the child is.
- Such a deprotection reaction can be carried out according to a known method (for example, Calvely, MJ, Tetrahedoron, 20, 4609-4619, 1987) when the silyl group is deprotected.
- the protective agent include tetrabutylammonium fluoride, pyridinum ⁇ -toluenesulfonate and the like.
- the compound represented by the above formula (2-2) used as a raw material in the method of the present invention can be synthesized, for example, according to the following scheme. The same applies when X is an iodine atom and the configuration is different.
- the lactone compound represented by the above formula (2-2) can be obtained by halomethylene-forming the lactone compound represented by the above formula (2-3).
- the compound represented by the above formula (2-3) is obtained by deoxidizing the lactone compound represented by the above formula (2'-5) if necessary, and then oxidizing it. can get.
- the lactone compound represented by the above formula (2-5) can be synthesized from the heptanoic acid derivative represented by the above formula (2-6).
- the lactone compound represented by the above formula (2-2) can also be derived from the heptanoic acid derivative represented by the above formula (214).
- the heptanoic acid derivative represented by the above formula (2-4) can be synthesized from the compound represented by the above formula (2-7).
- X represents a bromine atom or an iodine atom.
- R represents a hydrogen atom, a tri- (C, to C 7 hydrocarbon) silyl group, a C, to C 7 acyl group, or an acetal group together with a hydroxyl oxygen atom. Show. )
- X represents a bromine atom or an iodine atom
- Y represents a cyano group, a formyl group, a tosyl group, a mesyl group, a phenylsulfonyloxy group, and a tri (C, to (: 7 (Hydrocarbon) represents a silyl group, C, to (: 7- silyl group, or a hydroxyl group which may be protected with an acetal group together with an oxygen atom of a hydroxyl group.)
- R 1 of the lactone compound represented by the above formulas (2-3) and (2-5) is a methyl group
- the asymmetric center at the 3-position of the lactone ring has the (S) configuration.
- the asymmetric center at the 5-position may be either the (R) configuration or the (S) configuration, or may be a mixture of both in any ratio.
- the asymmetric center at the 4-position may be either (R) configuration or (S) configuration. A mixture of both in any proportion may be used.
- Specific examples of preferred compounds represented by the above formula (2-2) of the present invention are as follows.
- R represents a hydrogen atom or a C 3 alkyl group
- RI may represent a hydrogen atom or a single methylene group which may be substituted together with R ⁇ .
- R ⁇ represents a hydrogen atom, a tri (C, to C 1 hydrocarbon) silyl group, a C 2 to C 8 acyl group, or a group that forms an acetal bond with the oxygen atom of a hydroxyl group.
- Mi emissions D 3 derivative may represent a hydrogen atom or a single methylene group which may be substituted together with R ⁇ .
- R ⁇ represents a hydrogen atom, a tri (C, to C 1 hydrocarbon) silyl group, a C 2 to C 8 acyl group, or a group that forms an acetal bond with the oxygen atom of a hydroxyl group.
- R represents CC 3 alkyl
- specific examples thereof include a methyl, ethyl, and propyl group.
- R ⁇ and R ⁇ both represent one methylene group which may be substituted, the substituent is preferably a t-butyl group, a phenyl group or a methyl group. Can be done.
- R tritium (CC 7 carbohydrate) When it represents a silyl group, for example, tri (C, -C4 alkyl) such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl group Diphenyl (C, —C 4 alkyl) silinole groups such as a silyl group and a t-butyldiphenylsilyl group are preferred.
- tri (C, -C4 alkyl) such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl group
- Diphenyl (C, —C 4 alkyl) silinole groups such as a silyl group and a t-butyldiphenylsilyl group are preferred.
- R ⁇ represents a C 2 -C 8 acyl group
- acetyl, propionyl, n-butyryl, pinocylol, benzoyl, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl Groups and the like can be mentioned as preferred.
- R ⁇ represents a group that forms an acetal bond with an oxygen atom of a hydroxyl group, for example, methoxymethyl, 2-methoxyethoxymethyl, and 2-methoxyethoxy
- the configuration at the 25-position of the vitamin D 3 derivative of the present invention may be either the (R) configuration or the (S) configuration, and may be a mixture of both at an arbitrary ratio. Is also good.
- the present invention is to is found, the equation (3 - 1) Vita Mi emissions D 3 derivatives of the production method represented by, and the like.
- the configuration of may be either the (R) configuration or the (S) configuration. It may be a mixture of these stereoisomers in any ratio.
- the production of the vitamin D 3 derivative represented by the above formula (3-1) is carried out by preparing the heptanoic acid derivative represented by the above formula (3-2) and the enyne compound represented by the above formula (3-5) in a paradoxical manner.
- the reaction is carried out in the presence of a catalyst.
- the palladium catalyst used herein is, for example, a zero-valent or divalent organic palladium compound.
- Such palladium compounds include tetrakis (triphenylphosphine) palladium, tris (dibenzylideneaceton), and the like. Radium or tris (dibenzylideneaceton), radium chromate form, palladium acetate, etc.
- palladium catalysts include tris (dibenzylidene acetate), radium and triphenylphosphine (1: 1 to 1: 10) or tris (dibenzylidene acetate).
- a combination of radium-clo-form and triphenylphosphine (1: 1 to 1:10) is preferred.
- the enequin compound represented by the formula (325) undergoes a stoichiometric equimolar reaction, but it is desirable to use a small excess of an easily available compound.
- the palladium catalyst is used in the range of 0.1 to 100 mol%, preferably 1 to 20 mol%, based on the heptanoic acid derivative represented by the above formula (3-2).
- reaction solvent used in this reaction examples include hydrocarbon solvents such as hexane and toluene, ether solvents such as ether, tetrahydrofuran, dioxane, and dimethoxetane, and ⁇ , ⁇ -dimethylformamide. And water-soluble solvents such as acetonitrile and the like, and a mixed solvent thereof. It is preferable to use each of them after sufficiently degassing.
- reaction temperature a range from room temperature to the boiling point of the solvent is used.
- the reaction time depends on the reaction temperature.
- the heptanoic acid derivative represented by the above formula (3-2) or the above formula (3-5) is obtained using an analytical means such as thin-layer chromatography. It is desirable to do this until any of the enyne compounds represented are extinguished.
- the base is preferably used in an amount of 1 equivalent or more based on the heptanoic acid derivative represented by the above formula (3-2), and can also be used as a solvent.
- the vitamin D 3 derivative represented by the above formula (3-1) is produced in the reaction system, and the deprotection reaction can be further performed as necessary.
- a silyl group when it is to be deprotected, it can be carried out according to a known method (for example, Calveey, .J., Tetrahedron, 20, 4609 to 4619, 1987).
- the deprotecting agent include tetrabutylammonium fluoride and pyridini. Pam 11 tonnone sulfonate and the like can be mentioned.
- the following scheme shows an example of a method for synthesizing a heptanoic acid derivative represented by the above formula (3-2) used as a raw material in the method of the present invention.
- R I and R I are other groups.
- R 4 1 is a hydrogen atom, Application Benefits (C, -C 7 hydrocarbons ) A silyl group or a group that forms an acetal bond with an oxygen atom of a hydroxyl group. )
- R represents a hydrogen atom, CC alkyl group, R 3 2 is. Also properly represent a hydrogen atom, R and R ⁇ is one which may be substituted together methylate emissions group (Examples of the substituent in this case include C, to (: 6 alkyl groups such as methyl, t-butyl, and phenyl).)
- the heptanoic acid derivative represented by the above formula (3-2) ′ can be obtained by converting the heptanoic acid derivative represented by the above formula (3-3) into a promoter. Further, the heptanoic acid derivative represented by the above formula (3-3) can be oxidized after deprotection of the heptanoic acid derivative represented by the above (3-4) if necessary. You can get more. Specific examples of these reactions are given in the examples.
- the configuration at the 2-position of the heptanoic acid derivative represented by the above formula (3-2), (3-3) or (3-4) has an (R) configuration and an (S) configuration. It may be any one of them, and may be a mixture of any ratio thereof.
- Preferred examples of the heptenoic acid derivative represented by the above formula (3-2) of the present invention are as follows.
- Preferred examples of the heptanoic acid derivative represented by the above (3-3) of the present invention are as follows.
- Vita Mi emissions D 3 derivative represented by can a Mochiiruko as the osteogenic prompting Susumuzai.
- the heptanoic acid derivatives represented by the above formulas (3-2), (3-3) and (3-4) can be used as intermediates for their synthesis.
- an intermediate for producing the vitamin D 3 derivative according to the present invention is represented by the following formula (411):
- R represents a hydrogen atom, Application Benefits (C, -C 7 hydrocarbon) silyl group, C 2 -C? Of Ashiru group or a hydroxyl group to form a Asetaru bond with an oxygen atom, chi 4 Represents a bromine or iodine atom
- the asymmetric center at the C-13 and C-15 positions of the 2 (3 ⁇ ) -furanone ring is All three-dimensional configurations may be either (R) configuration or (S) configuration. Further, the present invention includes a mixture of these four stereoisomers in any ratio. Among them, the C-13 chiral center has the (R) configuration, the C-15 chiral center has the (R) configuration, and the C-13 chiral center has the (R) configuration. It is preferable that the asymmetric center at the C-5 position has the (S) configuration.
- the configuration of the carbon-carbon double bond in the halomethylene moiety is (E).
- exomethylene derivative represented by the above formula (4-1) of the present invention are as follows.
- the present invention further includes a method for producing the exomethylene derivative represented by the above formula (4-1).
- the starting material 2 (3) H-furanone derivative represented by the above formula (412)
- the configuration at the asymmetric center at the C-3 and C-15 positions of the H-furanone ring may be any of the (R.) configuration and the (S) configuration. Further, a mixture of these stereoisomers in any ratio may be used.
- the chiral center at the C-3 position of the 2 (3H) -furanone ring is (R) rooster
- the chiral center at the C-5 position is the (R) configuration.
- the configuration of these sites is preserved during the reaction, and the C-13 position of the 2 (3H) -furanone ring is preserved.
- An exomethylene derivative represented by the above formula (4-1) in which the asymmetric center has the (R) configuration and the C-15 center is the (R) configuration is obtained.
- the asymmetric center at the C-13 position of the 2 (3H) -1 furanone ring is (R)
- the asymmetric center at the C-13 position of the 2 (3H) -1 furanone ring is (R)
- the asymmetric center at the C-13 position of the 2 (3H) -1 furanone ring has the (S) configuration
- the 2 (3H) 1 The asymmetric center at the C-3 position of the furanone ring has the (R) configuration
- R ⁇ represents a tri (C, to C 7 hydrocarbon) silyl group
- specific examples thereof include trimethylnyl, triethylsilyl, and t-butyldimethylsilyl groups.
- Diphenyl (C1-C4 alkyl) silyl groups such as a silyl group and a t-butyldiphenylsilyl group can be mentioned as preferred.
- R represents a group that forms an acetal bond together with the oxygen atom of the hydroxyl group
- R represents a group that forms an acetal bond together with the oxygen atom of the hydroxyl group
- specific examples thereof include, for example, methoxymethyl, (2-methoxyethoxy) methyl, 2-methoxy-12-propyl, and 2-tert-methyl.
- Preferred are, for example, trahydrofuranyl and 2-tetrahydrovinylalyl groups.
- the exomethylene derivative represented by the above formula (4-1) is produced by subjecting the 2 (3H) -furanone derivative represented by the above formula (4-2) to a methylene triphenylphosphonium halide in the presence of a base. This is done by reacting with halide.
- Preferred examples of the halogenated methylene triphenylphosphonium halide used herein include bromomethylene triphenylphosphonium bromide and the like.
- the bases used include lithium diisopropyl amide and lithium. Preferable are bismuth trityl silyl amide, sodium bis trimethyl silyl amide, and the like.
- the amount of the base used is preferably 1 to 10 times the amount of the 2 (3H) -furanone derivative.
- reaction solvent used in this reaction examples include ether solvents such as diethyl ether, tetrahydrofuran, and dimethoxetane.
- reaction temperature a range from 60 ° C to room temperature is used.
- the reaction time varies depending on the reaction temperature, and is usually performed using an analytical means such as thin-layer chromatography until the 2 (3H) -furanone derivative represented by the above formula (412) disappears. This is desirable.
- the compound represented by the above formula (412) used as a raw material in the present invention can be synthesized, for example, according to the following scheme.
- R 4 and R 12 form a cetal bond with a hydrogen atom, a tri (C, to C 7 hydrocarbon) silyl group, a C 2 to C 7 acyl group, or an oxygen atom of a hydroxyl group. Represents a group.
- the reaction mixture was poured into 100 ml of ethyl acetate-20 ral of water and extracted.
- the organic layer was washed twice with a saturated aqueous solution of sodium hydrogen sulfate, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution, and then dried over anhydrous magnesium sulfate.
- the drying agent was separated by filtration, and the solvent was distilled off under reduced pressure to obtain 4.2 g of a crude product. This was put in lOOral eggplant flask, 2.04 g of imidazole was added, and 20 ml of dried dichloromethan was added thereto, followed by stirring under ice cooling.
- reaction solution was poured into 100 ml of ether-30 ml of water and extracted.
- the organic layer was washed four times with a saturated saline solution and dried over anhydrous magnesium sulfate.
- the drying agent was filtered off, and the solvent was distilled off under reduced pressure to obtain 1.29 g of a crude product.
- the compounds (1-12), (1S, 4S) 1-4-1 ((2R) -12-[(1R, 7aR) -one-octane-hydro-4-trimethylin-linoleoxy)
- One 7a—methyl-1H—indene—one yl] one propyl ⁇ one 1-Meru 2-Cyclopentene 1-1-260 mg is processed and the target substance (1-14), (IS, 4 S)-4- ⁇ (2 R)-2- ⁇ (1 R, 7 a R) 1-year-old hydro 4 — hydroxy 1 7 a—methyl 1 H—indene—1 yl—1 propyl ⁇ 1 1—methyl 1 2 —cyclopentene— 1 1 174 mg (84% yield) of all was obtained.
- the organic layer was washed twice with a saturated saline solution, and then dried over anhydrous magnesium sulfate.
- the obtained residue is dissolved in THF and stirred under ice-cooling, and 5 ml of tetra- (n-butyl) ammonium fluoride in THF (lmol / L) is added thereto and stirred under ice-cooling for 1 hour. did.
- reaction solution was extracted with 150 ml of ethyl acetate.
- the organic layer was washed twice with saturated saline and then dried over anhydrous magnesium sulfate.
- the drying agent was filtered off, and the solvent was distilled off under reduced pressure to obtain 5.0 g of a crude product.
- reaction solution was extracted by adding 50 ml of water and 200 ml of ethyl acetate.
- the organic layer was further washed three times with water and twice with a saturated saline solution, and then dried over anhydrous magnesium sulfate.
- the desiccant is filtered off, and the solvent is distilled off under reduced pressure.
- (5S) -5- ⁇ (2R) -2 — [(1R, 7aR) —octahydro-4—hydroxy 7a—Methyl-1H—indene-1-yl] propyl. ⁇ — 880 mg of 3-methylenedihydro1-2 (3H) —furanone was obtained.
- Example 2-4 (5 S)-5- ⁇ (2 R)-2-[(1 R, 7 R) —OctaHide Mouth 4 —Okitsu 2 7 a—Methyl-1 H—Indene-1 1-yl] Propyl ⁇ — 3—Methylene 1-Hydrogen 2 (3H) —Furanon Production
- reaction solution was extracted by adding 100 ml of water and 100 ml of ethyl acetate.
- the organic layer was washed three times with water and twice with a saturated saline solution, and then dried over anhydrous magnesium sulfate.
- the desiccant is filtered off, and the solvent is distilled off under reduced pressure.
- reaction solution was extracted by adding 10 ml of water and 10 ml of ethyl acetate.
- the organic layer was washed three times with water and twice with a saturated saline solution, and then dried over anhydrous magnesium sulfate.
- the desiccant is separated by filtration, and the solvent is distilled off under reduced pressure.
- (5R) -5- ⁇ (2R) —2-[(1R, 7aR) —Ok Styrene 7a—methyl 1H—indene 1—yl] propyl ⁇ —3-methylethylene hydro 2 (3H) —60 mg of furanone .
- the drying agent was separated by filtration, and the solvent was distilled off under reduced pressure to obtain 120 mg of a crude product.
- This was purified using a silica gel column (Merck gel, hexane / ethyl acetate 14/1 to 9-1), and 23 (S) and 25 (S) — 1 hydroquinone vitamin D was purified. There were obtained 52 mg (50% yield) of 3 — 26, 23 — lactone and 3 — pistrimethylsilyl ether. This is 2
- the mixture was placed in a 5 ml eggplant flask, and 5 ml of methanol was added to dissolve.
- the mixture was cooled in an ice cooling bath, 10.0 mg of pyridinyl toluene-4-sulfonate bonded to the polymer was added thereto, and the mixture was stirred for 15 hours.
- the reaction solution was filtered through celite, the solvent was distilled off under reduced pressure to obtain 110 mg of a crude product.
- reaction mixture was poured into 50 ml of a 50 ml aqueous solution of ethyl acetate-saturated hydrogen sulfate and extracted.
- the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution, and then dried over anhydrous sodium sulfate.
- Vitamin D 3 — 26, 23 — lactone-1 1 a, 3 — bistrimethylsilyl ether was obtained in an amount of 50 mg (40% yield). This was placed in a 25 ml eggplant flask, and 5 ml of methanol was added to dissolve it. The mixture was cooled in an ice-cooled bath, 100 mg of pyridinyl toluene-141 sulfonate bonded to the polymer was added thereto, and the mixture was stirred for 15 hours. After the reaction solution was filtered through celite, the solvent was distilled off under reduced pressure to obtain 11 O mg of a crude product.
- the excess reducing agent is decomposed with methanol and saturated sodium sulfate, and 300 ml of ethyl acetate and 80 ml of saturated aqueous ammonium chloride are added. The liquid was separated. After extraction from the aqueous layer with 100 ml of ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure to obtain 3.61 g of a crude product.
- Example 4-1 (7 R, 2 R) — 1, 2 — Epoxy 1 — Hydroxymethyl — 4 (t —butyldimethylsilyl) 1 7 — [((1 R, 7 a R) 1 year old 4 — Production of trimethylsilyloxy-7a-methyl-1H-indene-1-yl
- the reaction solution was poured into 10% tartaric acid aqueous solution (20 ml), stirred at the same temperature for 30 minutes, and then at room temperature for 1 hour, separated, and extracted from the aqueous layer with dichloromethane.
- the organic layer was washed with 10% aqueous tartaric acid and saturated saline, and dried over anhydrous magnesium sulfate. After filtration through celite, the solvent was distilled off under reduced pressure.
- the obtained residue was dissolved in 50 ml of ether, 18 ml of 1N sodium hydroxide was added, and the mixture was stirred under ice-cooling for 1 hour. After liquid separation, the aqueous layer was extracted with ether.
- Bromethylene triphenylphosphonium bromide was added to a 50 ml eggplant-shaped flask, and 0.3 g of the mixture was added. 7 ml of dry THF was added thereto, followed by stirring and cooling in a bath at 65 ° C. Next, 2.35 ml of a 1 M sodium bistrimethylsilylamide THF solution was added dropwise, and the mixture was stirred at the same temperature for 10 minutes and at room temperature for 30 minutes.
- mice C 5 7 / Black 6, 5 weeks old, O scan) femur, the bone marrow cells were separated from the tibia, 1 fire fly one MEM containing 1 0% fetal calf serum, 2 5 (0 H) 2 D 3 (1 ⁇ '- 8 ⁇ ) presence were added and cultured for 7 days compounds of constant concentration. Cells were stained with tartrate-resistant acid phosphatase (TRAP) and nuclei were stained with methyl green. Then, TRAP-stained cells (osteoclasts) with three or more nuclei were counted under a microscope. The results are shown in Table 5-1 below.
- TRAP tartrate-resistant acid phosphatase
- VD 3 (10- 8 M) + Example 2 - 16 10 "8 M 24.0 Soil 6.9
- Isolation of 1 and 25-dihydroxyvitamine D3 receptors in the cytoplasm of the small intestine mucosa of the nitrile and receptor binding affinity can be performed by a known method [Steroids, 37, 33-4]. 3 (1 98 1)]. That 1 2 X 7 5 mm poly pro pyrene tube of 2 0 pg [2 6, 2 7 - methyl one 3 H] 1 a, 2 5 - dihydric Dorokishibita Mi emissions D 3 (l 5 8 Ci / mmoK 1 6 , 800 dpm) and the test compound Additionally dissolved in Lumpur, this-phosphate buffer (.
- Example 1 1, 25- (0H) 2 D 3 1 1
- Example 1 11 compound (23) 104 1.2
- Example 2-15 compound 9.8 10.7
- Example 3-17 Compound 3.6> 500
- Example 5-4
- Collagen synthesis and non-collagen protein synthesis mouse osteoblastic cell lines in osteoblasts (MCJT cells) 1 0% fetal calf serum (FCS) were dispersed in containing non one ME M medium (1 X 1 0 4 cellsZml medium) This was inoculated in 2 ml portions into a 35 mm culture dish, and cultured at 37 under 5% CO 2 . After 4 days, co Nfuruen after reaching bets, after the replacement in the same culture medium, ethanol solutions (1 X 1 0- 4 M and 1 X 1,0 - 5 M) of test compound was added in 2 l. Ethanol only was added to the control group. These were cultured in 5% C_ ⁇ 2 under at 3 7 ° C.
- the medium was reconstituted with 0.1% bovine serum albumin (BSA), 0.1 mM ascorbic acid, and 0.5 mM fumaric acid // S-aminopropionitrile.
- BSA bovine serum albumin
- the medium was replaced with a medium, after 3 0 min incubation the ethanol solution or ethanolate Lumpur again test compound after the addition of the last the same amount, added 4 Ci [3 H] Pro Li in to each of the petri dish, 3 hours osteoblast
- the amount of synthesized collagen and the amount of non-collagen protein were measured by a method such as Perterko fsky. [Biochemistry 10, 988-99 (19771))
- Vita Mi emissions D 3 derivative according to the present invention is useful as a bone formation prompting Susumuzai.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/591,547 US5719297A (en) | 1994-06-07 | 1995-06-07 | Vitamin D3 derivatives and production process thereof |
CA2168728A CA2168728C (en) | 1994-06-07 | 1995-06-07 | Vitamin d3 derivative and production process thereof |
DE69513367T DE69513367T2 (de) | 1994-06-07 | 1995-06-07 | Vitamin d3 derivat und verfahren zu dessen herstellung |
EP95921131A EP0712843B1 (en) | 1994-06-07 | 1995-06-07 | Vitamin d3 derivative and process for producing the same |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP12514494 | 1994-06-07 | ||
JP6/125144 | 1994-06-07 | ||
JP22018594 | 1994-09-14 | ||
JP6/220185 | 1994-09-14 | ||
JP6/223229 | 1994-09-19 | ||
JP22322994 | 1994-09-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995033716A1 true WO1995033716A1 (fr) | 1995-12-14 |
Family
ID=27315056
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1995/001145 WO1995033716A1 (fr) | 1994-06-07 | 1995-06-07 | Derive de la vitamine d3 et son procede de production |
Country Status (6)
Country | Link |
---|---|
US (3) | US5719297A (ja) |
EP (3) | EP0712843B1 (ja) |
AT (3) | ATE205190T1 (ja) |
DE (3) | DE69513367T2 (ja) |
ES (1) | ES2138212T3 (ja) |
WO (1) | WO1995033716A1 (ja) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997041096A1 (de) * | 1996-04-30 | 1997-11-06 | Schering Aktiengesellschaft | Neue vitamin-d-derivate mit carbo- oder heterocyclischen substituenten an c-25, verfahren zu ihrer herstellung, zwischenprodukte und die verwendung zur herstellung von arzneimitteln |
EP1321141A1 (en) * | 2000-08-30 | 2003-06-25 | Teijin Limited | Parathyroid hormone production inhibitors containing vitamin d3 derivatives |
WO2004067525A1 (ja) | 2003-01-30 | 2004-08-12 | Teijin Pharma Limited | ビタミンd3ラクトン誘導体 |
WO2004067526A1 (ja) * | 2003-01-31 | 2004-08-12 | Teijin Pharma Limited | (23S)-1αーヒドロキシー27-ノルー25-メチレンビタミンD3-26,23-ラクトンの結晶およびその製造方法 |
EP1477483A4 (en) * | 2002-02-20 | 2006-12-06 | Teijin Ltd | VITAMIN D3 DERIVATIVES AND MEDICAMENTS IN WHICH THEY ARE USED |
WO2010053165A1 (ja) | 2008-11-04 | 2010-05-14 | 帝人ファーマ株式会社 | ビタミンd3ラクタム誘導体 |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
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DE69513367T2 (de) * | 1994-06-07 | 2000-06-08 | Teijin Ltd., Osaka | Vitamin d3 derivat und verfahren zu dessen herstellung |
GB2321244B (en) * | 1997-01-20 | 2000-11-22 | Pharmacia & Upjohn Spa | Vitamin D3 analogues,process for preparing them,and their use as antiproliferative and antitumour agents |
CN1090180C (zh) * | 1997-06-25 | 2002-09-04 | 帝人株式会社 | 维生素d3衍生物及其用于炎性呼吸道疾病的治疗剂 |
KR100676106B1 (ko) | 1998-10-23 | 2007-02-28 | 데이진 가부시키가이샤 | 비타민 d3 유도체 및 그것을 사용하는 염증성 호흡기질환 치료제 |
DE19935771A1 (de) | 1999-07-23 | 2001-02-01 | Schering Ag | Neue Vitamin D-Derivate mit cyclischen Substrukturen in den Seitenketten, Verfahren und Zwischenprodukte zu ihrer Herstellung und die Verwendung zur Herstellung von Arzneimitteln |
US20020137731A1 (en) | 2000-05-30 | 2002-09-26 | Gewirtz David A. | Combination of radiation and vitamin D3 analogs for the treatment of cancer |
AU2008202109B2 (en) * | 2001-06-13 | 2012-02-02 | Magnachem International Laboratories, Inc | Lactone formulations and method of use |
EP1406895B1 (en) * | 2001-06-13 | 2008-08-27 | Magnachem International Laboratories, Inc. | Lactone formulations and method of use |
EP1342796A3 (en) * | 2002-02-22 | 2004-01-02 | Teijin Limited | Compound for the treatment of paget's disease of bone |
US8188145B2 (en) | 2002-06-12 | 2012-05-29 | Magnachem International Laboratories, Inc. | Synthetic lactone formulations and method of use |
CA2504886C (en) | 2002-11-05 | 2011-07-05 | Magnachem International Laboratories, Inc. | Synthetic lactone formulations and method of use |
KR20110128785A (ko) | 2008-10-24 | 2011-11-30 | 매그나켐 인터내셔널 레버러토리즈 아이엔씨 | Rad9와 선택적으로 상호작용하는 화합물들의 스크리닝방법 |
KR101666255B1 (ko) * | 2013-01-08 | 2016-10-13 | 삼성에스디아이 주식회사 | 이차 전지 |
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JPS58118516A (ja) * | 1981-12-29 | 1983-07-14 | Teijin Ltd | 1α,25−ジヒドロキシビタミンD↓3−26,23−ラクトンを含有するカルシユウム調節剤 |
JPS58210011A (ja) * | 1982-05-31 | 1983-12-07 | Kureha Chem Ind Co Ltd | 抗腫瘍剤 |
JPS60185715A (ja) * | 1984-03-05 | 1985-09-21 | Teijin Ltd | 骨形成促進剤 |
CA2114830C (en) * | 1993-02-05 | 2000-06-06 | Masayasu Tabe | Lactone compound and process of production thereof |
DE69513367T2 (de) * | 1994-06-07 | 2000-06-08 | Teijin Ltd., Osaka | Vitamin d3 derivat und verfahren zu dessen herstellung |
-
1995
- 1995-06-07 DE DE69513367T patent/DE69513367T2/de not_active Expired - Lifetime
- 1995-06-07 EP EP95921131A patent/EP0712843B1/en not_active Expired - Lifetime
- 1995-06-07 AT AT98101654T patent/ATE205190T1/de active
- 1995-06-07 DE DE69521065T patent/DE69521065T2/de not_active Expired - Lifetime
- 1995-06-07 ES ES95921131T patent/ES2138212T3/es not_active Expired - Lifetime
- 1995-06-07 DE DE69522589T patent/DE69522589T2/de not_active Expired - Lifetime
- 1995-06-07 US US08/591,547 patent/US5719297A/en not_active Expired - Lifetime
- 1995-06-07 EP EP98101654A patent/EP0854139B1/en not_active Expired - Lifetime
- 1995-06-07 AT AT95921131T patent/ATE186721T1/de active
- 1995-06-07 EP EP98101653A patent/EP0854138B1/en not_active Expired - Lifetime
- 1995-06-07 AT AT98101653T patent/ATE201397T1/de active
- 1995-06-07 WO PCT/JP1995/001145 patent/WO1995033716A1/ja active IP Right Grant
-
1997
- 1997-11-14 US US08/971,201 patent/US5986112A/en not_active Expired - Lifetime
-
1999
- 1999-06-08 US US09/327,489 patent/US6177586B1/en not_active Expired - Lifetime
Non-Patent Citations (2)
Title |
---|
HORST, R.L. et al., "Recent Developments in Quantitation of Vitamin D2 and Vitamin D3 and their Metabolites in Biologic Fluids", PROC. WORKSHOP VITAM. D, 1985, 6th (Vitam. D), p. 807-816. * |
ISHIZUKA, S. et al., "Biological Activity and Characteristics of 1 alpha, 25-(OH)2 D3-26, 23- Lactone", PROC. WORKSHOP VITAM. D, 1985, 6th (Vitamin. D), p. 402-403. * |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997041096A1 (de) * | 1996-04-30 | 1997-11-06 | Schering Aktiengesellschaft | Neue vitamin-d-derivate mit carbo- oder heterocyclischen substituenten an c-25, verfahren zu ihrer herstellung, zwischenprodukte und die verwendung zur herstellung von arzneimitteln |
US6600058B1 (en) | 1996-04-30 | 2003-07-29 | Schering Aktiengellschaft | Vitamin D derivatives with carbo- or heterocyclic substituents at C-25, a process for their production, intermediate products and their use for producing medicaments |
US6613920B1 (en) | 1996-04-30 | 2003-09-02 | Schering Aktiengesellschaft | Vitamin D derivatives with carbo- or heterocyclic substituents at C-25, process for their production, intermediate products and use for the production of pharmaceutical agents |
US6642218B2 (en) | 1996-04-30 | 2003-11-04 | Schering Aktiengesellschaft | Vitamin D derivatives with carbo- or heterocyclic substituents at C-25, a process for their production, intermediate products and their use for producing medicaments |
EP1321141A1 (en) * | 2000-08-30 | 2003-06-25 | Teijin Limited | Parathyroid hormone production inhibitors containing vitamin d3 derivatives |
EP1321141A4 (en) * | 2000-08-30 | 2004-02-18 | Teijin Ltd | INHIBITORS OF PARATHORMONE PRODUCTION CONTAINING VITAMIN D3 DERIVATIVES |
EP1477483A4 (en) * | 2002-02-20 | 2006-12-06 | Teijin Ltd | VITAMIN D3 DERIVATIVES AND MEDICAMENTS IN WHICH THEY ARE USED |
WO2004067525A1 (ja) | 2003-01-30 | 2004-08-12 | Teijin Pharma Limited | ビタミンd3ラクトン誘導体 |
US9073885B2 (en) | 2003-01-30 | 2015-07-07 | Teijin Pharma Limited | Vitamin D3 lactone derivatives |
WO2004067526A1 (ja) * | 2003-01-31 | 2004-08-12 | Teijin Pharma Limited | (23S)-1αーヒドロキシー27-ノルー25-メチレンビタミンD3-26,23-ラクトンの結晶およびその製造方法 |
WO2010053165A1 (ja) | 2008-11-04 | 2010-05-14 | 帝人ファーマ株式会社 | ビタミンd3ラクタム誘導体 |
Also Published As
Publication number | Publication date |
---|---|
DE69521065T2 (de) | 2001-10-25 |
EP0854138A3 (en) | 1998-09-23 |
EP0854139A3 (en) | 1998-09-23 |
ES2138212T3 (es) | 2000-01-01 |
EP0712843A4 (en) | 1996-11-13 |
US6177586B1 (en) | 2001-01-23 |
ATE205190T1 (de) | 2001-09-15 |
DE69513367D1 (de) | 1999-12-23 |
EP0712843B1 (en) | 1999-11-17 |
DE69522589D1 (de) | 2001-10-11 |
DE69521065D1 (de) | 2001-06-28 |
EP0712843A1 (en) | 1996-05-22 |
DE69513367T2 (de) | 2000-06-08 |
US5986112A (en) | 1999-11-16 |
EP0854138B1 (en) | 2001-05-23 |
US5719297A (en) | 1998-02-17 |
ATE201397T1 (de) | 2001-06-15 |
ATE186721T1 (de) | 1999-12-15 |
EP0854139A2 (en) | 1998-07-22 |
EP0854139B1 (en) | 2001-09-05 |
EP0854138A2 (en) | 1998-07-22 |
DE69522589T2 (de) | 2002-04-18 |
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