JPS63115841A - 2-(2-fluoroalkyl)-2,5,12-trihydroxy-1,2,3,4-tetrahydro-naphthacene-6,11-dione derivative - Google Patents
2-(2-fluoroalkyl)-2,5,12-trihydroxy-1,2,3,4-tetrahydro-naphthacene-6,11-dione derivativeInfo
- Publication number
- JPS63115841A JPS63115841A JP25830586A JP25830586A JPS63115841A JP S63115841 A JPS63115841 A JP S63115841A JP 25830586 A JP25830586 A JP 25830586A JP 25830586 A JP25830586 A JP 25830586A JP S63115841 A JPS63115841 A JP S63115841A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- reaction
- trihydroxy
- acid
- fluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims abstract description 9
- -1 acyclic acetal Chemical class 0.000 claims abstract description 8
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 17
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 238000005893 bromination reaction Methods 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 abstract description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 abstract description 3
- 230000031709 bromination Effects 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 230000003327 cancerostatic effect Effects 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 230000001093 anti-cancer Effects 0.000 description 6
- RTEXIPZMMDUXMR-UHFFFAOYSA-N benzene;ethyl acetate Chemical compound CCOC(C)=O.C1=CC=CC=C1 RTEXIPZMMDUXMR-UHFFFAOYSA-N 0.000 description 6
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 6
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 150000001241 acetals Chemical class 0.000 description 4
- 229940045799 anthracyclines and related substance Drugs 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000004210 ether based solvent Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- GGFDHOKVCVFSRP-WMPUSZARSA-N (9s)-7-(4-amino-5-hydroxy-6-methyloxan-2-yl)oxy-9-(2-fluoroacetyl)-6,9,11-trihydroxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(=O)CF)C1 GGFDHOKVCVFSRP-WMPUSZARSA-N 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 2
- ZUFQFGSMHXKORU-UHFFFAOYSA-N 9-acetyl-6,7,9,11-tetrahydroxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1C(O)=C1C(O)CC(C(=O)C)(O)CC1=C2O ZUFQFGSMHXKORU-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 125000004036 acetal group Chemical class 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 210000004748 cultured cell Anatomy 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- PQXKHYXIUOZZFA-UHFFFAOYSA-M lithium fluoride Chemical compound [Li+].[F-] PQXKHYXIUOZZFA-UHFFFAOYSA-M 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RWNXXQFJBALKAX-UHFFFAOYSA-N 1-(dipropoxymethoxy)propane Chemical compound CCCOC(OCCC)OCCC RWNXXQFJBALKAX-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 206010025280 Lymphocytosis Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- OCJUNNNZCBGXCC-UHFFFAOYSA-N [Br].ClC(Cl)(Cl)Cl Chemical compound [Br].ClC(Cl)(Cl)Cl OCJUNNNZCBGXCC-UHFFFAOYSA-N 0.000 description 1
- 238000006359 acetalization reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 210000001217 buttock Anatomy 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229910021386 carbon form Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- WPJRFCZKZXBUNI-HCWXCVPCSA-N daunosamine Chemical class C[C@H](O)[C@@H](O)[C@@H](N)CC=O WPJRFCZKZXBUNI-HCWXCVPCSA-N 0.000 description 1
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
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- 239000003814 drug Substances 0.000 description 1
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- 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 1
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- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
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- 239000000543 intermediate Substances 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 238000000034 method Methods 0.000 description 1
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- 230000002107 myocardial effect Effects 0.000 description 1
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
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- 239000002244 precipitate Substances 0.000 description 1
- 229960003857 proglumide Drugs 0.000 description 1
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- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 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 description 1
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- 235000013024 sodium fluoride Nutrition 0.000 description 1
- KUJFKFWQVGCSAR-UHFFFAOYSA-M sodium;ethyl acetate;hydrogen carbonate Chemical compound [Na+].OC([O-])=O.CCOC(C)=O KUJFKFWQVGCSAR-UHFFFAOYSA-M 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- QSUJAUYJBJRLKV-UHFFFAOYSA-M tetraethylazanium;fluoride Chemical compound [F-].CC[N+](CC)(CC)CC QSUJAUYJBJRLKV-UHFFFAOYSA-M 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 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
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- ZNEOHLHCKGUAEB-UHFFFAOYSA-N trimethylphenylammonium Chemical compound C[N+](C)(C)C1=CC=CC=C1 ZNEOHLHCKGUAEB-UHFFFAOYSA-N 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は一般式
（式中、Ｒ１は水素原子または水酸基を表わし、Ｒ意及
びＲ３は結合している炭素と一体となって環式あるいは
非環式アセタールを形成し、または、Ｒｔ及びＲ３は一
体となって酸素原子を表わす、）で表わされる２−（２
−フルオロアルキル）−２゜５．１２−トリヒドロキシ
−１，２，３，４−テトラヒドロナフタセン−６，１１
−ジオン誘導体に関する。Detailed Description of the Invention [Industrial Application Field] The present invention relates to the general formula (wherein R1 represents a hydrogen atom or a hydroxyl group, and R and R3 together with the bonded carbon form a cyclic or 2-(2
-fluoroalkyl)-2゜5.12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11
-Relating to dione derivatives.
本発明の一般式（１）で表わされる２−（２−フルオロ
アルキル）−２，５，１２−）リヒドロキシ−１，２，
３，４−テトラヒド口ナフタセン−６，１１−ジオン誘
導体は、ダウノサミン誘導体とのグリコジル化反応によ
り、優れた制癌活性を有する１４−フルオロ−４−デメ
トキシダウノルビシンに導くことができる重要合成中間
体である。2-(2-fluoroalkyl)-2,5,12-)lihydroxy-1,2, represented by general formula (1) of the present invention,
3,4-tetrahydro-naphthacene-6,11-dione derivatives are important synthetic intermediates that can be converted into 14-fluoro-4-demethoxydaunorubicin, which has excellent anticancer activity, through a glycosylation reaction with daunosamine derivatives. It is.
優れた制癌剤の開発は社会の強力な要請であり、急務を
有する事項である。アドリアマイシンに代表されるアン
トラサイクリン誘導体は、その強力な制癌活性により制
癌剤として医薬における重要な位置をしめており、現在
までに数多くのアントラサイクリン誘導体が開発されて
いる。しかしながら、それらの誘導体は制癌活性と脱毛
、心筋毒性等の副作用の関連などにおいて一１実際の癌
の治療に使用するには未だ不満足なものである。この事
からより優れた特徴的な制癌活性を示す新規なアントラ
サイクリン誘導体！体の開発が強く望まれている。The development of excellent anticancer drugs is a strong demand from society and is an urgent matter. Anthracycline derivatives, represented by adriamycin, play an important role in medicine as anticancer agents due to their strong anticancer activity, and a large number of anthracycline derivatives have been developed to date. However, these derivatives are still unsatisfactory for use in actual cancer treatment due to the relationship between anticancer activity and side effects such as alopecia and myocardial toxicity. This is a new anthracycline derivative that exhibits superior and unique anticancer activity! Physical development is strongly desired.
（発明が解決しようとする問題点〕
上記の背景にありで、本発明者らは、優れた制癌活性を
有する新規なアントラサイクリン類縁体を探索した結果
、新規な１４−フルオロ−４−デメトキシダウノルビシ
ンが強力な制癌活性を有することを見い出し本発明を完
成した。(Problems to be Solved by the Invention) Against the above background, the present inventors have searched for novel anthracycline analogues with excellent anticancer activity, and as a result discovered a novel 14-fluoro-4-dehyde. The inventors discovered that methoxydaunorubicin has strong anticancer activity and completed the present invention.
前記一般式（１）で表わされる新規な２−（２−フルオ
ロアルキル）−２，５，１２−）ジヒドロキシ−１，２
，３，４−テトラヒドロナフタセン−６，１１−ジオン
誘導体は、以下の反応式に従い製造することができる。Novel 2-(2-fluoroalkyl)-2,5,12-)dihydroxy-1,2 represented by the general formula (1)
, 3,4-tetrahydronaphthacene-6,11-dione derivatives can be produced according to the following reaction formula.
（式中、Ｒ４及びＲ２は結合している炭素と一体となっ
て環式あるいは非環式アセタールを形成する。）
〔第１工程〕
本工程は（Ｒ）−２−アセチル−２，５，１２−トリヒ
ドロキシ−１，２，３，４−テトラヒドロナフタセン−
６，１１−ジオン（フープオキシ−４−デメトキシダウ
ノマイシノン） （■）と臭素化剤を反応させ、反応成
績体として得られる２−ブロモアセチル体を、一般式
％式％（）
ことにより、前記一般式（Ｉａ）で表わされる（Ｒ）−
２−（２−フルオロアセチル）−２，５゜１２−トリヒ
ドロキシ−１，２，３，４−テトラヒドロナフタセン−
６，１１−ジオン（７−ゾオキシー１４−フルオロ−４
−デメトキシダウノマイシノン）を製造するものである
。(In the formula, R4 and R2 combine with the carbon to which they are bonded to form a cyclic or acyclic acetal.) [First step] This step consists of (R)-2-acetyl-2,5, 12-trihydroxy-1,2,3,4-tetrahydronaphthacene-
By reacting 6,11-dione (hoopoxy-4-demethoxydaunomycinone) (■) with a brominating agent, the 2-bromoacetyl form obtained as a reaction product is expressed by the general formula % formula % (). , (R)- represented by the general formula (Ia) above
2-(2-fluoroacetyl)-2,5゜12-trihydroxy-1,2,3,4-tetrahydronaphthacene-
6,11-dione (7-zooxy-14-fluoro-4
-demethoxydaunomycinone).
本発明の原料である前記一般式（ＩＩ）で表わされる（
Ｒ）−２−アセチル−２，５，１２−トリヒドロキシ−
１，２，３，４−テトラヒドロナフタセン−６，１１−
ジオンは、（±）−２−アセチル−２，５，１２−トリ
ヒドロキシ−１，２゜３．４−テトラヒドロナフタセン
−６，１１−ジオンの光学活性アセタールによる光学分
割（Ｋ。The raw material of the present invention, represented by the general formula (II)
R)-2-acetyl-2,5,12-trihydroxy-
1,2,3,4-tetrahydronaphthacene-6,11-
The dione is obtained by optical resolution (K.
Ｔａｍｏｔｏ、ａｔ ａｌ、、Ｔｅｔｒａｈｅ−ｄｒ
ｏｎ、４０．４１６７ （１９８４）参照、）、または
（Ｒ）−２，５，１２−トリヒドロキシ−１、２，３，
４−テトラヒドロナフタセン−６゜１１−ジオン−２−
カルボン酸からの変換（Ｙ。Tamoto, at al,, Tetrahe-dr.
on, 40.4167 (1984), or (R)-2,5,12-trihydroxy-1,2,3,
4-tetrahydronaphthacene-6゜11-dione-2-
Conversion from carboxylic acid (Y.
Ｋｌｍｕｒａ、ａｔ ａｌ、、Ｂ’ｕｌ １．Ｃｈｅ
ｍ。Klmura, at al,, B'ul 1. Che
m.
Ｓｏｅ、 Ｊｐｎ、 、 ５９．４１５ （１９８６）
参照、）等により容易に合成できる化合物である。Soe, Jpn, 59.415 (1986)
It is a compound that can be easily synthesized by methods such as (see ).
■の臭素化に用いられる臭素化剤としては、臭素、ピリ
ジニウムプロミドベルブロ識ド、フェニルトリメチルア
ンモニウムトリプロミド等が例示できる０反応は溶媒中
で行うことが望ましく、反応溶媒としては、テトラヒド
ロフラン、ジオキサン、ジオキソラン等のエーテル系溶
媒が好ましく用いられる０反応温度は、０℃〜５０℃で
円滑に進行する。Examples of the brominating agent used in the bromination of (2) include bromine, pyridinium bromide, phenyltrimethylammonium tripromide, etc. It is preferable to carry out the reaction in a solvent. Examples of the reaction solvent include tetrahydrofuran, Ether solvents such as dioxane and dioxolane are preferably used, and the reaction proceeds smoothly at a temperature of 0°C to 50°C.
前記一般式（ｍ）で表わされるフッ化物としては、フン
化テトラブチルアンモニウム、フン化テトラエチルアン
モニウムなどの四級アンモニウム塩、および、フン化リ
チウム、フン化ナトリウム、フン化カリウム、フン化セ
シウム、フン化銀などまたは有機酸あるいはその塩を共
存させることにより、目的物を収率よく得ることができ
る。使用できる酸としては塩酸、臭化水素酸、硫酸、リ
ン酸などの無機酸、あるいは酢酸、プロピオン酸、マレ
イン酸、コへり酸、安息香酸、メタンスルホン酸、ｐ−
）ルエンスルホン酸、トリフルオロメタンスルホン酸な
どの有機酸が例示でき、また、これらの酸との塩として
は、ピリジン、トリブチルアミン、トリエチルアミンな
どの塩基から形成されるアンモニウム塩などが例示でき
る０本反応は溶媒中で行うことが望ましく、溶媒として
はテトラヒドロフラン、ジオキサン、ジオキソラン、ジ
グライム等のエーテル系溶媒、ジメチルスルホキシド、
Ｎ、Ｎ−ジメチルホルムアミド、アセトニトリル等の非
プロトン性溶媒が好適である０反応はＯ℃〜１００℃で
円滑に進行する。Examples of the fluoride represented by the general formula (m) include quaternary ammonium salts such as tetrabutylammonium fluoride and tetraethylammonium fluoride, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, and fluoride. By coexisting silver oxide, etc., or an organic acid or a salt thereof, the desired product can be obtained in good yield. Examples of acids that can be used include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as acetic acid, propionic acid, maleic acid, cohelic acid, benzoic acid, methanesulfonic acid, and p-
) Examples include organic acids such as luenesulfonic acid and trifluoromethanesulfonic acid, and examples of salts with these acids include ammonium salts formed from bases such as pyridine, tributylamine, and triethylamine. It is desirable to carry out in a solvent, and examples of the solvent include ether solvents such as tetrahydrofuran, dioxane, dioxolane, and diglyme, dimethyl sulfoxide,
The reaction, in which aprotic solvents such as N,N-dimethylformamide and acetonitrile are suitable, proceeds smoothly at 0°C to 100°C.
〔第２工程〕
本工程は、第１工程で得られた（Ｒ）−２−（２−フル
オロアセチル）−２，５，１２−トリヒドロキシ−１，
２，３，４−テトラヒドロナフタセン−６，１１−ジオ
ン（１４−フルオロ−４−デメトキシダウノマイシノン
） （Ｉａ）の２位のカルボニル基をアセタール基の
形で保護し、アセタール体（１ｂ）を得るものである。[Second Step] In this step, the (R)-2-(2-fluoroacetyl)-2,5,12-trihydroxy-1,
The carbonyl group at the 2-position of 2,3,4-tetrahydronaphthacene-6,11-dione (14-fluoro-4-demethoxydaunomycinone) (Ia) is protected in the form of an acetal group, and the acetal body ( 1b).
アセタール化反応は、たとえば、トリメチルシリルトリ
フレート存在下、トリアルコキシメタンを作用させるこ
とによって行われる。トリアルコキシメタンとしては、
トリメトキシメタン、トリエトキシメタン、トリプロポ
キシメタンなどが例示できる。The acetalization reaction is carried out, for example, by reacting trialkoxymethane in the presence of trimethylsilyl triflate. As trialkoxymethane,
Examples include trimethoxymethane, triethoxymethane, and tripropoxymethane.
本工程は溶媒中で行なうことが望ましく、メタノール、
エタノール、プロパツール等のアルコール系溶媒、塩化
メチレン、１，２−ジクロロエタン、クロロホルム、四
塩化炭素等のハロゲン化炭化水素系溶媒、テトラヒドロ
フラン、ジオキサン等のエーテル系溶媒、あるいは、こ
れらの混合溶媒が用いられる０反応温度は、０℃〜室温
で円滑に進行する。This step is preferably carried out in a solvent; methanol,
Alcohol solvents such as ethanol and propatool, halogenated hydrocarbon solvents such as methylene chloride, 1,2-dichloroethane, chloroform, and carbon tetrachloride, ether solvents such as tetrahydrofuran and dioxane, or mixed solvents thereof are used. The reaction proceeds smoothly at a temperature of 0° C. to room temperature.
また、ここで得られた非環式アセタール誘導体は、エチ
レングリコール、トリメチレングリコール、２６２−ジ
メチルプロパン−１，３−ジオールなどのジオール類を
用いて、酸触媒存在下、アセタール交換反応を行うこと
により、環式アセタール誘導体に効率よく導くことがで
きる。アセタール交換反応に用いられる酸触媒としては
、ｐ、−トルホン酸、硫酸、塩酸などの無機酸が例示で
きる。In addition, the acyclic acetal derivative obtained here can be subjected to an acetal exchange reaction using diols such as ethylene glycol, trimethylene glycol, and 262-dimethylpropane-1,3-diol in the presence of an acid catalyst. Accordingly, a cyclic acetal derivative can be efficiently derived. Examples of acid catalysts used in the acetal exchange reaction include inorganic acids such as p,-tulfonic acid, sulfuric acid, and hydrochloric acid.
また、反応溶媒としては、塩化メチレン、１． ２−ジ
クロロエタン、クロロホルム、四塩化炭素等のハロゲン
化炭化水素系溶媒、または、ベンゼン、トルエン、キシ
レン等の芳香族炭化水素系溶媒が好ましく用いられる０
反応温度は０℃〜１００℃で円滑に進行する。In addition, as a reaction solvent, methylene chloride, 1. Halogenated hydrocarbon solvents such as 2-dichloroethane, chloroform, and carbon tetrachloride, or aromatic hydrocarbon solvents such as benzene, toluene, and xylene are preferably used.
The reaction proceeds smoothly at a temperature of 0°C to 100°C.
〔第３工程〕
本工程は、−ｍ式（Ｉｂ）で表わされる化合物の４位を
臭素化し、得られた臭化物の水酸化物への変換、さらに
、アセタール基の除去により、−般式（ＩＣ）で表わさ
れる（２３．４３）−２−（２−フルオロアセチル）−
２，５，４，１２−テトラヒドロキシ−１，２，３，４
−テトラヒドロナフタセン−６，１１−ジオン（１４−
フルオロ−４−デメトキシダウノマイシノン）を製造す
るものである。[Third Step] In this step, the 4-position of the compound represented by the -m formula (Ib) is brominated, the obtained bromide is converted to a hydroxide, and the acetal group is further removed to form the compound represented by the general formula (Ib). (23.43)-2-(2-fluoroacetyl)- represented by IC)
2,5,4,12-tetrahydroxy-1,2,3,4
-tetrahydronaphthacene-6,11-dione (14-
fluoro-4-demethoxydaunomycinone).
臭素化は、塩化メチレン、クロロホルム、１． ２−ジ
クロロエタン、四塩化炭素などのハロゲン系溶媒中、臭
素、Ｎ−ブロモコハク酸イミド、Ｎ−ブロモアセトアミ
ド、１．３−ジブロモ−５，５−ジメチルヒダントイン
などを臭素化剤に用いて行われる６反応はθ℃〜１００
℃で円滑に進行する。臭化物を水酸基で置換する反応は
臭素化反応の反応液を０．１〜１．０Ｍのアルカリ水溶
液で処理することによって行われる０反応はＯ℃〜５０
℃で円滑に進行する。５
アルカリ水溶液としては、水酸化ナトリウム、水酸化カ
リウム、水酸化バリウムなどの水溶液が例↓
不きる。Bromination includes methylene chloride, chloroform, 1. This is carried out in a halogenated solvent such as 2-dichloroethane or carbon tetrachloride using a brominating agent such as bromine, N-bromosuccinimide, N-bromoacetamide, or 1,3-dibromo-5,5-dimethylhydantoin. The reaction is θ℃~100
Proceeds smoothly at ℃. The reaction of replacing bromide with a hydroxyl group is carried out by treating the reaction solution of the bromination reaction with an aqueous alkali solution of 0.1 to 1.0M.
Proceeds smoothly at ℃. 5 Examples of alkaline aqueous solutions include aqueous solutions of sodium hydroxide, potassium hydroxide, barium hydroxide, etc.
アセタールの脱保護は、テトラヒドロフラン、ジオキサ
ン、１，２−ジメトキシメタン等の溶媒中、酸性条件下
に行うことができる。ｆａ性条件に用いられる酸として
は、塩酸、硫酸などが好ましく用いられる０反応は室温
〜１００℃の間で行われる。Deprotection of acetal can be carried out under acidic conditions in a solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxymethane, or the like. As the acid used for fa conditions, hydrochloric acid, sulfuric acid, etc. are preferably used. The reaction is carried out between room temperature and 100°C.
以下、参考例、実施例、試験例により本発明の詳細な説
明するが、本発明はこれらに限定されるものではない。Hereinafter, the present invention will be explained in detail with reference to Reference Examples, Examples, and Test Examples, but the present invention is not limited thereto.
なお、例中の略号の意味は次のとおりである。The meanings of the abbreviations in the examples are as follows.
ＴＨＦ ：テトラヒドロフラン
ｐＮＢ鵞 ：ｐ−ニトロベンツ゛イＪし基ＰＰＴＳ ：
ピリジニウムｐ−トルエンスルホネート
実施例１
０Ｈ
（Ｒ）−７−ジオキシ−４−デメトキシダウノマイシノ
ン２０４ｓｉｒ （０，５７８ｍｍｏ ｌ）をＴＨＦ２
０ｍｌに溶解し、ピリジニウムプロミドペルブロミド２
４２ｇ （０，７５６ｍｍｏ １）を加えて室温で２時
間攪拌した０反応混合物を酢酸エチルで希釈し、５０％
食塩水、飽和食塩水で順次洗浄した後、無水硫酸ナトリ
ウム上で乾燥した。THF: Tetrahydrofuran pNB: p-nitrobenzyl group PPTS:
Pyridinium p-toluenesulfonate Example 1 0H (R)-7-Dioxy-4-demethoxydaunomycinone 204sir (0,578 mmol) was dissolved in THF2
Pyridinium promide perbromide dissolved in 0 ml
The reaction mixture was diluted with ethyl acetate and diluted with ethyl acetate to give 50%
After sequentially washing with brine and saturated brine, it was dried over anhydrous sodium sulfate.
溶媒を減圧下留去し、粗製の７−ジオキシ−１４−プロ
モー４−デメトキシダウノマイシノンを橙色粉末として
得た。このものをＴＨＦ４０ｍｌに懸濁し、無水ｐ−）
ルエンスルホン酸３１０■（１，８０ｍｍｏ １） 、
テトラブチルアンモニウムフルオリドーＴＨＦＩＭ溶液
２．９ｍｌ （２，９０ｍｍｏｌ）を順次加えて室温
で３０分間攪拌した後、加熱還流を行った。１時間後、
テトラプチルアンモニウムフルオリド０．６ｍｌを追加
し、さらに３時間加熱還流を行った。冷却後、反応混合
物を５０％食塩水中に注加し、酢酸エチルで抽出した。The solvent was distilled off under reduced pressure to obtain crude 7-dioxy-14-promo-4-demethoxydaunomycinone as an orange powder. Suspend this in 40 ml of THF, anhydrous p-)
Luenesulfonic acid 310■ (1,80mmo 1),
2.9 ml (2.90 mmol) of tetrabutylammonium fluoride THFIM solution was successively added and stirred at room temperature for 30 minutes, followed by heating under reflux. 1 hour later
0.6 ml of tetrabutylammonium fluoride was added, and the mixture was further heated under reflux for 3 hours. After cooling, the reaction mixture was poured into 50% brine and extracted with ethyl acetate.
抽出液を水、飽和食塩水で順次洗浄した後、無水硫酸ナ
トリウム上で乾燥した。？８媒を減圧上留去して得られ
た赤色残渣２３９■をカラムクロマトグラフィー（シリ
カゲル、ベンゼン−酢酸エチル２０：１）を用いて精製
し、“（Ｒ）−７−ゾオキシー°１４−フルオロー４−
デメトキシダウノマイシノン１４９ｓｇ（６９％）を朱
色粉末として得た。このものの一部をトルエンから再結
晶して赤色針状結晶を得、分析用サンプルとした。The extract was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. ? The red residue obtained by distilling off solvent 8 under reduced pressure (239 cm) was purified using column chromatography (silica gel, benzene-ethyl acetate 20:1) to obtain "(R)-7-zooxy-14-fluoro4 −
149 sg (69%) of demethoxydaunomycinone was obtained as a vermilion powder. A portion of this product was recrystallized from toluene to obtain red needle-like crystals, which were used as a sample for analysis.
ｍｐ、２５１〜２５５℃。mp, 251-255°C.
〔α〕げ’−３４，８° （ＣＯ，０５８，ジオキサン
）。[α] Age'-34,8° (CO, 058, dioxane).
ＮＭＲ（ＣＤＣＩｓ） ： δ−１，９８〜２．２２
（２Ｈ１臀）、２．８０ （ＩＨ，ｓ）、２．８５〜３
．２８ （４Ｈ，ｍ）、 ５．４４ （２Ｈ，ｄ
。NMR (CDCIs): δ-1,98~2.22
(2H1 buttocks), 2.80 (IH, s), 2.85-3
．． 28 (4H, m), 5.44 (2H, d
.
Ｊ−４７Ｈｚ）、７．７３〜７．９６ （２Ｈ，ｍ）
。J-47Hz), 7.73-7.96 (2H, m)
.
８．２６〜８．５２ （２Ｈ，ｍ）、 １３．５０
（２Ｈ，ｓ）。8.26-8.52 (2H, m), 13.50
(2H, s).
ＩＲ（ＫＢｒ） ：３５１０． １７３５゜１６２５
、 １５９０ｃｍ−’。IR (KBr): 3510. 1735°1625
, 1590cm-'.
ＭＳ （ｍ／ｅ） ： ３７０ （Ｍ”″）、３
５２゜３０９゜
元素分析値二０３゜１（＋５ＦＯａとして計算値ｊ Ｃ
，６４，８７； Ｈ，４，０８％。MS (m/e): 370 (M""), 3
52゜309゜Elemental analysis value 203゜1 (+5FOa calculated value j C
, 64,87; H, 4,08%.
分析値＋ Ｃ，６４，７Ｂ 、Ｈ，４，１７％。Analysis value + C, 64, 7B, H, 4, 17%.
実施例２
０α（
（Ｒ）−７−ジオキシ−４−デメトキシダウノマイシノ
ン１０．７＊ （０，０３０４ｍｍｏ １）をＴＨＦｌ
ｍｌに溶解し、とりジ二つムプロミドペルブロミド１３
．５Ｎ （０，０４２２ｍｍｏ １）を加えて室温で２
．５時間反応した。実施例１と同様に処理して得た粗製
の７−ジオキシ−１４−プロモー４−デメトキシダウノ
マイシノンを２ｍｌのＴＨＦに溶解し、ＰＰＴ３２４．
３■（０，０９６７ｍｍｏｌ）、テトラプチルアンモニ
ウムフルオリドーＩＭＴＨＦ溶液０．１８ｍ１ （０
，１８ｍｍｏ りを順次加えて室温で３０分間、次いで
１時間加熱還流した。実施例１と同様に処理し、得られ
た残渣をカラムクロマトグラフィー（シリカゲル、ベン
ゼン−酢酸エチル２０：１）にて精製して（Ｒ）−７−
ジオキシ−１４−ツルオロー４−デメトキシダウノマイ
シノン６．１＊（５４％）を赤色固体として得た。この
もののＮＭＲスペクトルは、実施例１で得たものに一敗
した。Example 2 0α((R)-7-dioxy-4-demethoxydaunomycinone 10.7* (0,0304 mmo 1) was dissolved in THFl
Dissolve in 13 ml of dipromide perbromide.
．． Add 5N (0,0422mmo 1) and heat at room temperature for 2
．． The reaction took place for 5 hours. Crude 7-dioxy-14-promo-4-demethoxydaunomycinone obtained in the same manner as in Example 1 was dissolved in 2 ml of THF, and PPT324.
3■ (0,0967 mmol), tetrabutylammonium fluoride IMTHF solution 0.18 ml (0
. The treatment was carried out in the same manner as in Example 1, and the obtained residue was purified by column chromatography (silica gel, benzene-ethyl acetate 20:1) to obtain (R)-7-
Dioxy-14-truol-4-demethoxydaunomycinone 6.1* (54%) was obtained as a red solid. The NMR spectrum of this product was completely inferior to that obtained in Example 1.
実施例３
（Ｒ）−７−ジオキシ−１４−ツルオロー４−−デメト
キシダウノマイシノン３３７■（０，９０９ｍｍｏ １
）を塩化メチレン６７ｍ！に懸濁し、オルトギ酸メチル
２．０ｍｌ （１８，３ｍｍｏｌ）、）リメチルシリ
ルトリフレートーヘキサンＩＭ溶液０．１８ｍ１ （
０，１８ｍｍｏ １）を加えて水冷下３０分間、室温で
２時間攪拌した。Example 3 (R)-7-dioxy-14-truol 4--demethoxydaunomycinone 337 μ (0,909 mmo 1
) to methylene chloride 67m! 2.0 ml (18.3 mmol) of methyl orthoformate, 0.18 ml (
0.18 mmol 1) was added thereto, and the mixture was stirred for 30 minutes under water cooling and for 2 hours at room temperature.
反応液を飽和重曹水中に江刺し、塩化メチレンで抽出し
た。抽出液を水、飽和食塩水で順次洗浄し、無水硫酸ナ
トリウム上で乾燥した。溶媒を減圧上留去し、赤色固体
残渣３６８■をカラムクロマトグラフィー（シリカゲル
、ベンゼン−酢酸エチル１００＋１）にて精製して、（
Ｒ）−２−（２−フルオロ−１，１−ジメトキシエチル
）−２，５゜１２−トリヒドロキシ−１，２，３，４−
テトラヒドロナフタセン−６，１１−ジオン３３１■（
８８％）を赤色粉末として得た。The reaction solution was poured into saturated sodium bicarbonate solution and extracted with methylene chloride. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the red solid residue (368 cm) was purified by column chromatography (silica gel, benzene-ethyl acetate 100+1) to give (
R)-2-(2-fluoro-1,1-dimethoxyethyl)-2,5°12-trihydroxy-1,2,3,4-
Tetrahydronaphthacene-6,11-dione 331■ (
88%) was obtained as a red powder.
ｍｐ、２０６．５〜２０９．５℃。mp, 206.5-209.5°C.
ＮＭＲ（ＣＤＣ１，）：δ−１，６２〜２．３７（２Ｍ
、ｍ）、２．５３ （１８，り、２．６０〜３．３０
（４Ｈ，ｍ）、３．５６ （３Ｂ、ｓ）。NMR (CDC1,): δ-1,62~2.37 (2M
, m), 2.53 (18, ri, 2.60-3.30
(4H, m), 3.56 (3B, s).
３．６０ （３Ｈ，ｓ）、 ４．６２ （２Ｈ，
ｄ。3.60 (3H, s), 4.62 (2H,
d.
Ｊ−４７Ｈｚ） 、 ７．７２〜７．９５ （２Ｈ，ｍ
） 。J-47Hz), 7.72-7.95 (2H, m
).
８．２２〜８．５７ （２Ｈ，ｍ）、 １３．５３
（ＩＨ，ｓ）、 １３．５８ （ＩＨ，ｓ）。8.22-8.57 (2H, m), 13.53
(IH,s), 13.58 (IH,s).
ＩＲ（ＫＢｒ） ：３６Ｇ０． ３４７０゜１６２０
、 １５８５ｃｍ−’。IR (KBr): 36G0. 3470°1620
, 1585 cm-'.
ＭＳ （ｍ／ｅ） ： ４１６ （Ｍ”） 、
１０７゜実施例４
（Ｒ）−７−ジオキシ−１４−ツルオロー４−デメトキ
シダウノマイシノン４．５■（０，０１２２ｍ ｍ ｏ
１ ） 、オルトギ酸メチル０．１２ｍ１、ＴＨＦｌ
ｍｌ、メタノール０．５ｍｌの混合物に、触媒量のトリ
メチルシリルトリフレートを加え、０℃で３０分間、室
温で２２時間攪拌した０反応混合物を飽和重曹水中に注
ぎ、塩化メチレンで抽出した。抽出液を無水硫酸ナトリ
ウム上で乾燥し、溶媒を減圧上留去して、粗製の（Ｒ）
−２−（２−フルオロ−１，１，−ジメトキシエチル）
−２，５゜１２−トリヒドロキシ−１，２，３，４−テ
トラヒドロナフタセン−６，１１−ジオンを得た。この
ものをベンゼンに溶解し、エチレングリコール、触媒量
のカンファースルホン酸を加えて１８時間加熱還流を行
ワた１反応混合物を飽和重曹水中に注ぎ、酢酸エチルで
抽出した。抽出液を水、飽和食塩水で順次洗浄し、無水
硫酸ナトリウム上で乾燥した。溶媒を減圧上留去し、得
られた残渣をカラムクロマトグラフィー（シリカゲル、
ベンゼン−酢酸エチル２０：１）を用いて精製して、（
Ｒ）−２−（２−フルオロメチル−１，３−ジオキソラ
ン−２−イル）−２，５，１２−）リヒドロキシ−１，
２，３，４−テトラヒドロナフタセン−６，１１−ジオ
ン４．９ｍ（９７％）を橙色固体として得た。MS (m/e): 416 (M”),
107゜Example 4 (R)-7-Dioxy-14-Truol 4-demethoxydaunomycinone 4.5■ (0,0122 m m o
1), methyl orthoformate 0.12ml, THFl
ml of methanol and 0.5 ml of methanol was added with a catalytic amount of trimethylsilyl triflate and stirred at 0° C. for 30 minutes and at room temperature for 22 hours. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the crude (R)
-2-(2-fluoro-1,1,-dimethoxyethyl)
-2,5°12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione was obtained. This product was dissolved in benzene, ethylene glycol and a catalytic amount of camphorsulfonic acid were added, and the mixture was heated under reflux for 18 hours.The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel,
Purification using benzene-ethyl acetate 20:1) to give (
R)-2-(2-fluoromethyl-1,3-dioxolan-2-yl)-2,5,12-)lihydroxy-1,
4.9 m (97%) of 2,3,4-tetrahydronaphthacene-6,11-dione was obtained as an orange solid.
ｍｐ、２１８〜２２１．５℃。mp, 218-221.5°C.
ＮＭＲ（ＣＤＣｌ２） ：δ−１，６０〜２．４８（２
Ｈ，ｍ） 、 ２．０６ （ＩＨ，ｓ） 、
２．５５〜３．３３ （４Ｈ，ｍ）、４．０２〜
４．４５（４Ｈ，ｍ）、４．７５ （２Ｈ，ｄ、Ｊ−
４８Ｈｚ）、７．６５〜８．００ （２Ｈ，ｍ）。NMR (CDCl2): δ-1,60~2.48(2
H, m), 2.06 (IH, s),
2.55~3.33 (4H, m), 4.02~
4.45 (4H, m), 4.75 (2H, d, J-
48Hz), 7.65-8.00 (2H, m).
８．２４〜８．５７ （２Ｈ，ｍ）、１３．５１（Ｉ
Ｈ，ｓ）、１３．５４ （ＩＨ，ｓ）。8.24-8.57 (2H, m), 13.51 (I
H,s), 13.54 (IH,s).
ＩＲ（ＫＢｒ） ｚ３４６０，１６２０゜１５９０ｃ
１１−’。IR (KBr) z3460, 1620°1590c
11-'.
ＭＳ （ｍ／ａ） ： ４１４ （Ｍ”ｌ 、 １
０５゜実施例５
（Ｒ）−２−（２−フルオロ−１，１−ジメトキシエチ
ル）−２，５，１２−１−リヒドロキシー１．２．３．
４−テトラヒドロナフタセン−６゜１１−ジオン３０
ｉｌｌｗ（０，７２２ｍｍｏ Ｉ） 、クロロホルム３
０ｍ１、四塩化炭素１５ｍｌ、水２２．５ｍｌの混合物
に臭素−四塩化炭素０．０６７Ｍ溶液５．８ｍｌを加え
、白色光照射下、６０℃油浴上で加熱還流を行った。１
５分後さらに臭素溶液１．７ｍ ｌを加え、次いで５分
毎に１．６５ｍ１ずつ４回、計１４．１ｍｌ （０，
９３９ｍｍｏ １）を加えて２時間反応を行った。冷却
後、１０％水酸化ナトリウム水溶液１．５ｍｌ （３
，７５ｍｍｏ ｌ）を加えて０℃で１０分、さらに室温
で２５分間攪拌した０反応混合物にＩＭ塩酸３４ｍ１を
加えて中和した後、クロロホルムで抽出した。抽出液を
水、飽和食塩水で順次洗浄し、無水硫酸ナトリウム上で
乾燥した。１＊媒を減圧上留去して得た赤色残渣をＴＨ
Ｆ３０ｍｌに溶解し、濃塩酸５ｍｌを加えて室温で１６
．５時間攪拌した０反応混合物を水で希釈し、クロロホ
ルムで抽出した。抽出液を水、飽和食塩水で順次洗浄し
、無水硫酸ナトリウム上で乾燥した。溶媒を減圧上留去
し、残渣をカラムクロマトグラフィー（シリカゲル、ベ
ンゼン−酢酸エチル２０：１→１１１）を用いて分離精
製して、（＋）−１４−フルオロ−４−デメトキシダウ
ノマイシノン１７１ｇ（６１％）を朱色粉末として得た
。このものをベンゼンおよびベンゼン−ヘキサン混合溶
媒から再結晶して、分析用サンプルを得た。MS (m/a): 414 (M”l, 1
05° Example 5 (R)-2-(2-fluoro-1,1-dimethoxyethyl)-2,5,12-1-lihydroxy 1.2.3.
4-tetrahydronaphthacene-6゜11-dione 30
illw (0,722 mmo I), chloroform 3
5.8 ml of bromine-carbon tetrachloride 0.067M solution was added to a mixture of 0 ml, 15 ml of carbon tetrachloride, and 22.5 ml of water, and the mixture was heated to reflux on a 60° C. oil bath under irradiation with white light. 1
After 5 minutes, add another 1.7 ml of bromine solution, then add 4 times of 1.65 ml every 5 minutes for a total of 14.1 ml (0,
939 mmol 1) was added and the reaction was carried out for 2 hours. After cooling, add 1.5 ml of 10% aqueous sodium hydroxide solution (3
, 75 mmol) and stirred at 0° C. for 10 minutes and then at room temperature for 25 minutes. The reaction mixture was neutralized by adding 34 ml of IM hydrochloric acid, and then extracted with chloroform. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The red residue obtained by distilling off the 1* medium under reduced pressure was
Dissolve in 30ml of F, add 5ml of concentrated hydrochloric acid and stir at room temperature for 16 hours.
．． The reaction mixture stirred for 5 hours was diluted with water and extracted with chloroform. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated and purified using column chromatography (silica gel, benzene-ethyl acetate 20:1 → 111) to obtain (+)-14-fluoro-4-demethoxydaunomycinone. 171 g (61%) was obtained as a vermilion powder. This product was recrystallized from benzene and a benzene-hexane mixed solvent to obtain a sample for analysis.
ｍｐ、 １２９．５〜１３２℃。mp, 129.5-132°C.
（α〕７”＋ １６２ ” （ＣＯ，１１１，ジオキ
サン）ＮＭＲ（ＣＤＣＩり） ：δ繍２．２３ （Ｉ
Ｈ。(α]7”+162” (CO, 111, dioxane) NMR (CDCI): δ 2.23 (I
H.
ｄｄ、Ｊ−１４および５Ｈｚ）、２．４２（ＩＨ，ｄｔ
、Ｊ−１４および２Ｈｚ）。dd, J-14 and 5Hz), 2.42 (IH, dt
, J-14 and 2Hz).
３．０４ （ＩＨ，ｄ、Ｊ＝１９Ｈｚ）、３．２７（
ＩＨ，ｄｄ、Ｊ−１９および２Ｈｚ）。3.04 (IH, d, J=19Hz), 3.27 (
IH, dd, J-19 and 2Hz).
３．３６ （ＩＨ，ｔ、Ｊ−３Ｈｚ）、４．６３（Ｉ
Ｈ，ｓ）、、５．３３〜５．４８ （ＩＨ，ｍ）。3.36 (IH, t, J-3Hz), 4.63 (I
H,s), 5.33-5.48 (IH,m).
５．５７ （２Ｈ，ｄ、Ｊ−４８Ｈｚ）、７．７５〜
８．０２ （２Ｈ，ｍ）、８．２５〜８．５３（２Ｈ
，ｍ）、 １３．２５ （ＩＨ，ｓ）。5.57 (2H, d, J-48Hz), 7.75~
8.02 (2H, m), 8.25-8.53 (2H
, m), 13.25 (IH, s).
１３．５７ （Ｉ Ｈ，ｓ）。13.57 (IH,s).
ＩＲ（ＫＢｒ）：３４５０．１７３５゜１６２０、 １
５８５個−１゜
ＭＳ （ｍ／ｅ） ： ３８６ （Ｍ”） 、
３６８゜３５０、 ３０７゜
元素分析値： Ｃ＊ｓＨ＋５ＦＯｖとして計算値ｊ Ｃ
，６２，１８ｉ Ｈ，３，９１％。IR (KBr): 3450.1735°1620, 1
585 pieces - 1°MS (m/e): 386 (M"),
368° 350, 307° Elemental analysis value: Calculated value as C*sH+5FOv j C
,62,18i H,3,91%.
分析値： Ｃ，６２，１８ｉ Ｈ，３，９２％。Analysis values: C, 62,18i H, 3,92%.
実施例６ｒ−１
（Ｒ）−２−（２−フルオロメチル−１，３−ジオキソ
ラン−２−イル） −２，５，１２−）リヒドロキシー
１． ２． ３． ４−テトラヒドロナフタセン−６，
１１−ジオン４．９■（０，０１１８ｍｍｏ １） 、
クロロホルム１ｍｌ、四塩化炭素０．５ｍ ｔ 、水０
．８ｍｌの混合物に、臭素−０，０６７Ｍ四塩化炭素溶
液０．２３ｍ ｌ （０，０１５３ｍｍｏｌ）を４回
に分けて加え、６０Ｗタングステンランプ照射下７０分
間加熱還流した。冷却後、０℃にて１０％水酸化ナトリ
ウム水溶液０．０３ｍ１ （０，０７５ｍｍｏ １）
を加え、同温度で１５分間、さらに室温で１０分間攪拌
した。１Ｍ塩酸で中和した後、酢酸エチルで抽出した。Example 6r-1 (R)-2-(2-fluoromethyl-1,3-dioxolan-2-yl)-2,5,12-)rihydroxyl. 2. 3. 4-tetrahydronaphthacene-6,
11-dione 4.9■ (0,0118mmo 1),
1 ml of chloroform, 0.5 m t of carbon tetrachloride, 0 water
．． To 8 ml of the mixture, 0.23 ml (0,0153 mmol) of bromine-0,067M carbon tetrachloride solution was added in four portions, and the mixture was heated under reflux for 70 minutes under irradiation with a 60 W tungsten lamp. After cooling, add 10% aqueous sodium hydroxide solution 0.03 ml (0,075 mmo 1) at 0°C.
was added, and the mixture was stirred at the same temperature for 15 minutes and then at room temperature for 10 minutes. After neutralizing with 1M hydrochloric acid, the mixture was extracted with ethyl acetate.
抽出液を水、飽和食塩水で順次洗浄し、無水硫酸ナトリ
ウム上で乾燥した。ｔＳ媒を減圧上留去して得た赤色残
渣を次いでＴＨＦｌｍｌに溶解し、製塩ｔ１１２ ｍ
ｌを加えて１６．５時間加熱還流を行った０反応混合物
を水で希釈し、クロロホルムで抽出した。抽出液を水、
飽和食塩水で順次洗浄し、無水硫酸ナトリウム上で乾燥
した。溶媒を減圧上留去し、残渣をカラムクロマトグラ
フィー（シリカゲル、ベンゼン−酢酸エチル２０：１−
１０：１）を用いて分離精製して、（＋）−１４−フル
オロ−４−デメトキシダウノマイシノン０．６ｇ（１３
％）を朱色粉末として得た。このもののＮＭＲスペクト
ルは実施例５で得たものに一致した。The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The red residue obtained by distilling off the tS medium under reduced pressure was then dissolved in 1 ml of THF, and the salt was prepared at 112 m
The reaction mixture was diluted with water and extracted with chloroform. Add the extract to water,
It was washed successively with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (silica gel, benzene-ethyl acetate 20:1-
10:1) to separate and purify (+)-14-fluoro-4-demethoxydaunomycinone 0.6 g (13
%) was obtained as a vermilion powder. The NMR spectrum of this product matched that obtained in Example 5.
参考例１
２．３．６−）リゾオキシ−１，４−ジー〇−ｐ−ニト
ロベンゾイル−３−トリフルオロアセトアミド−α−Ｌ
−リキソヘキソピラノース１０８ｗ （０，１９９ｍｍ
ｏ １） １．％Ｌ／キｓ、 ラ−’ｉ −フス４Ａ８
Ｇ３■、塩化メチレン１０ｍ１．エーテル８ ｍ ｌの
混合物に、アルゴン雰囲気下、−４０℃にてトリメチル
シリルトリフレート０．０８ｍ１（０，４１４ｍｍｏ
１）を加え、水冷下、４０分間攪拌した０次いで反応液
を一２０℃に冷却し、（＋）−１４−フルオロ−４−デ
メトキシダウノマイシノン４３．４ｗ （０，１１２ｍ
ｍｏ １）のＴＨＦＨＦ溶液６奎ｌ下して、−１０℃〜
−１５℃で５．５時間反応した６反応混合物を飽和重曹
水−酢酸エチル混合溶液中に江刺し、酢酸エチルで抽出
した。抽出液を水、飽和食塩水で順次洗浄し、無水硫酸
ナトリウム上で乾燥したのち、溶媒を減圧上留去して、
粗製のグリコシドを得た。このものを、次にメタノール
１００ｍ１に溶解し、水冷下０．１Ｍ水酸化ナトリウム
水溶液２．Ｏｍｌを加えて、同温度で２０分間攪拌した
。１０％酢酸で中和したのち、水で希釈し、酢酸エチル
で抽出した。Reference Example 1 2.3.6-) Lysooxy-1,4-di〇-p-nitrobenzoyl-3-trifluoroacetamide-α-L
-Lixohexopyranose 108w (0,199mm
o 1) 1. %L/kis, Ra-'i-hus4A8
G3■, methylene chloride 10ml. 0.08 ml (0,414 mmol) of trimethylsilyl triflate was added to a mixture of 8 ml ether at -40°C under an argon atmosphere.
1) was added and stirred for 40 minutes under water cooling.Then, the reaction mixture was cooled to -20°C, and 43.4w (0,112m
Pour 6 ml of THFHF solution of mo 1) and heat to -10℃~
The 6 reaction mixtures reacted at -15°C for 5.5 hours were poured into a saturated aqueous sodium bicarbonate-ethyl acetate mixed solution and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
Crude glycosides were obtained. This product was then dissolved in 100ml of methanol, and 2.0ml of 0.1M aqueous sodium hydroxide solution was cooled with water. After adding Oml, the mixture was stirred at the same temperature for 20 minutes. After neutralizing with 10% acetic acid, it was diluted with water and extracted with ethyl acetate.
抽出液を水、飽和食塩水で順次洗浄後、無水硫酸ナトリ
ウム上で乾燥し、溶媒を減圧上留去して赤色残渣を得た
。カラムクロマトグラフィー（シリカゲル、クロロホル
ム→クロロホルムーア七トン３１１）を用いて分離精製
し、（＋）−３’−Ｎ−）リフルオロアセチル−１４−
フルオロ−４−デメトキシダウノルビシン６２，６■（
９１％）を橙色粉末として得た。The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a red residue. Separation and purification using column chromatography (silica gel, chloroform → chloroformur 7ton 311) resulted in (+)-3'-N-)lifluoroacetyl-14-
Fluoro-4-demethoxydaunorubicin 62,6■ (
91%) was obtained as an orange powder.
ｍｐ、１６１−１６３．５℃。mp, 161-163.5°C.
（α）７”＋１７３ ” （ｃ Ｏ，１３３，ジオキ
サン）。(α)7”+173” (c O, 133, dioxane).
ＮＭＲ（ＣＤＣＩｓ）：’δ−１，３３（３Ｈ。NMR (CDCIs): 'δ-1,33 (3H.
ｄ、Ｊ＝６Ｈｚ）、１．６５〜２．２０ （２Ｈ。d, J=6Hz), 1.65-2.20 (2H.
ｍ）、２．２７ （ＩＨ，ｄａ、Ｊ−１５および５Ｈｚ
）、２．４０． （ＩＨ，ｄｔ、Ｊ−１５および２Ｈ
ｚ） 、 ３．１２ （（ＩＨ，ｄ、 Ｊ −１９
Ｈｚ）、３．３７ （ＩＨ，ｄｄ、Ｊ−１９および２Ｈ
ｚ）、３．７１ （ＩＨ，ｄｄ、Ｊ−９および３Ｈｚ）
、４．０６〜４．４０ （２Ｈ，ｍ）。m), 2.27 (IH, da, J-15 and 5Hz
), 2.40. (IH, dt, J-15 and 2H
z), 3.12 ((IH, d, J-19
Hz), 3.37 (IH, dd, J-19 and 2H
z), 3.71 (IH, dd, J-9 and 3Hz)
, 4.06-4.40 (2H, m).
４．４４ （ＩＨ，ｓ）、５．３７ （ＩＨ，ｔ。4.44 (IH, s), 5.37 (IH, t.
Ｊ−４Ｈｚ＞ 、５．５７ （２Ｈ，ｄ、Ｊ−４８Ｈｚ
）、５．５８ （１８，ｄ、Ｊ−３Ｈｚ）。J-4Hz>, 5.57 (2H, d, J-48Hz
), 5.58 (18,d, J-3Hz).
６．７１ （ＩＨ，ｄ、Ｊ−９Ｈｚ）、７．７８〜８
．０３ （２Ｈ，ｍ） 、 ８．３０〜８．５４ （２
Ｈ。6.71 (IH, d, J-9Hz), 7.78-8
．． 03 (2H, m), 8.30~8.54 (2
H.
ｍ）、１３．３６ （Ｉ Ｈ，ｓ）、１３．６７（Ｉ
Ｈ，ｓ）。m), 13.36 (I H,s), 13.67 (I
H,s).
ＩＲ（ＫＢｒ）：３４５０．１７４０゜１７２０．１６
２５．１５９０ｏ１１−’。IR (KBr): 3450.1740°1720.16
25.1590o11-'.
ＭＳ （ｍ／ａ）：６１１ （Ｍ”）、３８６゜３
６８．３５０．３０７゜
元素分析値：
Ｃ＊ｓＨｍｓＦ４ＮＯ＋ｍ・０．７５Ｈ＊Ｏとして計算
値：
Ｃ，５３，８１； Ｈ，４，２７； Ｎ、２．２４％。MS (m/a): 611 (M”), 386°3
68.350.307° Elemental analysis value: Calculated value as C*sHmsF4NO+m・0.75H*O: C, 53,81; H, 4,27; N, 2.24%.
分析値： Ｃ，５３，７８； Ｈ，４，１８ｉ Ｎ、２．３６％。Analysis value: C, 53,78; H, 4,18i N, 2.36%.
参考例２
（＋）−３’−）リフルオロアセチル−１４＝フルオロ
−４−デメトキシダウノルビシン２２．９＊ （０，０
３？５ｍｍｏ １）をＴＨＦｏ、４５ｍ１に懸濁し、０
．０５Ｍ水酸化ナトリウム水溶液３．８ｍ１を加えて室
温で４０分間攪拌した０反応混合物を１Ｍ塩酸を用いて
ｐＨ９に調整し、クロロホルムで抽出した。抽出液を水
で洗浄し、無水硫酸ナトリウム上で乾燥した ｆＪ媒を
減圧下約２ｍｌに濃縮し、（１２５Ｍ塩酸−メタノール
溶液０．７５ｍ１を加えた後に約３０ ｍ Ｊのエーテ
ルを加えて沈殿を析出させた。上清をデカンチーシラン
によって除き、さらにエーテルでトリチェレートするこ
とにより、（＋）−１４−フルオロ−４−デメトキシダ
ウノルビシン塩酸塩４．８■（２３％）を橙色粉末とし
て得た。Reference example 2 (+)-3'-)lifluoroacetyl-14=fluoro-4-demethoxydaunorubicin 22.9* (0,0
3-5 mmo 1) was suspended in 45 ml of THFo,
．． After adding 3.8 ml of 5M aqueous sodium hydroxide solution and stirring at room temperature for 40 minutes, the reaction mixture was adjusted to pH 9 using 1M hydrochloric acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The fJ medium was concentrated under reduced pressure to about 2 ml (0.75 ml of 125 M hydrochloric acid-methanol solution was added, and then about 30 mJ of ether was added to remove the precipitate. The supernatant was removed with decanethisilane and tricerated with ether to obtain 4.8 μ (23%) of (+)-14-fluoro-4-demethoxydaunorubicin hydrochloride as an orange powder. .
ｍｐ、２３１〜２３５℃。mp, 231-235°C.
（α） ”Ｏ”ｌ ２２ ” （ｃ ０８０８２．メ
９／−ｎｔ） −ＮＭＲ（（ＣＤ３） ｔｓｏ）’δ−
１，１７（３Ｈ。(α) “O”l 22 ” (c 08082.me9/-nt) -NMR((CD3) tso)'δ-
1,17 (3H.
ｄ、Ｊ−６，６Ｈｚ）、１．６９ （ＬＨ，ｄｄ。d, J-6,6Hz), 1.69 (LH, dd.
Ｊ−１２，５および４．１Ｈｚ）、１．８９ （ＩＨ
。J-12,5 and 4.1Hz), 1.89 (IH
.
ａｔ、Ｊ＝１２．５および３．３Ｈｚ）。at, J = 12.5 and 3.3 Hz).
２．１５ （ＩＨ，ｄｄ、Ｊ−１４，１および５．４Ｈ
ｚ）、２．２３ （ＩＨ，ｄ、Ｊ−１４，１Ｈｚ）、２
．９４ （ＩＨ，ｄ、Ｊ＝１８．４Ｈｚ）。2.15 (IH, dd, J-14, 1 and 5.4H
z), 2.23 (IH, d, J-14, 1Hz), 2
．． 94 (IH, d, J=18.4Hz).
３．１２ （ＩＨ，ｄ、Ｊ＝１８．４Ｈｚ）。3.12 (IH, d, J=18.4Hz).
３．５６ （ＩＮ、 ｂｒｄ、 Ｊ−６，０Ｈｚ
＞。3.56 (IN,brd,J-6,0Hz
>.
４．１７ （ＩＨ，ｑ、 Ｊ−６，６Ｈｚ）、
４．９９（ＩＨ，ｄｄ、Ｊ−５，４および３．０Ｈｚ）
。4.17 (IH, q, J-6, 6Hz),
4.99 (IH, dd, J-5, 4 and 3.0Hz)
.
５．３１ （ＩＨ，ｂｒｄ、 Ｊ−３，３Ｈｚ）。5.31 (IH,brd,J-3,3Hz).
５．４６ （ＩＨ，ｄ、 Ｊ−６，０Ｈｚ）、
５．５８（ＩＨ，ｄｄ、Ｊ−４７，３および１７．５Ｈ
ｚ）。5.46 (IH, d, J-6,0Hz),
5.58 (IH, dd, J-47, 3 and 17.5H
z).
５．６２ （ＩＨ，ｄｄ、Ｊ−４７，３および１７．
５Ｈｚ）、 ５．６６ （ＬＨ，ｓ）、 ７．９
７〜８．０４ （２Ｈ，ｍ）、 ８．２７〜８．３
４（２Ｈ，ｍ）。5.62 (IH, dd, J-47, 3 and 17.
5Hz), 5.66 (LH,s), 7.9
7-8.04 (2H, m), 8.27-8.3
4 (2H, m).
ＩＲ（ＫＢｒ） ：３４５０． １７４０゜ｌ ６２
５、 ｌ ５９０（２）−１゜試 験 例 （癌細胞増
殖阻害作用）
マウスリンパ性白血病培養細胞（ｐ ３８８）をｌθ％
仔牛脂児血清含有のＲＰＭＩ−１６４０培養液に加え、
培養細胞数を５Ｘ１０’個／ｍｌに調製し、本発明の新
規１４−フルオロ−４−デメトキシダウノルビシン塩酸
塩を所定の濃度となるように添加し、３７℃で２日間培
養した。コールタ−カウンターを用い、浮遊細胞数を計
数して、対照区に対する増殖阻害率から、５０％細胞増
殖阻害濃度ＩＣ５０を求めた結果を表１に示す。IR (KBr): 3450. 1740゜l 62
5, l 590(2)-1゜Test example (cancer cell growth inhibition effect) Mouse lymphocytic leukemia cultured cells (p 388) at lθ%
In addition to RPMI-1640 culture solution containing calf fat serum,
The number of cultured cells was adjusted to 5×10′ cells/ml, the novel 14-fluoro-4-demethoxydaunorubicin hydrochloride of the present invention was added to a predetermined concentration, and the cells were cultured at 37° C. for 2 days. The number of floating cells was counted using a Coulter counter, and the 50% cell growth inhibition concentration IC50 was determined from the growth inhibition rate relative to the control group. The results are shown in Table 1.
表１ （＋）−１４−フルオロ−４−デメトキシダ
ウノルビシン塩酸塩のマウスリンパ性白蔓Table 1 (+)-14-Fluoro-4-demethoxydaunorubicin hydrochloride mouse lymphocytosis
Claims (1)
２及びＲ＾３は結合している炭素と一体となって環式あ
るいは非環式アセタールを形成し、または、Ｒ＾２及び
Ｒ＾３は一体となって酸素原子を表わす。）で表わされ
る２−（２−フルオロアルキル）−２，５，１２−トリ
ヒドロキシ−１，２，３，４−テトラヒドロナフタセン
−６，１１−ジオン誘導体。[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 represents a hydrogen atom or a hydroxyl group, and R^
2 and R^3 together with the carbon to which they are bonded form a cyclic or acyclic acetal, or R^2 and R^3 together represent an oxygen atom. ) 2-(2-fluoroalkyl)-2,5,12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61258305A JPH0629212B2 (en) | 1986-10-31 | 1986-10-31 | 2- (2-Fluoroalkyl) -2,5,12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61258305A JPH0629212B2 (en) | 1986-10-31 | 1986-10-31 | 2- (2-Fluoroalkyl) -2,5,12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63115841A true JPS63115841A (en) | 1988-05-20 |
| JPH0629212B2 JPH0629212B2 (en) | 1994-04-20 |
Family
ID=17318410
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61258305A Expired - Lifetime JPH0629212B2 (en) | 1986-10-31 | 1986-10-31 | 2- (2-Fluoroalkyl) -2,5,12-trihydroxy-1,2,3,4-tetrahydronaphthacene-6,11-dione derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0629212B2 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5742649A (en) * | 1980-08-29 | 1982-03-10 | Sumitomo Chem Co Ltd | Novel anthracyclinone derivative |
-
1986
- 1986-10-31 JP JP61258305A patent/JPH0629212B2/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5742649A (en) * | 1980-08-29 | 1982-03-10 | Sumitomo Chem Co Ltd | Novel anthracyclinone derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0629212B2 (en) | 1994-04-20 |
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