JP5258261B2 - Labeled glycyrrhetinic acid and its derivatives - Google Patents
Labeled glycyrrhetinic acid and its derivatives Download PDFInfo
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- JP5258261B2 JP5258261B2 JP2007289794A JP2007289794A JP5258261B2 JP 5258261 B2 JP5258261 B2 JP 5258261B2 JP 2007289794 A JP2007289794 A JP 2007289794A JP 2007289794 A JP2007289794 A JP 2007289794A JP 5258261 B2 JP5258261 B2 JP 5258261B2
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- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 title claims description 108
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 title claims description 45
- 229960003720 enoxolone Drugs 0.000 title claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 350
- 238000004519 manufacturing process Methods 0.000 claims description 64
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 239000012279 sodium borohydride Substances 0.000 claims description 11
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 11
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 10
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 9
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 8
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 7
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- 229910052703 rhodium Inorganic materials 0.000 claims description 6
- 239000010948 rhodium Substances 0.000 claims description 6
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 6
- 239000001632 sodium acetate Substances 0.000 claims description 6
- 235000017281 sodium acetate Nutrition 0.000 claims description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 4
- 239000005695 Ammonium acetate Substances 0.000 claims description 4
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003810 Jones reagent Substances 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- 229940043376 ammonium acetate Drugs 0.000 claims description 4
- 235000019257 ammonium acetate Nutrition 0.000 claims description 4
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 4
- 229940073608 benzyl chloride Drugs 0.000 claims description 4
- JEHCHYAKAXDFKV-UHFFFAOYSA-J lead tetraacetate Chemical compound CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O JEHCHYAKAXDFKV-UHFFFAOYSA-J 0.000 claims description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 description 86
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 39
- 229910052799 carbon Inorganic materials 0.000 description 36
- 150000001721 carbon Chemical group 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 230000002829 reductive effect Effects 0.000 description 23
- 239000004378 Glycyrrhizin Substances 0.000 description 22
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 22
- 229960004949 glycyrrhizic acid Drugs 0.000 description 22
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 22
- 235000019410 glycyrrhizin Nutrition 0.000 description 22
- 239000000203 mixture Substances 0.000 description 18
- 239000012046 mixed solvent Substances 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 230000000704 physical effect Effects 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 239000013078 crystal Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 150000008282 halocarbons Chemical class 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- 238000010979 pH adjustment Methods 0.000 description 10
- 238000000605 extraction Methods 0.000 description 9
- 238000007254 oxidation reaction Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 0 CC(C)(C(CC1)[C@](C)(CC2)C3[C@]1(C)[C@](C)(CC[C@@](C)(CC1)[C@]4C[C@@]1(C)C(OCc1ccccc1)=O)C4=CC3)C2=* Chemical compound CC(C)(C(CC1)[C@](C)(CC2)C3[C@]1(C)[C@](C)(CC[C@@](C)(CC1)[C@]4C[C@@]1(C)C(OCc1ccccc1)=O)C4=CC3)C2=* 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 150000001975 deuterium Chemical group 0.000 description 7
- 229910052805 deuterium Inorganic materials 0.000 description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
- LPLVUJXQOOQHMX-MOGLOQIBSA-N (2s,3s,4s,5r,6r)-6-[(2r,3r,4s,5s,6s)-2-[[(3s,4ar,6ar,6bs,8as,11s,12ar,14ar,14bs)-11-carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1h-picen-3-yl]oxy]-6-carboxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-c Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-MOGLOQIBSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 229910052722 tritium Inorganic materials 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical group [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 238000002372 labelling Methods 0.000 description 5
- 230000004060 metabolic process Effects 0.000 description 5
- 125000004430 oxygen atom Chemical group O* 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- -1 hydroxyimino group Chemical group 0.000 description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000007142 ring opening reaction Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 150000003648 triterpenes Chemical class 0.000 description 3
- UFDULEKOJAEIRI-UHFFFAOYSA-N (2-acetyloxy-3-iodophenyl) acetate Chemical compound CC(=O)OC1=CC=CC(I)=C1OC(C)=O UFDULEKOJAEIRI-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 2
- 239000012022 methylating agents Substances 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- ZZPQSQFQHIGCRC-OOFFSTKBSA-N (2s,3s,4s,5r,6r)-6-[(2s,3r,4s,5s,6s)-2-[[(3s,4ar,6ar,6bs,8as,11s,12ar,14ar,14bs)-11-carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1h-picen-3-yl]oxy]-6-carboxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-c Chemical compound [Zn].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O ZZPQSQFQHIGCRC-OOFFSTKBSA-N 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- MPDGHEJMBKOTSU-VOPRYAMFSA-N CC(C)(C(CC[C@@]1(C)[C@](C)(CC[C@@](C)(CC2)[C@H]3C[C@@]2(C)C(O)=O)C3=C2)[C@](C)(CC3)C1C2=O)[C@H]3O Chemical compound CC(C)(C(CC[C@@]1(C)[C@](C)(CC[C@@](C)(CC2)[C@H]3C[C@@]2(C)C(O)=O)C3=C2)[C@](C)(CC3)C1C2=O)[C@H]3O MPDGHEJMBKOTSU-VOPRYAMFSA-N 0.000 description 1
- XQIVDOSRZQSWFL-KMRFLIQDSA-N CC(C)(CC[C@]1(C)CC[C@@]2(C)[C@](C)(CC3)C4[C@@](C)(CC5)C3C(C)(C)C5=O)C[C@H]1C2=CC4=O Chemical compound CC(C)(CC[C@]1(C)CC[C@@]2(C)[C@](C)(CC3)C4[C@@](C)(CC5)C3C(C)(C)C5=O)C[C@H]1C2=CC4=O XQIVDOSRZQSWFL-KMRFLIQDSA-N 0.000 description 1
- PHZPDTTXRHBSGT-RWSHLYLPSA-N C[C@@H](C(CC[C@@]1(C)[C@](C)(CC[C@](C)(CC2)CC[C@]2(C)C(OCc2ccccc2)=O)C(C)=CCC11)[C@]1(C)C=C1)C1=O Chemical compound C[C@@H](C(CC[C@@]1(C)[C@](C)(CC[C@](C)(CC2)CC[C@]2(C)C(OCc2ccccc2)=O)C(C)=CCC11)[C@]1(C)C=C1)C1=O PHZPDTTXRHBSGT-RWSHLYLPSA-N 0.000 description 1
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 241001391944 Commicarpus scandens Species 0.000 description 1
- 240000004670 Glycyrrhiza echinata Species 0.000 description 1
- 235000001453 Glycyrrhiza echinata Nutrition 0.000 description 1
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 1
- 235000017382 Glycyrrhiza lepidota Nutrition 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QYTDEUPAUMOIOP-UHFFFAOYSA-N TEMPO Chemical group CC1(C)CCCC(C)(C)N1[O] QYTDEUPAUMOIOP-UHFFFAOYSA-N 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical class O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000850 deacetylating effect Effects 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 125000004431 deuterium atom Chemical group 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000002168 glycyrrhetinic acid group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-BJUDXGSMSA-N iodomethane Chemical class I[11CH3] INQOMBQAUSQDDS-BJUDXGSMSA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229940010454 licorice Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical compound N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
本発明は、標識化されたグリチルレチン酸及びその誘導体に関する。また、本発明は、これら化合物の製造方法に関する。 The present invention relates to labeled glycyrrhetinic acid and derivatives thereof. The present invention also relates to a method for producing these compounds.
甘草の主成分であるグリチルリチン、及びそのアグリコンであるグリチルレチン酸は、優れた抗炎症作用をはじめ、種々の薬理作用を有することが知られている。しかしこれら薬理作用を発現する際の作用機序や生体内代謝に関しては、まだ十分に明らかにされていないのが現状である。 It is known that glycyrrhizin, which is a main component of licorice, and glycyrrhetinic acid, which is an aglycon thereof, have various pharmacological actions including excellent anti-inflammatory action. However, regarding the mechanism of action and metabolism in vivo when these pharmacological effects are manifested, the current situation has not yet been fully clarified.
通常、化学物質の生体内における動態を解析するためには、例えば、該化学物質を構成する原子の一部を放射性同位元素で置き換えることで標識化した標識化化学物質を生体内に導入し、生体内で該標識化化学物質が発する放射線をシグナルとして検出する手法が汎用される。この手法は、上記したような化学物質の作用機序や生体内代謝の解析にも適用され、例えば、解析対象の化学物質中の水素原子の一部をトリチウム（３Ｈ）で置換した標識化化学物質が使用されることがある。そして、グリチルリチン及びグリチルレチン酸についても、トリチウム標識したものを使用した解析が試みられている（非特許文献１及び２参照）。 Usually, in order to analyze the dynamics of a chemical substance in a living body, for example, a labeled chemical substance labeled by replacing a part of atoms constituting the chemical substance with a radioisotope is introduced into the living body, A technique for detecting radiation emitted from the labeled chemical substance in vivo as a signal is widely used. This technique is also applied to the analysis of the action mechanism and in vivo metabolism of the chemical substance as described above. For example, labeling in which a part of hydrogen atoms in the chemical substance to be analyzed is substituted with tritium ( 3 H). Chemical substances may be used. An analysis using tritium-labeled glycyrrhizin and glycyrrhetinic acid has also been attempted (see Non-Patent Documents 1 and 2).
また、放射性同位元素としては、トリチウム以外にも種々のものがあり、これらを同様の目的で使用することが考えられる。例えば、代表的なものとして１４Ｃや１３Ｃが挙げられ、作用機序や生体内代謝の解析を目的に、１４Ｃが２位に導入されたトリテルペン（非特許文献３参照）、１３Ｃが２位に導入されたステロイド（非特許文献４参照）が報告されている。
しかしながら、トリチウムで標識化された化学物質は、比較的容易に調製できるという長所がある反面、解析を高精度に行うのに支障が出易いという問題点がある。その理由は、トリチウムが不安定であるだけでなく、例えば、炭素−トリチウム結合が比較的切れ易く、生体内で水の水素原子と置換し易いためである。これはグリチルリチン及びグリチルレチン酸においても例外ではない。 However, while a chemical substance labeled with tritium has the advantage that it can be prepared relatively easily, there is a problem that it is difficult to perform analysis with high accuracy. The reason is not only that tritium is unstable, but also because, for example, the carbon-tritium bond is relatively easy to break and is easily replaced with hydrogen atoms in the living body. This is no exception in glycyrrhizin and glycyrrhetinic acid.
また、１４Ｃや１３Ｃで標識化された化学物質は、炭素−１４Ｃ結合や炭素−１３Ｃ結合が安定なため、解析を高精度に行うのに適している反面、調製が困難であるという問題点がある。その理由としては、まず炭素−炭素結合が安定であるために、これを切断して１４Ｃや１３Ｃを導入することが容易ではないことが挙げられる。加えて従来は、トリテルペンやステロイドにおける１４Ｃや１３Ｃの導入に際し環構造の開環及び閉環工程が必要であり、その際に例えば、１４ＣＨ３Ｌｉや１４ＣＨ３ＭｇＩなどの特殊な原料の調製も別途必要であり、工程が複雑であることが挙げられる。例えば、非特許文献３及び４に開示されている標識化化学物質の合成方法では、１４Ｃや１３Ｃを導入する部位（２位）の炭素原子が含まれる環構造（Ａ環）を開環し、該当する炭素原子を除去してから、１４Ｃや１３Ｃの導入と閉環を行うという複雑な工程を採用している。
そしてこれまでに、１４Ｃや１３Ｃで標識化されたグリチルリチン及びグリチルレチン酸、並びにこれらの合成方法は開示されていない。
In addition, a chemical substance labeled with 14 C or 13 C is suitable for performing analysis with high accuracy because of its stable carbon- 14 C bond and carbon- 13 C bond, but is difficult to prepare. There is a problem. The reason for this is that, first, since the carbon-carbon bond is stable, it is not easy to cut it and introduce 14 C or 13 C. In addition, conventionally, the introduction of 14 C and 13 C in triterpenes and steroids requires ring-opening and ring-closing steps of the ring structure. For example, special raw materials such as 14 CH 3 Li and 14 CH 3 MgI are used. Preparation is also required separately, and the process is complicated. For example, in the method for synthesizing a labeled chemical substance disclosed in Non-Patent Documents 3 and 4, a ring structure (ring A) containing a carbon atom at the site (position 2) for introducing 14 C or 13 C is opened. Then, after removing the corresponding carbon atom, a complicated process of introducing 14 C or 13 C and closing the ring is adopted.
So far, glycyrrhizin and glycyrrhetinic acid labeled with 14 C and 13 C and methods for synthesizing these have not been disclosed.
本発明は上記事情に鑑みてなされたものであり、生体内において安定な標識化されたグリチルレチン酸及びその誘導体、そしてこれら化合物の効率的な製造方法を提供することを課題とする。 The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a labeled glycyrrhetinic acid and derivatives thereof which are stable in vivo, and an efficient production method of these compounds.
本発明者らは、上記課題を解決するために鋭意研究を行った結果、グリチルレチン酸のＡ環の２３位の炭素原子にヒドロキシ基を結合させ、レトロアルドール反応を行うことで、開環を行わなくても穏やかな条件下で２３位の炭素原子が除去でき、次いでＣＤ３Ｉを反応させることで、位置選択的に２３位の炭素原子に重水素原子を導入できることを見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above-mentioned problems, the present inventors performed ring opening by attaching a hydroxy group to the carbon atom at position 23 of the A ring of glycyrrhetinic acid and performing a retroaldol reaction. The present inventors completed the present invention by discovering that a carbon atom at the 23-position can be removed under mild conditions without the need, and then deuterium atoms can be introduced into the carbon atom at the 23-position regioselectively by reacting with CD 3 I. It came to do.
すなわち、上記課題を解決するため、
請求項１に記載の発明は、下記式（８ａ）で表される化合物である。
That is, to solve the above problem,
The invention described in claim 1 is a compound represented by the following formula (8a).
請求項２に記載の発明は、下記式（９）で表される化合物である。 Invention of Claim 2 is a compound represented by following formula (9).
（式中、Ｂｎはベンジル基である。） (In the formula, Bn is a benzyl group.)
請求項３に記載の発明は、下記式（５）で表される化合物である。 Invention of Claim 3 is a compound represented by following formula (5).
（式中、Ｂｎはベンジル基である。） (In the formula, Bn is a benzyl group.)
請求項４に記載の発明は、下記式（７ａ）で表される化合物である。
請求項５に記載の発明は、下記式（７ｂ）で表される化合物である。
The invention according to claim 4 is a compound represented by the following formula (7a) .
The invention according to claim 5 is a compound represented by the following formula (7b).
（式中、Ｂｎはベンジル基である。） (In the formula, Bn is a benzyl group.)
請求項６に記載の発明は、下記式（６ａ）で表される化合物である。
請求項７に記載の発明は、下記式（６ｂ）で表される化合物である。
The invention according to claim 6 is a compound represented by the following formula (6a) .
The invention according to claim 7 is a compound represented by the following formula (6b).
（式中、Ｂｎはベンジル基である。） (In the formula, Bn is a benzyl group.)
請求項８に記載の発明は、下記式（２ａ）で表される化合物である。
請求項９に記載の発明は、下記式（２ｂ）で表される化合物である。
請求項１０に記載の発明は、下記式（２ｃ）で表される化合物である。
請求項１１に記載の発明は、下記式（２ｄ）で表される化合物である。
請求項１２に記載の発明は、下記式（２ｅ）で表される化合物である。
The invention according to claim 8 is a compound represented by the following formula (2a) .
The invention according to claim 9 is a compound represented by the following formula (2b).
The invention according to claim 10 is a compound represented by the following formula (2c).
The invention according to claim 11 is a compound represented by the following formula (2d).
The invention according to claim 12 is a compound represented by the following formula (2e).
（式中、Ｂｎはベンジル基であり；Ａｃはアセチル基である。） (In the formula, Bn is a benzyl group; Ac is an acetyl group .)
請求項１３に記載の発明は、下記式（３）で表される化合物である。 The invention according to claim 13 is a compound represented by the following formula (3).
（式中、Ｂｎはベンジル基である。） (In the formula, Bn is a benzyl group.)
請求項１４に記載の発明は、下記式（４）で表される化合物である。 The invention according to claim 14 is a compound represented by the following formula (4).
（式中、Ｂｎはベンジル基である。） (In the formula, Bn is a benzyl group.)
請求項１５に記載の発明は、下記式（１）で表されるグリチルレチン酸に、濃塩酸存在下で亜鉛を作用させ、次いでジョーンズ試薬を作用させ、次いで塩化ベンジルを作用させて、下記式（２ａ）で表される化合物とし、
下記式（２ａ）で表される化合物に、ヒドロキシルアミン塩酸塩を作用させて下記式（２ｂ）で表される化合物とし、
下記式（２ｂ）で表される化合物に、酢酸ナトリウム及び塩化パラジウム二ナトリウムを作用させ、次いで無水酢酸を作用させ、次いで四酢酸鉛を作用させてから水素化ホウ素ナトリウムを作用させて下記式（２ｃ）で表される化合物とし、
下記式（２ｃ）で表される化合物に塩基を作用させて下記式（２ｄ）で表される化合物とし、
下記式（２ｄ）で表される化合物に、トリクロロチタン及び酢酸アンモニウムを作用させて下記式（２ｅ）で表される化合物とし、
下記式（２ｅ）で表される化合物に塩基を作用させて下記式（３）で表される化合物とし、
下記式（３）で表される化合物に、リチウムビストリメチルシリルアミドを作用させ、次いでクロロトリメチルシランを作用させ、次いで酢酸パラジウムを作用させて下記式（４）で表される化合物とし、
下記式（４）で表される化合物に、リチウムビストリメチルシリルアミドを作用させ、次いで一般式「ＣＤ３Ｌ」で表される化合物（「Ｌ」はハロゲン原子を表す）を作用させて下記式（５）で表される化合物とする、
ことを特徴とする下記式（５）で表される化合物の製造方法である。
In the invention according to claim 15 , zinc is allowed to act on glycyrrhetinic acid represented by the following formula (1) in the presence of concentrated hydrochloric acid, then Jones reagent is allowed to act, and then benzyl chloride is allowed to act. A compound represented by 2a),
Hydroxylamine hydrochloride is allowed to act on the compound represented by the following formula (2a) to obtain a compound represented by the following formula (2b).
To the compound represented by the following formula (2b), sodium acetate and disodium palladium chloride are allowed to act, then acetic anhydride is allowed to act, then lead tetraacetate is allowed to act, and then sodium borohydride is allowed to act. A compound represented by 2c),
A base is allowed to act on the compound represented by the following formula (2c) to obtain a compound represented by the following formula (2d),
A compound represented by the following formula (2e) is prepared by allowing trichlorotitanium and ammonium acetate to act on the compound represented by the following formula (2d).
A base is allowed to act on the compound represented by the following formula (2e) to obtain a compound represented by the following formula (3),
Lithium bistrimethylsilylamide is allowed to act on the compound represented by the following formula (3), then chlorotrimethylsilane is allowed to act, and then palladium acetate is allowed to act to obtain a compound represented by the following formula (4).
Lithium bistrimethylsilylamide is allowed to act on a compound represented by the following formula (4), and then a compound represented by the general formula “CD 3 L” (“L” represents a halogen atom) is allowed to act on the compound represented by the following formula ( A compound represented by 5),
It is a manufacturing method of the compound represented by following formula (5) characterized by the above-mentioned.
（式中、Ｂｎはベンジル基である。） (In the formula, Bn is a benzyl group.)
請求項１６に記載の発明は、請求項１５に記載の製造方法で製造された下記式（５）で表される化合物に水素ガス存在下でパラジウムカーボンを作用させて下記式（６ａ）で表される化合物とし、
下記式（６ａ）で表される化合物にヨウ化銅及びｔ−ブチルヒドロペルオキシドを作用させて下記式（７ａ）で表される化合物とし、
下記式（７ａ）で表される化合物に水素化ホウ素ナトリウムを作用させて下記式（８ａ）で表される標識化されたグリチルレチン酸とする、
ことを特徴とする標識化グリチルレチン酸の製造方法である。
The invention according to claim 16 is represented by the following formula (6a) by allowing palladium carbon to act on the compound represented by the following formula (5) produced by the production method according to claim 15 in the presence of hydrogen gas. A compound to be
The compound represented by the following formula (6a) is allowed to act on copper iodide and t-butyl hydroperoxide to obtain a compound represented by the following formula (7a).
By allowing sodium borohydride to act on the compound represented by the following formula (7a), a labeled glycyrrhetinic acid represented by the following formula (8a) is obtained.
This is a method for producing labeled glycyrrhetinic acid.
（式中、Ｂｎはベンジル基である。） (In the formula, Bn is a benzyl group.)
請求項１７に記載の発明は、請求項１５に記載の製造方法で製造された下記式（５）で表される化合物に水素ガス存在下でロジウム触媒を作用させて下記式（６ｂ）で表される化合物とし、
下記式（６ｂ）で表される化合物にヨウ化銅及びｔ−ブチルヒドロペルオキシドを作用させて下記式（７ｂ）で表される化合物とし、
下記式（７ｂ）で表される化合物に水素化ホウ素ナトリウムを作用させて下記式（９）で表される化合物とする、
ことを特徴とする下記式（９）で表される化合物の製造方法である。
The invention according to claim 17 is represented by the following formula (6b) by reacting a compound represented by the following formula (5) produced by the production method according to claim 15 with a rhodium catalyst in the presence of hydrogen gas. A compound to be
The compound represented by the following formula (6b) is allowed to act on copper iodide and t-butyl hydroperoxide to obtain a compound represented by the following formula (7b).
By allowing sodium borohydride to act on the compound represented by the following formula (7b), a compound represented by the following formula (9) is obtained.
It is a manufacturing method of the compound represented by following formula (9) characterized by the above-mentioned.
（式中、Ｂｎはベンジル基である。） (In the formula, Bn is a benzyl group.)
本発明により、生体内において安定な標識化されたグリチルレチン酸及びその誘導体を効率的に提供でき、グリチルリチン及びグリチルレチン酸の薬理作用を発現する際の作用機序や生体内代謝に関する高精度な解析が可能となる。 According to the present invention, stable labeled glycyrrhetinic acid and derivatives thereof in vivo can be efficiently provided, and a high-precision analysis on the mechanism of action and in vivo metabolism in expressing the pharmacological action of glycyrrhizin and glycyrrhetinic acid can be achieved. It becomes possible.
以下、本発明について詳しく説明する。なお、以下に示すグリチルリチン及びグリチルレチン酸並びにこれらの誘導体の炭素原子の番号表記について、グリチルレチン酸（式（１）で表される化合物、以下、グリチルレチン酸（１）と略記する）を例に挙げて以下に示す。 The present invention will be described in detail below. In addition, glycyrrhetinic acid (a compound represented by the formula (1), hereinafter abbreviated as glycyrrhetic acid (1)) is given as an example for the glycyrrhizin and glycyrrhetinic acid and the carbon atom number notation of these derivatives shown below. It is shown below.
また、本明細書において「Ｂｎ」は「ベンジル基」を、「Ｂｚ」は「ベンゾイル基」をそれぞれ表すものとする。 In the present specification, “Bn” represents a “benzyl group” and “Bz” represents a “benzoyl group”.
［化合物］
＜式（８ａ）で表される化合物＞
本発明の第一の実施形態に係る化合物は、下記式（８ａ）で表される。すなわち、グリチルレチン酸の２３位の炭素原子を含むメチル基が、−ＣＤ３に変換されたグリチルレチン酸誘導体（以下、化合物（８ａ）又は標識化グリチルレチン酸（８ａ）と略記する）である。
[Compound]
<Compound represented by Formula (8a)>
The compound according to the first embodiment of the present invention is represented by the following formula (8a). In other words, a methyl group contains 23 carbon atom of glycyrrhetinic acid, glycyrrhetinic acid derivatives which are converted into -CD 3 (hereinafter, compound (8a) or labeled glycyrrhetinic acid (8a) and abbreviated).
＜式（９）で表される化合物＞
本発明の第二の実施形態に係る化合物は、下記式（９）で表される（以下、化合物（９）と略記する）。すなわち、前記化合物（８ａ）の、３０位の炭素原子を含むカルボキシ基がベンジル基で保護された標識化グリチルレチン酸の誘導体である。
そして化合物（９）は、３位の炭素原子に結合しているヒドロキシ基において配糖化を行い、後記する標識化グリチルリチン（８ｂ）を合成するための重要な中間体である。
<Compound represented by Formula (9)>
The compound according to the second embodiment of the present invention is represented by the following formula (9) (hereinafter abbreviated as compound (9)). That is, the compound (8a) is a derivative of labeled glycyrrhetic acid in which a carboxy group containing a carbon atom at position 30 is protected with a benzyl group.
Compound (9) is an important intermediate for synthesizing labeled glycyrrhizin (8b) described below by glycosylation at the hydroxy group bonded to the 3-position carbon atom.
＜式（５）で表される化合物＞
本発明の第三の実施形態に係る化合物は、下記式（５）で表される（以下、化合物（５）と略記する）。
化合物（５）は、標識化グリチルレチン酸（８ａ）及び標識化グリチルリチン（８ｂ）を合成するための重要な共通中間体である。
<Compound represented by Formula (5)>
The compound according to the third embodiment of the present invention is represented by the following formula (5) (hereinafter abbreviated as compound (5)).
Compound (5) is an important common intermediate for synthesizing labeled glycyrrhetinic acid (8a) and labeled glycyrrhizin (8b).
＜一般式（７）で表される化合物＞
本発明の第四の実施形態に係る化合物は、下記一般式（７）で表される（以下、化合物（７）と略記する）。
<Compound represented by formula (7)>
The compound according to the fourth embodiment of the present invention is represented by the following general formula (7) (hereinafter abbreviated as compound (7)).
式中、Ｒ２は水素原子又はベンジル基である。すなわち、具体的には、２３位の炭素原子を含むメチル基が重水素原子で標識化されている、下記式（７ａ）及び（７ｂ）で表される化合物（以下、それぞれ化合物（７ａ）及び化合物（７ｂ）と略記する）である。 In the formula, R 2 is a hydrogen atom or a benzyl group. Specifically, specifically, a compound represented by the following formulas (7a) and (7b) in which a methyl group containing a carbon atom at the 23-position is labeled with a deuterium atom (hereinafter referred to as compound (7a) and (Abbreviated as compound (7b)).
＜一般式（６）で表される化合物＞
本発明の第五の実施形態に係る化合物は、下記一般式（６）で表される（以下、化合物（６）と略記する）。
<Compound represented by formula (6)>
The compound according to the fifth embodiment of the present invention is represented by the following general formula (6) (hereinafter abbreviated as compound (6)).
式中、Ｒ２は水素原子又はベンジル基である。すなわち、具体的には、２３位の炭素原子を含むメチル基が重水素原子で標識化されている、下記式（６ａ）及び（６ｂ）で表される化合物（以下、それぞれ化合物（６ａ）及び化合物（６ｂ）と略記する）である。
化合物（６ａ）及び（７ａ）はいずれも、化合物（５）から標識化グリチルレチン酸（８ａ）を合成する際の中間体である。
また、化合物（６ｂ）及び（７ｂ）はいずれも、化合物（５）から化合物（９）を合成する際の中間体である。
In the formula, R 2 is a hydrogen atom or a benzyl group. That is, specifically, a compound represented by the following formulas (6a) and (6b) in which a methyl group containing a carbon atom at the 23-position is labeled with a deuterium atom (hereinafter referred to as compound (6a) and (Abbreviated as compound (6b)).
Compounds (6a) and (7a) are both intermediates for the synthesis of labeled glycyrrhetinic acid (8a) from compound (5).
In addition, both compounds (6b) and (7b) are intermediates for the synthesis of compound (9) from compound (5).
＜一般式（２）で表される化合物＞
本発明の第六の実施形態に係る化合物は、下記一般式（２）で表される（以下、化合物（２）と略記する）。
<Compound represented by formula (2)>
The compound according to the sixth embodiment of the present invention is represented by the following general formula (2) (hereinafter abbreviated as compound (2)).
式中、Ｚは酸素原子、＝Ｎ−ＯＨで表される基又は＝Ｎ−Ｏ−Ｃ（＝Ｏ）ＣＨ３で表される基である。
また、Ｒ１はメチル基、ヒドロキシメチル基又は−ＣＨ２−Ｏ−Ｃ（＝Ｏ）ＣＨ３で表される基である。
ただし、Ｚが酸素原子又は＝Ｎ−ＯＨで表される基である場合には、Ｒ１はメチル基又はヒドロキシメチル基であり、Ｚが＝Ｎ−Ｏ−Ｃ（＝Ｏ）ＣＨ３で表される基である場合には、Ｒ１は−ＣＨ２−Ｏ−Ｃ（＝Ｏ）ＣＨ３で表される基である。すなわち、具体的には、下記式（２ａ）、（２ｂ）、（２ｃ）、（２ｄ）及び（２ｅ）で表される化合物（以下、それぞれ化合物（２ａ）、化合物（２ｂ）、化合物（２ｃ）、化合物（２ｄ）、化合物（２ｅ）と略記する）である。
In the formula, Z is an oxygen atom, a group represented by ═N—OH, or a group represented by ═N—O—C (═O) CH 3 .
R 1 is a group represented by a methyl group, a hydroxymethyl group, or —CH 2 —O—C (═O) CH 3 .
However, when Z is an oxygen atom or a group represented by ═N—OH, R 1 is a methyl group or a hydroxymethyl group, and Z is represented by ═N—O—C (═O) CH 3 . R 1 is a group represented by —CH 2 —O—C (═O) CH 3 . Specifically, specifically, compounds represented by the following formulas (2a), (2b), (2c), (2d) and (2e) (hereinafter referred to as compound (2a), compound (2b), compound (2c), respectively) ), Compound (2d), and compound (2e)).
化合物（２ａ）〜（２ｅ）は、いずれもグリチルレチン酸（１）から化合物（５）を合成する際の中間体である。 Compounds (2a) to (2e) are all intermediates for the synthesis of compound (5) from glycyrrhetinic acid (1).
＜式（３）で表される化合物＞
本発明の第七の実施形態に係る化合物は、下記式（３）で表される（以下、化合物（３）と略記する）。
<Compound represented by Formula (3)>
The compound according to the seventh embodiment of the present invention is represented by the following formula (3) (hereinafter abbreviated as compound (3)).
＜式（４）で表される化合物＞
本発明の第八の実施形態に係る化合物は、下記式（４）で表される（以下、化合物（４）と略記する）。
<Compound represented by Formula (4)>
The compound according to the eighth embodiment of the present invention is represented by the following formula (4) (hereinafter abbreviated as compound (4)).
化合物（３）及び（４）はいずれも、化合物（２ｅ）から化合物（５）を合成する際の中間体である。 Compounds (3) and (4) are both intermediates for the synthesis of compound (5) from compound (2e).
［化合物の製造方法］
本発明の化合物の製造方法について説明する。
標識化グリチルレチン酸（８ａ）は、グリチルレチン酸（１）を出発原料とし、化合物（５）を中間体として製造される。
具体的には、化合物（５）は、グリチルレチン酸（１）を出発原料として、化合物（２ａ）、（２ｂ）、（２ｃ）、（２ｄ）及び（２ｅ）、並びに化合物（３）及び（４）を経て製造される。そして、化合物（５）からは、化合物（６ａ）及び（７ａ）を経て標識化グリチルレチン酸（８ａ）が製造され、化合物（６ｂ）及び（７ｂ）を経て化合物（９）が製造される。さらに化合物（９）からは、後記するように化合物（１０ａ）、（１０ｂ）、（１０ｃ）、（１０ｄ）及び（１０ｅ）を経て標識化グリチルリチン（８ｂ）が製造される。
以下、本発明の化合物の製造方法を、各工程ごとに詳しく説明する。
[Method for producing compound]
The manufacturing method of the compound of this invention is demonstrated.
Labeled glycyrrhetic acid (8a) is produced using glycyrrhetic acid (1) as a starting material and compound (5) as an intermediate.
Specifically, the compound (5) includes compounds (2a), (2b), (2c), (2d) and (2e), and compounds (3) and (4) starting from glycyrrhetinic acid (1). ) Is manufactured through. From compound (5), labeled glycyrrhetinic acid (8a) is produced via compounds (6a) and (7a), and compound (9) is produced via compounds (6b) and (7b). Further, from compound (9), labeled glycyrrhizin (8b) is produced through compounds (10a), (10b), (10c), (10d) and (10e) as described later.
Hereafter, the manufacturing method of the compound of this invention is demonstrated in detail for every process.
＜化合物（５）の製造方法＞
本発明の第九の実施形態に係る化合物（５）の製造方法における代表的な合成ルートを、以下に示す。
<Method for producing compound (5)>
A typical synthesis route in the method for producing the compound (5) according to the ninth embodiment of the present invention is shown below.
（Ａ）化合物（２ａ）の製造
化合物（１）の１１位の炭素原子を含むカルボニル基を還元してメチレン基とし、３位の炭素原子にヒドロキシ基が結合している部位を酸化してカルボニル基とし、２０位の炭素原子に結合しているカルボキシ基をベンジル基で保護することで、化合物（２ａ）が得られる。
還元反応は、好ましくはジオキサン等の溶媒中で、濃塩酸存在下、亜鉛粉末を用いて行うのが好ましい。反応温度は１５〜４０℃が好ましく、２０〜３０℃がより好ましい。
酸化反応は、好ましくはテトラヒドロフラン等の溶媒中で、ジョーンズ試薬を用いて行うのが好ましい。
カルボキシ基のベンジル基による保護は、好ましくはジメチルホルムアミド等の溶媒中で、炭酸カリウム等の塩基存在下、塩化ベンジルで行うのが好ましい。反応温度は５０〜８０℃が好ましく、６５〜７５℃がより好ましい。
反応終了後は、適宜必要に応じて、ｐＨ調整、抽出、洗浄、濃縮等を行い、カラムクロマトグラフィー等による精製を行っても良い。
(A) Production of Compound (2a) The carbonyl group containing the 11th carbon atom of compound (1) is reduced to a methylene group, and the site where the hydroxy group is bonded to the 3rd carbon atom is oxidized to carbonyl. By protecting the carboxy group bonded to the carbon atom at the 20-position with a benzyl group, the compound (2a) is obtained.
The reduction reaction is preferably performed in a solvent such as dioxane using zinc powder in the presence of concentrated hydrochloric acid. The reaction temperature is preferably 15 to 40 ° C, and more preferably 20 to 30 ° C.
The oxidation reaction is preferably performed using a Jones reagent in a solvent such as tetrahydrofuran.
Protection of the carboxy group with a benzyl group is preferably carried out with benzyl chloride in a solvent such as dimethylformamide in the presence of a base such as potassium carbonate. The reaction temperature is preferably 50 to 80 ° C, more preferably 65 to 75 ° C.
After completion of the reaction, pH adjustment, extraction, washing, concentration, etc. may be performed as necessary, followed by purification by column chromatography or the like.
（Ｂ）化合物（２ｂ）の製造
化合物（２ａ）の、３位の炭素原子と共にカルボニル基を構成している酸素原子を、ヒドロキシイミノ基に変換することで、化合物（２ｂ）が得られる。
反応は、例えば、化合物（２ａ）に対し、好ましくはハロゲン化炭化水素及びアルコールの混合溶媒を用い、塩基存在下、ヒドロキシルアミン塩酸塩を加えて行うのが好ましい。
ここで、ハロゲン化炭化水素としては、塩化メチレン、クロロホルム等が例示でき、塩化メチレンが特に好ましい。アルコールとしては、メタノール、エタノール等が例示でき、メタノールが特に好ましい。塩基は弱塩基性の無機塩基が好ましく、酢酸ナトリウムが特に好ましい。反応温度は３０〜７０℃が好ましく、４０〜６０℃がより好ましい。
反応終了後は、適宜必要に応じて濃縮等を行い、結晶化させて目的物を取り出すことができる。
(B) Production of Compound (2b) Compound (2b) is obtained by converting the oxygen atom constituting the carbonyl group together with the 3-position carbon atom of compound (2a) to a hydroxyimino group.
The reaction is preferably performed, for example, on the compound (2a), preferably using a mixed solvent of a halogenated hydrocarbon and an alcohol and adding hydroxylamine hydrochloride in the presence of a base.
Here, examples of the halogenated hydrocarbon include methylene chloride and chloroform, and methylene chloride is particularly preferable. Examples of the alcohol include methanol and ethanol, and methanol is particularly preferable. The base is preferably a weakly basic inorganic base, particularly preferably sodium acetate. The reaction temperature is preferably 30 to 70 ° C, more preferably 40 to 60 ° C.
After completion of the reaction, the desired product can be taken out by concentrating and crystallizing as necessary.
（Ｃ）化合物（２ｃ）の製造
化合物（２ｂ）のヒドロキシイミノ基をアセチルオキシイミノ基に変換し、２３位の炭素原子に結合している一つの水素原子をアセチルオキシ基に変換することで、化合物（２ｃ）が得られる。
具体的には、例えば、まず化合物（２ｂ）に酢酸、酢酸ナトリウム及び塩化パラジウム二ナトリウムを加えて反応を行う。反応温度は１５〜４０℃が好ましく、２０〜３０℃がより好ましい。
次いで、塩基の存在下、好ましくはハロゲン化炭化水素を溶媒として用い、無水酢酸を加えてアセチル化反応を行う。
ここで、塩基としては弱塩基性の有機塩基が好ましく、トリエチルアミンが特に好ましい。また、ここでは触媒を用いることが好ましく、ジメチルアミノピリジン（ＤＭＡＰ）を用いることが特に好ましい。また、ハロゲン化炭化水素としては、塩化メチレン、クロロホルム等が例示でき、塩化メチレンが特に好ましい。反応温度は１５〜４０℃が好ましく、２０〜３０℃がより好ましい。
次いで、四酢酸鉛を好ましくは酢酸に溶解させた状態で加えて酸化反応を行った後、水素化ホウ素ナトリウムを好ましくは水酸化ナトリウム水溶液に溶解させた状態で加えて還元反応を行うことで、化合物（２ｃ）が得られる。酸化反応及び還元反応を行うときの反応温度は、１５〜４０℃が好ましく、２０〜３０℃がより好ましい。
各反応終了後は、適宜必要に応じて結晶化、濃縮、乾燥等を行い、カラムクロマトグラフィー等による精製を行っても良い。
(C) Production of Compound (2c) By converting the hydroxyimino group of compound (2b) to an acetyloxyimino group and converting one hydrogen atom bonded to the 23rd carbon atom to an acetyloxy group, Compound (2c) is obtained.
Specifically, for example, first, acetic acid, sodium acetate and disodium palladium chloride are added to the compound (2b) to carry out the reaction. The reaction temperature is preferably 15 to 40 ° C, and more preferably 20 to 30 ° C.
Subsequently, in the presence of a base, preferably using a halogenated hydrocarbon as a solvent, acetic anhydride is added to carry out an acetylation reaction.
Here, as the base, a weakly basic organic base is preferable, and triethylamine is particularly preferable. Here, a catalyst is preferably used, and dimethylaminopyridine (DMAP) is particularly preferably used. Examples of the halogenated hydrocarbon include methylene chloride and chloroform, and methylene chloride is particularly preferable. The reaction temperature is preferably 15 to 40 ° C, and more preferably 20 to 30 ° C.
Next, lead tetraacetate is preferably added in a state dissolved in acetic acid to perform an oxidation reaction, and then sodium borohydride is preferably dissolved in an aqueous sodium hydroxide solution to perform a reduction reaction, Compound (2c) is obtained. 15-40 degreeC is preferable and, as for reaction temperature when performing an oxidation reaction and a reductive reaction, 20-30 degreeC is more preferable.
After completion of each reaction, crystallization, concentration, drying, etc. may be performed as necessary, followed by purification by column chromatography or the like.
（Ｄ）化合物（２ｄ）の製造
化合物（２ｄ）は、化合物（２ｃ）を脱アセチル化することで得られる。
脱アセチル化は、例えば、化合物（２ｄ）に、好ましくはアルコールを溶媒として用い、塩基を加えて反応させれば良い。
ここで、アルコールとしてはメタノールが特に好ましい。塩基は弱塩基性の無機塩基が好ましく、炭酸ナトリウムが特に好ましい。反応温度は１５〜４０℃が好ましく、２０〜３０℃がより好ましい。
反応終了後は、必要に応じて抽出、洗浄等を行い、濃縮や再結晶等により目的物が得られる。
(D) Production of Compound (2d) Compound (2d) is obtained by deacetylating compound (2c).
In the deacetylation, for example, the compound (2d) is preferably reacted using an alcohol as a solvent and adding a base.
Here, methanol is particularly preferable as the alcohol. The base is preferably a weakly basic inorganic base, and sodium carbonate is particularly preferred. The reaction temperature is preferably 15 to 40 ° C, and more preferably 20 to 30 ° C.
After completion of the reaction, extraction, washing, etc. are performed as necessary, and the target product is obtained by concentration, recrystallization or the like.
（Ｅ）化合物（２ｅ）の製造
化合物（２ｄ）のヒドロキシイミノ基を酸素原子に変換することで、化合物（２ｅ）が得られる。
反応は、トリクロロチタン及び酢酸アンモニウムの塩酸水溶液に、化合物（２ｄ）を好ましくはテトラヒドロフラン溶液として加えて行うのが好ましい。反応温度は１５〜４０℃が好ましく、２０〜３０℃がより好ましい。
反応終了後は、適宜必要に応じて、抽出、洗浄、濃縮等を行い、カラムクロマトグラフィー等による精製を行っても良い。
ここまでの工程で、２３位の炭素原子にヒドロキシ基が導入される。これは、次工程においてレトロアルドール反応を行うために必要な構造である。
(E) Production of Compound (2e) Compound (2e) is obtained by converting the hydroxyimino group of compound (2d) to an oxygen atom.
The reaction is preferably carried out by adding the compound (2d), preferably as a tetrahydrofuran solution, to an aqueous hydrochloric acid solution of trichlorotitanium and ammonium acetate. The reaction temperature is preferably 15 to 40 ° C, and more preferably 20 to 30 ° C.
After completion of the reaction, extraction, washing, concentration, etc. may be performed as necessary, and purification by column chromatography or the like may be performed as necessary.
Through the steps so far, a hydroxy group is introduced into the 23rd carbon atom. This is a structure necessary for performing the retroaldol reaction in the next step.
（Ｆ）化合物（３）の製造
化合物（２ｅ）のヒドロキシメチル基を水素原子に変換することで、化合物（３）が得られる。
反応は、例えば、化合物（２ｅ）に対し、好ましくはアルコールを溶媒として用い、塩基を加えて行うのが好ましい。
ここで、アルコールとしてはメタノールが特に好ましい。塩基は弱塩基性の無機塩基が好ましく、炭酸ナトリウムが特に好ましい。反応温度は１５〜４０℃が好ましく、２０〜３０℃がより好ましい。
反応終了後は、適宜必要に応じて、ｐＨ調整、抽出、洗浄、濃縮等を行い、カラムクロマトグラフィー等による精製を行っても良い。
本工程では、レトロアルドール反応により、４位の炭素原子に結合しているヒドロキシメチル基が除去されて、分子中の炭素原子数が一つ減少する。これは、後の工程において、重水素原子で標識化されたメチル基（標識化メチル基）を４位の炭素原子に結合させるために必要な構造である。
(F) Production of Compound (3) Compound (3) is obtained by converting the hydroxymethyl group of compound (2e) to a hydrogen atom.
The reaction is preferably performed, for example, on the compound (2e), preferably using an alcohol as a solvent and adding a base.
Here, methanol is particularly preferable as the alcohol. The base is preferably a weakly basic inorganic base, and sodium carbonate is particularly preferred. The reaction temperature is preferably 15 to 40 ° C, and more preferably 20 to 30 ° C.
After completion of the reaction, pH adjustment, extraction, washing, concentration, etc. may be performed as necessary, followed by purification by column chromatography or the like.
In this step, the hydroxymethyl group bonded to the 4-position carbon atom is removed by the retroaldol reaction, and the number of carbon atoms in the molecule is reduced by one. This is a structure necessary for bonding a methyl group labeled with a deuterium atom (labeled methyl group) to a carbon atom at the 4-position in a later step.
（Ｇ）化合物（４）の製造
化合物（３）の１位及び２位の炭素原子間の結合を二重結合とすることで、化合物（４）が得られる。
具体的には、例えば、化合物（３）に対し、好ましくはテトラヒドロフランを溶媒として用いて、リチウムビストリメチルシリルアミド（ＬＨＭＤＳ）を加えて反応させる。反応温度は、まず好ましくは−９０〜−６０℃、より好ましくは−８０〜−７０℃とした後、昇温して好ましくは−２０〜１０℃、より好ましくは−１０〜５℃とする。
次いで、クロロトリメチルシラン（ＴＭＳＣｌ）を加えて反応を行う。反応温度は、まず好ましくは−９０〜−６０℃、より好ましくは−８０〜−７０℃とした後、昇温して好ましくは１５〜４０℃、より好ましくは２０〜３０℃とする。
次いで、好ましくはテトラヒドロフラン及びアセトニトリルの混合溶媒を用い、酢酸パラジウムを加えて反応を行う。反応温度は１５〜４０℃が好ましく、２０〜３０℃がより好ましい。
各反応終了後は、適宜必要に応じて、ｐＨ調整、抽出、ろ過、洗浄、濃縮等を行い、カラムクロマトグラフィー等による精製を行っても良い。
化合物（４）は、次工程において、前記標識化メチル基を導入して分子中の炭素原子数を増加させる際に、該標識化メチル基を２位の炭素原子ではなく４位の炭素原子に選択的に導入するために必要な構造である。
(G) Production of compound (4) Compound (4) is obtained by making the bond between the 1st and 2nd carbon atoms of compound (3) a double bond.
Specifically, for example, the compound (3) is reacted with lithium bistrimethylsilylamide (LHMDS), preferably using tetrahydrofuran as a solvent. The reaction temperature is preferably −90 to −60 ° C., more preferably −80 to −70 ° C., and then the temperature is raised, preferably −20 to 10 ° C., more preferably −10 to 5 ° C.
Next, chlorotrimethylsilane (TMSCl) is added to carry out the reaction. The reaction temperature is preferably −90 to −60 ° C., more preferably −80 to −70 ° C., and then the temperature is raised to preferably 15 to 40 ° C., more preferably 20 to 30 ° C.
Next, the reaction is preferably carried out by adding palladium acetate using a mixed solvent of tetrahydrofuran and acetonitrile. The reaction temperature is preferably 15 to 40 ° C, and more preferably 20 to 30 ° C.
After completion of each reaction, purification by column chromatography or the like may be performed by adjusting pH, extraction, filtration, washing, concentration, etc. as necessary.
When the compound (4) increases the number of carbon atoms in the molecule by introducing the labeled methyl group in the next step, the labeled methyl group is changed to the 4-position carbon atom instead of the 2-position carbon atom. This structure is necessary for selective introduction.
（Ｈ）化合物（５）の製造
化合物（４）の４位の炭素原子に結合している水素原子を、−ＣＤ３に変換することで、化合物（５）が得られる。
反応は、例えば、化合物（４）に対し、好ましくはテトラヒドロフランを溶媒として用い、リチウムビストリメチルシリルアミド（ＬＨＭＤＳ）を加えて反応させた後、さらに一般式「ＣＤ３Ｌ」で表される化合物を加えて反応を行うのが好ましい。ここで一般式中、「Ｌ」はハロゲン原子を表し、ヨウ素原子であることが特に好ましい。反応温度は、まず好ましくは−９０〜−６０℃、より好ましくは−８０〜−７０℃とした後、昇温して好ましくは−２０〜１０℃、より好ましくは−１０〜５℃とする。
反応終了後は、適宜必要に応じて、ｐＨ調整、抽出、洗浄、濃縮等を行い、カラムクロマトグラフィー等による精製を行っても良い。
化合物（５）は、４位の炭素原子に結合しているメチル基が、重水素原子で標識化された化合物であり、同様に標識化された目的物である標識化グリチルレチン酸（８ａ）の中間体である。
(H) Production of Compound (5) A compound (5) is obtained by converting a hydrogen atom bonded to the 4-position carbon atom of the compound (4) into —CD 3 .
For example, the reaction is performed by adding lithium bistrimethylsilylamide (LHMDS) to compound (4), preferably using tetrahydrofuran as a solvent, and then adding a compound represented by the general formula “CD 3 L”. It is preferable to carry out the reaction. Here, in the general formula, “L” represents a halogen atom, and particularly preferably an iodine atom. The reaction temperature is preferably −90 to −60 ° C., more preferably −80 to −70 ° C., and then the temperature is raised, preferably −20 to 10 ° C., more preferably −10 to 5 ° C.
After completion of the reaction, pH adjustment, extraction, washing, concentration, etc. may be performed as necessary, followed by purification by column chromatography or the like.
The compound (5) is a compound in which the methyl group bonded to the carbon atom at the 4-position is labeled with a deuterium atom. Similarly, the labeled glycyrrhetinic acid (8a), which is the target product, is labeled. It is an intermediate.
以上のように、本発明においては、グリチルレチン酸（１）誘導体の２３位の炭素原子が結合している環構造（１位〜５位及び１０位の炭素原子で構成されるＡ環）を開環することなく、４位の炭素原子に結合しているメチル基を、重水素原子で標識化されたメチル基に変換することで、化合物（５）を得る。このように開環を伴うことなく標識化が可能となったのは、２３位の炭素原子にヒドロキシ基を結合させた後、レトロアルドール反応を行うことで分子中の炭素原子数を一つ減少させる合成法を適用したことによる。開環及び閉環を行う必要がないので、標識化までの工程数が削減できると共に、これら工程を従来よりも穏やかな条件下で行うことができる。そして標識化に使用する原料として、例えば、ＣＤ３Ｉなど市販品が利用でき、これらを別途調製する必要がない。 As described above, in the present invention, the ring structure in which the 23rd carbon atom of the glycyrrhetinic acid (1) derivative is bonded (the A ring composed of the 1st to 5th and 10th carbon atoms) is opened. The compound (5) is obtained by converting the methyl group bonded to the 4-position carbon atom into a methyl group labeled with a deuterium atom without ringing. In this way, labeling without ring-opening is possible by reducing the number of carbon atoms in the molecule by attaching a hydroxy group to the carbon atom at position 23 and then performing a retroaldol reaction. This is because the synthesis method is applied. Since there is no need to perform ring opening and ring closing, the number of steps until labeling can be reduced, and these steps can be performed under milder conditions than in the past. And as a raw material to be used for labeling, for example, CD 3 I like available commercial products, it is not necessary to prepare these separately.
なお、上記一般式「ＣＤ３Ｌ」で表される化合物の代わりに、一般式「１４ＣＨ３Ｌ」（一般式中、「Ｌ」は前記と同様である）で表される化合物を用いることで、化合物（５）と同様に、化合物（５）の−ＣＤ３が−１４ＣＨ３に置換された化合物が得られる。この場合、一般式「１４ＣＨ３Ｌ」で表される化合物としては、例えば、１４ＣＨ３Ｉなどの市販品を利用できる。 Instead of the compound represented by the above general formula “CD 3 L”, a compound represented by the general formula “ 14 CH 3 L” (wherein “L” is as defined above) is used. In the same manner as in the compound (5), a compound in which —CD 3 of the compound (5) is substituted with — 14 CH 3 is obtained. In this case, as the compound represented by the general formula “ 14 CH 3 L”, for example, commercially available products such as 14 CH 3 I can be used.
＜標識化グリチルレチン酸（８ａ）の製造方法＞
本発明の第十の実施形態に係る標識化グリチルレチン酸（８ａ）の製造方法における代表的な合成ルートを、以下に示す。
<Method for producing labeled glycyrrhetinic acid (8a)>
A typical synthesis route in the method for producing labeled glycyrrhetinic acid (8a) according to the tenth embodiment of the present invention is shown below.
（Ｉ）化合物（６ａ）の製造
化合物（５）に水素を付加し、１位及び２位の炭素原子間の結合を飽和結合とし、脱ベンジル化することで、化合物（６ａ）が得られる。
反応は、例えば、化合物（５）に対し、好ましくは酢酸エチル及びエタノールの混合溶媒を用い、パラジウム触媒を加え、水素ガス雰囲気下で攪拌することにより行うのが好ましい。前記パラジウム触媒としては、パラジウムカーボンが好ましい。
反応終了後は、ろ過により不溶物を除去した後、濃縮や再結晶等により目的物が得られる。
(I) Production of Compound (6a) Compound (6a) is obtained by adding hydrogen to Compound (5) to form a bond between the 1st and 2nd carbon atoms as a saturated bond and debenzylation.
The reaction is preferably performed, for example, by using a mixed solvent of ethyl acetate and ethanol, adding a palladium catalyst to the compound (5), and stirring in a hydrogen gas atmosphere. As the palladium catalyst, palladium carbon is preferable.
After completion of the reaction, the insoluble matter is removed by filtration, and then the desired product is obtained by concentration, recrystallization or the like.
（Ｊ）化合物（７ａ）の製造
化合物（６ａ）の、１１位の炭素原子を含むメチレン基をカルボニル基に変換することで、化合物（７ａ）が得られる。
反応は、例えば、化合物（６ａ）に対し、好ましくはジクロロメタン、アセトニトリル及びピリジンの混合溶媒を用い、ヨウ化銅及びｔ−ブチルヒドロペルオキシド（ＴＢＨＰ）を加えて行うのが好ましい。反応温度は２０〜６０℃が好ましく、３０〜５０℃がより好ましい。
反応終了後は、適宜必要に応じて、抽出、洗浄、濃縮等を行い、カラムクロマトグラフィー等による精製を行っても良い。
(J) Production of Compound (7a) Compound (7a) is obtained by converting a methylene group containing a carbon atom at the 11-position of compound (6a) to a carbonyl group.
The reaction is preferably performed, for example, on compound (6a), preferably using a mixed solvent of dichloromethane, acetonitrile and pyridine, and adding copper iodide and t-butyl hydroperoxide (TBHP). The reaction temperature is preferably 20 to 60 ° C, more preferably 30 to 50 ° C.
After completion of the reaction, extraction, washing, concentration, etc. may be performed as necessary, and purification by column chromatography or the like may be performed as necessary.
（Ｋ）化合物（８ａ）の製造
化合物（７ａ）の３位の炭素原子に結合している酸素原子をヒドロキシ基に変換することで、化合物（８ａ）が得られる。
反応は、例えば、化合物（７ａ）に対し、好ましくはテトラヒドロフラン及びメタノールの混合溶媒を用い、水素化ホウ素ナトリウムを加えて行うのが好ましい。反応温度は１５〜４０℃が好ましく、２０〜３０℃がより好ましい。
反応終了後は、適宜必要に応じて、ｐＨ調整、抽出、洗浄、濃縮等を行い、カラムクロマトグラフィー等による精製を行っても良い。
(K) Production of Compound (8a) Compound (8a) is obtained by converting the oxygen atom bonded to the 3-position carbon atom of compound (7a) to a hydroxy group.
The reaction is preferably performed, for example, on the compound (7a), preferably using a mixed solvent of tetrahydrofuran and methanol and adding sodium borohydride. The reaction temperature is preferably 15 to 40 ° C, and more preferably 20 to 30 ° C.
After completion of the reaction, pH adjustment, extraction, washing, concentration, etc. may be performed as necessary, followed by purification by column chromatography or the like.
＜化合物（９）の製造方法＞
本発明の第十一の実施形態に係る化合物（９）の製造方法における代表的な合成ルートを、以下に示す。
<Method for producing compound (9)>
A typical synthesis route in the method for producing compound (9) according to the eleventh embodiment of the present invention is shown below.
（Ｌ）化合物（６ｂ）の製造
化合物（５）に水素を付加し、１位及び２位の炭素原子間の結合を飽和結合とすることで、化合物（６ａ）が得られる。
反応は、例えば、化合物（５）に対し、好ましくはベンゼン及びエタノールの混合溶媒を用い、ロジウム触媒を加え、水素ガス雰囲気下で攪拌することにより行うのが好ましい。前記ロジウム触媒としては、クロロトリストリフェニルホスフィンロジウムが好ましい。反応温度は１５〜４０℃が好ましく、２０〜３０℃がより好ましい。
反応終了後は、ろ過により不溶物を除去した後、濃縮や再結晶等により目的物が得られ、カラムクロマトグラフィー等による精製を行っても良い。
(L) Production of Compound (6b) Compound (6a) is obtained by adding hydrogen to Compound (5) and making the bond between the 1-position and 2-position carbon atoms a saturated bond.
The reaction is preferably performed, for example, by using a mixed solvent of benzene and ethanol, adding a rhodium catalyst to the compound (5), and stirring in a hydrogen gas atmosphere. As the rhodium catalyst, chlorotristriphenylphosphine rhodium is preferable. The reaction temperature is preferably 15 to 40 ° C, and more preferably 20 to 30 ° C.
After completion of the reaction, the insoluble matter is removed by filtration, and then the desired product is obtained by concentration, recrystallization or the like, and may be purified by column chromatography or the like.
このように、化合物（５）に対する水素付加反応で用いる触媒種を使い分けることで、化合物（６ａ）及び化合物（６ｂ）を作り分けることが可能であり、化合物（５）を標識化グリチルレチン酸（８ａ）及び化合物（９）の共通中間体とすることができる。そして、化合物（９）は、後記するように標識化グリチルリチン（８ｂ）の中間体なので、化合物（５）を用いることにより、標識化グリチルレチン酸（８ａ）及び標識化グリチルリチン（８ｂ）を効率良く製造できる。 Thus, it is possible to make the compound (6a) and the compound (6b) separately by properly using the catalyst species used in the hydrogenation reaction for the compound (5), and the compound (5) is labeled with glycyrrhetinic acid (8a). ) And compound (9). Since compound (9) is an intermediate of labeled glycyrrhizin (8b) as described later, labeled glycyrrhetinic acid (8a) and labeled glycyrrhizin (8b) are efficiently produced by using compound (5). it can.
（Ｍ）化合物（７ｂ）の製造
化合物（７ｂ）は、化合物（６ａ）に代わり化合物（６ｂ）を用いること以外は、前記化合物（７ａ）の場合と同様の方法で得られる。ただし、反応温度は化合物（７ａ）の製造の場合よりも低めで良く、１５〜４０℃が好ましく、２０〜３０℃がより好ましい。
(M) Production of Compound (7b) Compound (7b) is obtained in the same manner as in the case of Compound (7a) except that Compound (6b) is used instead of Compound (6a). However, reaction temperature may be lower than the case of manufacture of a compound (7a), 15-40 degreeC is preferable and 20-30 degreeC is more preferable.
（Ｎ）化合物（９）の製造
化合物（９）は、化合物（７ａ）に代わり化合物（７ｂ）を用いること以外は、前記化合物（８ａ）の場合と同様の方法で得られる。
(N) Production of Compound (9) Compound (9) is obtained in the same manner as in the case of compound (8a) except that compound (7b) is used instead of compound (7a).
先に述べた通り、化合物（５）と同様に、化合物（５）の−ＣＤ３が−１４ＣＨ３に置換された化合物が得られるので、この化合物を化合物（５）の代わりに用いること以外は、化合物（８ａ）又は化合物（９）の製造方法と同様の方法で、化合物（８ａ）又は化合物（９）の−ＣＤ３が−１４ＣＨ３に置換された化合物を得ることもできる。このように、１４Ｃで標識化された化合物が得られるのは、標識化メチル基が−ＣＤ３及び−１４ＣＨ３のいずれであっても、上記製造方法における各合成反応が大差なく進行するからである。これは、合成反応においては、−ＣＤ３の特性と−１４ＣＨ３の特性との差は些少であり、いずれの標識化メチル基で標識化されていても、標識化化合物を同様に取り扱うことが可能だからである。 As described above, a compound in which —CD 3 of compound (5) is substituted with — 14 CH 3 is obtained in the same manner as compound (5), except that this compound is used instead of compound (5). Can also be obtained by a method similar to the method for producing compound (8a) or compound (9), wherein -CD 3 of compound (8a) or compound (9) is substituted with- 14 CH 3 . In this way, a compound labeled with 14 C is obtained because each synthetic reaction in the above production method proceeds without any difference, regardless of whether the labeled methyl group is —CD 3 or − 14 CH 3. Because. This is because, in the synthesis reaction, -CD 3 characteristics and - the difference between the characteristics of the 14 CH 3 is insignificant, be labeled with any labeling methyl group, the handling of labeled compound in the same manner Because it is possible.
上記本発明の製造方法によれば、例えば、トリテルペンやステロイドの内、３位の炭素原子に水酸基が一つ結合し、４位の炭素原子にメチル基が二つ結合した、グリチルレチン酸（１）と類似の構造を有する化合物についても、グリチルレチン酸（１）と同様に、４位の炭素原子に結合している一方のメチル基を、重水素原子で標識化されたメチル基又は１４Ｃで標識化されたメチル基に置換できる。 According to the production method of the present invention, for example, among triterpenes and steroids, glycyrrhetinic acid (1) in which one hydroxyl group is bonded to the 3rd carbon atom and two methyl groups are bonded to the 4th carbon atom. As with glycyrrhetinic acid (1), one of the methyl groups bonded to the 4-position carbon atom is labeled with a methyl group labeled with a deuterium atom or 14 C, as in the case of glycyrrhetinic acid (1). The substituted methyl group can be substituted.
＜標識化グリチルリチン（８ｂ）の製造方法＞
次に、化合物（９）を用いて、２３位の炭素原子を含むメチル基が重水素原子で標識化された標識化グリチルリチン（８ｂ）を製造する方法について説明する。化合物（９）の代わりに、化合物（９）の−ＣＤ３が−１４ＣＨ３に置換された化合物を用いることで、同様に、２３位の炭素原子を含むメチル基が１４Ｃで標識化された標識化グリチルリチンが製造でき、化合物（９）の代わりに、化合物（９）の−ＣＤ３がメチル基に置換された化合物（すなわち、グリチルレチン酸のカルボキシ基がベンジル基で保護された化合物）を用いることで、同様にグリチルリチンが製造できる。その理由は、先に述べたように、−ＣＤ３の特性と−１４ＣＨ３の特性との差は些少だからであり、これらの標識化メチル基の特性とメチル基の特性との差も些少だからである。
標識化グリチルリチン（８ｂ）の製造方法における代表的な合成ルートを、以下に示す。本合成ルートは、化合物（９）から、下記式（１０ａ）、（１０ｂ）、（１０ｃ）、（１０ｄ）、（１０ｅ）及び（１０ｆ）で表される化合物（以下、それぞれ化合物（１０ａ）、化合物（１０ｂ）、化合物（１０ｃ）、化合物（１０ｄ）、化合物（１０ｅ）、化合物（１０ｆ）と略記する）を中間体として、標識化グリチルリチン（８ｂ）を得るものである。
<Method for producing labeled glycyrrhizin (8b)>
Next, a method for producing labeled glycyrrhizin (8b) in which a methyl group containing a carbon atom at the 23-position is labeled with a deuterium atom using compound (9) will be described. By using a compound in which -CD 3 of compound (9) is substituted with- 14 CH 3 instead of compound (9), the methyl group containing the carbon atom at the 23-position is similarly labeled with 14 C. Labeled glycyrrhizin can be produced, and instead of compound (9), a compound in which —CD 3 of compound (9) is substituted with a methyl group (that is, a compound in which the carboxy group of glycyrrhetinic acid is protected with a benzyl group) By using it, glycyrrhizin can be produced similarly. This is because, as mentioned earlier, -CD 3 characteristics and - the difference between the characteristics of the 14 CH 3 is because it insignificant, insignificant also the difference between the characteristics of the characteristics and methyl groups of these labeled methyl group That's why.
A typical synthesis route in the method for producing labeled glycyrrhizin (8b) is shown below. This synthesis route is carried out from the compound (9) to the compounds represented by the following formulas (10a), (10b), (10c), (10d), (10e) and (10f) (hereinafter referred to as the compound (10a), Labeled glycyrrhizin (8b) is obtained using compound (10b), compound (10c), compound (10d), compound (10e) and compound (10f) as intermediates.
（Ｏ）化合物（１０ａ）の製造
化合物（９）に前記化学式（１１）で表される化合物（以下、化合物（１１）と略記する）を反応させることで、化合物（１０ａ）が得られる。
反応は、例えば、化合物（９）に対し、好ましくはハロゲン化炭化水素を溶媒として用い、化合物（１１）を加え、窒素ガス雰囲気下で酸を加えて攪拌することにより行うのが好ましい。
ここで用いる酸としては、ルイス酸が好ましく、ＢＦ３−ＯＥｔ２が特に好ましい。
また、ハロゲン化炭化水素としては、塩化メチレン、クロロホルム等が例示でき、塩化メチレンが特に好ましい。反応温度は−４０〜５℃が好ましく、−５〜５℃がより好ましい。
反応終了後は、適宜必要に応じて、ｐＨ調整、ろ過による不溶物の除去、濃縮等を行い、カラムクロマトグラフィー等による精製を行っても良い。
(O) Production of Compound (10a) Compound (10a) is obtained by reacting compound (9) with a compound represented by the above chemical formula (11) (hereinafter abbreviated as compound (11)).
The reaction is preferably carried out, for example, by using halogenated hydrocarbon as a solvent for compound (9), adding compound (11), adding an acid in a nitrogen gas atmosphere and stirring.
As the acid used here, a Lewis acid is preferable, and BF 3 -OEt 2 is particularly preferable.
Examples of the halogenated hydrocarbon include methylene chloride and chloroform, and methylene chloride is particularly preferable. The reaction temperature is preferably -40 to 5 ° C, more preferably -5 to 5 ° C.
After completion of the reaction, purification by column chromatography or the like may be performed as necessary by adjusting pH, removing insoluble matters by filtration, concentrating, and the like.
（Ｐ）化合物（１０ｂ）の製造
化合物（１０ａ）を脱ベンゾイル化することで、化合物（１０ｂ）が得られる。
反応は、例えば、化合物（１０ａ）に対し、好ましくはメタノール及び１，４−ジオキサンの混合溶媒を用い、ナトリウムメトキシド等の塩基を加えて行うのが好ましい。反応温度は２０〜６０℃が好ましく、３０〜５０℃がより好ましい。
反応終了後は、適宜必要に応じて、ｐＨ調整、濃縮等を行い、カラムクロマトグラフィー等による精製を行っても良い。
(P) Production of Compound (10b) Compound (10b) is obtained by debenzoylating compound (10a).
The reaction is preferably performed, for example, on the compound (10a), preferably using a mixed solvent of methanol and 1,4-dioxane, and adding a base such as sodium methoxide. The reaction temperature is preferably 20 to 60 ° C, more preferably 30 to 50 ° C.
After completion of the reaction, if necessary, pH adjustment, concentration and the like may be performed, and purification by column chromatography or the like may be performed.
（Ｑ）化合物（１０ｃ）の製造
化合物（１０ｃ）は、化合物（９）に代わり化合物（１０ｂ）を用いること以外は、前記化合物（１０ａ）の場合と同様の方法で得られる。
(Q) Production of Compound (10c) Compound (10c) is obtained in the same manner as in the case of Compound (10a) except that Compound (10b) is used instead of Compound (9).
（Ｒ）化合物（１０ｄ）の製造
化合物（１０ｄ）は、前記化合物（１０ｃ）を脱アセタール化することで得られる。
反応は、例えば、化合物（１０ｃ）に対し、好ましくはハロゲン化炭化水素及びアルコールの混合溶媒を用い、酸を加えて行うのが好ましい。
ここで、ハロゲン化炭化水素としては、塩化メチレン、クロロホルム等が例示でき、クロロホルムが特に好ましい。アルコールとしては、メタノール、エタノール等が例示でき、メタノールが特に好ましい。酸としては有機酸が好ましく、ｐ−トルエンスルホン酸（ｐＴｓＯＨ）が特に好ましい。反応温度は１５〜４０℃が好ましく、２０〜３０℃がより好ましい。
反応終了後は、適宜必要に応じて、ｐＨ調整、濃縮等を行い、カラムクロマトグラフィー等による精製を行っても良い。
(R) Production of Compound (10d) The compound (10d) is obtained by deacetalizing the compound (10c).
The reaction is preferably performed, for example, on the compound (10c), preferably using a mixed solvent of a halogenated hydrocarbon and an alcohol and adding an acid.
Here, examples of the halogenated hydrocarbon include methylene chloride and chloroform, and chloroform is particularly preferable. Examples of the alcohol include methanol and ethanol, and methanol is particularly preferable. As the acid, an organic acid is preferable, and p-toluenesulfonic acid (pTsOH) is particularly preferable. The reaction temperature is preferably 15 to 40 ° C, and more preferably 20 to 30 ° C.
After completion of the reaction, if necessary, pH adjustment, concentration and the like may be performed, and purification by column chromatography or the like may be performed.
（Ｓ）化合物（１０ｅ）の製造
化合物（１０ｄ）の糖部分を酸化し、得られたカルボキシ基をメチルエステル化することで、化合物（１０ｅ）が得られる。ここで糖部分とは、前記化合物（１１）に由来する部分を指す。
酸化反応では、糖部分の第一級ヒドロキシ基が炭素原子に結合している部位をカルボキシ基に変換する。
酸化反応は、ハロゲン化炭化水素及び水の混合溶媒中で行うのが好ましく、ハロゲン化炭化水素として塩化メチレンを用いるのが特に好ましい。また、酸化反応は、触媒量の２，２，６，６−テトラメチルピペリジン１−オキシル（ＴＥＭＰＯ）を共酸化剤と併用する方法で行うのが好ましく、共酸化剤としては、ビス（アセトキシ）ヨウドベンゼン（ＢＡＩＢ）が特に好ましい。ＴＥＭＰＯ及び共酸化剤を併用する方法により、糖部分の第一級ヒドロキシ基が炭素原子に結合している二つの部位を、高選択的に一度にカルボキシ基に変換できるので、工程数を削減でき、目的物の収率を向上させるのに有利である。反応温度は１５〜４０℃が好ましく、２０〜３０℃がより好ましい。
酸化反応終了後は、例えば、チオ硫酸ナトリウム等を加えた後、適宜必要に応じてｐＨ調整、抽出、濃縮等の後処理を行うことができる。
(S) Production of Compound (10e) Compound (10e) is obtained by oxidizing the sugar moiety of compound (10d) and methylating the resulting carboxy group. Here, the sugar moiety refers to a moiety derived from the compound (11).
In the oxidation reaction, the site where the primary hydroxy group of the sugar moiety is bonded to the carbon atom is converted to a carboxy group.
The oxidation reaction is preferably performed in a mixed solvent of a halogenated hydrocarbon and water, and it is particularly preferable to use methylene chloride as the halogenated hydrocarbon. The oxidation reaction is preferably carried out by a method in which a catalytic amount of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) is used in combination with a cooxidant. As the cooxidant, bis (acetoxy) Iodobenzene (BAIB) is particularly preferred. By using TEMPO and a co-oxidant in combination, the two sites where the primary hydroxyl group of the sugar moiety is bonded to the carbon atom can be highly selectively converted to a carboxy group at a time, reducing the number of steps. This is advantageous in improving the yield of the target product. The reaction temperature is preferably 15 to 40 ° C, and more preferably 20 to 30 ° C.
After completion of the oxidation reaction, for example, after adding sodium thiosulfate or the like, post-treatment such as pH adjustment, extraction, and concentration can be performed as necessary.
次いで、前記酸化反応で得られたカルボキシ基をメチルエステル化する。メチルエステル化は、酸化反応で得られた化合物に対し、メチル化剤を作用させれば良い。メチル化剤は、求電子試薬として作用するものが好ましく、硫酸ジメチル、トリフルオロメタンスルホン酸メチル、ジアゾメタンがより好ましく、ジアゾメタンが特に好ましい。ジアゾメタンは、ジエチルエーテル溶液として用いることが好ましい。反応温度は１５〜４０℃が好ましく、２０〜３０℃がより好ましい。
反応終了後は、適宜必要に応じて、ｐＨ調整、濃縮等を行い、カラムクロマトグラフィー等による精製を行っても良い。
Next, the carboxy group obtained by the oxidation reaction is methyl esterified. For methyl esterification, a methylating agent may be allowed to act on the compound obtained by the oxidation reaction. The methylating agent is preferably one that acts as an electrophilic reagent, more preferably dimethyl sulfate, methyl trifluoromethanesulfonate, or diazomethane, and particularly preferably diazomethane. Diazomethane is preferably used as a diethyl ether solution. The reaction temperature is preferably 15 to 40 ° C, and more preferably 20 to 30 ° C.
After completion of the reaction, if necessary, pH adjustment, concentration and the like may be performed, and purification by column chromatography or the like may be performed.
（Ｔ）化合物（１０ｆ）の製造
化合物（１０ｆ）は、化合物（１０ｅ）を脱ベンジル化することで得られる。
反応は、例えば、化合物（１０ｆ）に対し、好ましくはメタノール等のアルコールを溶媒として用い、パラジウムカーボンを加え、水素ガス雰囲気下で攪拌するのが好ましい。
反応終了後は、適宜必要に応じて、ｐＨ調整、ろ過、濃縮等を行い、カラムクロマトグラフィー等による精製を行っても良い。
(T) Production of Compound (10f) Compound (10f) is obtained by debenzylating compound (10e).
In the reaction, for example, it is preferable to add an alcohol such as methanol as a solvent to the compound (10f), add palladium carbon, and stir in a hydrogen gas atmosphere.
After completion of the reaction, if necessary, pH adjustment, filtration, concentration, etc. may be performed and purification by column chromatography or the like may be performed.
（Ｕ）標識化グリチルリチン（８ｂ）の製造
標識化グリチルリチン（８ｂ）は、化合物（１０ｆ）を脱ベンゾイル化し、メチルエステルを加水分解することで得られる。
反応は、例えば、化合物（１０ｆ）に対し、好ましくはメタノール等のアルコールを溶媒として用い、ナトリウムメトキシド等の塩基を加えて攪拌するのが好ましい。
反応終了後は、適宜必要に応じて、ｐＨ調整、ろ過、濃縮等を行い、カラムクロマトグラフィー等による精製を行っても良い。
(U) Production of labeled glycyrrhizin (8b) Labeled glycyrrhizin (8b) is obtained by debenzoylating the compound (10f) and hydrolyzing the methyl ester.
For example, the reaction is preferably performed by adding a base such as sodium methoxide to the compound (10f), preferably using an alcohol such as methanol as a solvent.
After completion of the reaction, if necessary, pH adjustment, filtration, concentration, etc. may be performed and purification by column chromatography or the like may be performed.
ここに示す標識化グリチルリチン（８ｂ）の製造方法によれば、化合物（１１）を二段階で反応させて配糖化を行うことで、化合物（１０ｃ）が容易に得られる。そして該化合物（１０ｃ）は、その糖部分の水酸基に対して、脱アセタール化及び酸化を行うことで、グルクロン酸誘導体二分子がグリチルレチン酸に結合した構造の所望の中間体に容易に変換されるので、化合物（１０ｅ）を極めて効率的に得られる。そして、該化合物（１０ｅ）は、公知の方法で容易に脱保護できる。このように、従来にない合理的な合成ルートを採用することにより、前記化合物（９）を原料として、標識化グリチルリチン（８ｂ）を短工程且つ高収率で化学合成できる。 According to the method for producing labeled glycyrrhizin (8b) shown here, compound (10c) can be easily obtained by reacting compound (11) in two steps to carry out glycosylation. The compound (10c) is easily converted to a desired intermediate having a structure in which two molecules of a glucuronic acid derivative are bonded to glycyrrhetinic acid by deacetalizing and oxidizing the hydroxyl group of the sugar moiety. Therefore, the compound (10e) can be obtained very efficiently. And this compound (10e) can be easily deprotected by a well-known method. Thus, by adopting an unprecedented rational synthesis route, the labeled glycyrrhizin (8b) can be chemically synthesized in a short process and in a high yield using the compound (9) as a raw material.
以下、具体的に実施例を挙げ、本発明についてさらに詳しく説明する。ただし、本発明は以下に示す実施例に何ら限定されるものではない。 Hereinafter, the present invention will be described in more detail with specific examples. However, the present invention is not limited to the following examples.
［実施例１］
（化合物（２ａ）の製造）
グリチルレチン酸（１）３．０ｇをジオキサン７０ｍＬに溶かし、亜鉛粉末３．３６ｇと濃塩酸１４ｍＬを加え、室温で一夜撹拌した。反応液をろ過後、減圧濃縮した。濃縮物をテトラヒドロフラン７０ｍＬに溶かし、反応が終結するまでジョーンズ試薬を加えた。反応終結後、反応液に水を加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。濃縮物をジメチルホルムアミド７０ｍＬに溶かし、炭酸カリウム２．５０ｇと塩化ベンジル０．８ｍＬを加え、７０℃で一夜加熱撹拌した。反応液を５％塩酸で中和後、酢酸エチルで抽出し、水洗し、無水硫酸ナトリウムで乾燥して、減圧濃縮後、シリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル＝８：１）で精製し、３．４７ｇの化合物（２ａ）を白色結晶として得た（収率９９％）。
得られた化合物（２ａ）の物性を確認したところ、以下のようであった。
[Example 1]
(Production of Compound (2a))
Glycyrrhetinic acid (1) (3.0 g) was dissolved in dioxane (70 mL), zinc powder (3.36 g) and concentrated hydrochloric acid (14 mL) were added, and the mixture was stirred overnight at room temperature. The reaction solution was filtered and concentrated under reduced pressure. The concentrate was dissolved in 70 mL of tetrahydrofuran and Jones reagent was added until the reaction was complete. After completion of the reaction, water was added to the reaction solution, extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was dissolved in 70 mL of dimethylformamide, 2.50 g of potassium carbonate and 0.8 mL of benzyl chloride were added, and the mixture was heated and stirred overnight at 70 ° C. The reaction solution was neutralized with 5% hydrochloric acid, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1). 3.47 g of compound (2a) was obtained as white crystals (yield 99%).
When the physical property of the obtained compound (2a) was confirmed, it was as follows.
融点；157-160℃.
1H-NMR (400MHz, CDCl3) δppm: 7.36-7.31 (5H, m), 5.18 (1H, t, J = 3.9 Hz), 5.19 (1H, d, J = 12.4 Hz), 5.08 (1H, d, J = 12.4 Hz), 2.59-2.51 (2H, m), 2.39-2.35 (1H, m) , 1.15 (3H, s), 1.13 (3H, s), 1.09 (3H, s), 1.07 (3H, s), 1.06 (3H, s), 1.00 (3H, s), 0.75 (3H, s).
13C-NMR (100MHz, CDCl3) δppm: 217.6, 176.8, 144.3, 136.3, 128.4, 127.98, 127.96, 122.3, 66.0, 55.2, 48.1, 47.4, 46.8, 44.2, 42.7, 41.6, 39.7, 39.2, 38.2, 36.6, 34.2, 32.1 , 31.9, 31.3, 28.5, 28.1, 26.9, 26.4, 26.1, 25.8, 23.6, 21.5, 19.6, 16.7, 15.2.
MS (ESI-TOF) [M + H]+ 545.3992.
Melting point: 157-160 ° C.
1 H-NMR (400MHz, CDCl 3 ) δppm: 7.36-7.31 (5H, m), 5.18 (1H, t, J = 3.9 Hz), 5.19 (1H, d, J = 12.4 Hz), 5.08 (1H, d , J = 12.4 Hz), 2.59-2.51 (2H, m), 2.39-2.35 (1H, m), 1.15 (3H, s), 1.13 (3H, s), 1.09 (3H, s), 1.07 (3H, s), 1.06 (3H, s), 1.00 (3H, s), 0.75 (3H, s).
13 C-NMR (100 MHz, CDCl 3 ) δppm: 217.6, 176.8, 144.3, 136.3, 128.4, 127.98, 127.96, 122.3, 66.0, 55.2, 48.1, 47.4, 46.8, 44.2, 42.7, 41.6, 39.7, 39.2, 38.2, 36.6, 34.2, 32.1, 31.9, 31.3, 28.5, 28.1, 26.9, 26.4, 26.1, 25.8, 23.6, 21.5, 19.6, 16.7, 15.2.
MS (ESI-TOF) [M + H] + 545.3992.
［実施例２］
（化合物（２ｂ）の製造）
化合物（２ａ）３．４７ｇをメタノール６０ｍＬとジクロロメタン６０ｍＬの混合溶媒に溶かし、ヒドロキシルアミン塩酸塩８８５ｍｇと酢酸ナトリウム９７９ｍｇを加えて、５０℃で４時間加熱撹拌した。反応液を減圧濃縮後、ろ取した結晶を水洗、乾燥し、２．９１ｇの化合物（２ｂ）を白色結晶として得た（収率８０％）。
得られた化合物（２ｂ）の物性を確認したところ、以下のようであった。
[Example 2]
(Production of Compound (2b))
3.47 g of compound (2a) was dissolved in a mixed solvent of 60 mL of methanol and 60 mL of dichloromethane, 885 mg of hydroxylamine hydrochloride and 979 mg of sodium acetate were added, and the mixture was heated and stirred at 50 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and the collected crystals were washed with water and dried to give 2.91 g of compound (2b) as white crystals (yield 80%).
When the physical property of the obtained compound (2b) was confirmed, it was as follows.
融点；216-217℃.
1H-NMR (400MHz, CDCl3) δppm: 7.34-7.30 (5H, m), 5.18 (1H, d, J = 12.4 Hz), 5.17 (1H, t, J = 3.4 Hz), 5.08 (1H, d, J = 12.4 Hz), 3.09-3.06 (1H, m), 2.19-2.15 (1H, m), 1.16 (3H, s), 1.14 (3H, s), 1.11 (3H, s), 1.07 (3H, s), 1.05 (3H, s), 0.98 (3H, s), 0.74 (3H, s).
13C-NMR (100MHz, CDCl3) δppm: 176.8, 167.1, 144.3, 136.4, 128.4, 127.99, 127.95, 122.4, 66.0, 55.7 , 48.1, 47.1, 44.2, 42.7, 41.6, 40.3, 39.8, 38.6, 38.2, 37.0, 32.4, 31.9, 31.3, 28.5, 28.1, 27.2, 26.9, 26.1, 25.8, 23.6, 23.3, 19.1, 17.0, 16.8, 15.1.
MS (ESI-TOF) [M + H]+ 560.4106.
Melting point: 216-217 ° C.
1 H-NMR (400MHz, CDCl 3 ) δppm: 7.34-7.30 (5H, m), 5.18 (1H, d, J = 12.4 Hz), 5.17 (1H, t, J = 3.4 Hz), 5.08 (1H, d , J = 12.4 Hz), 3.09-3.06 (1H, m), 2.19-2.15 (1H, m), 1.16 (3H, s), 1.14 (3H, s), 1.11 (3H, s), 1.07 (3H, s), 1.05 (3H, s), 0.98 (3H, s), 0.74 (3H, s).
13 C-NMR (100 MHz, CDCl 3 ) δppm: 176.8, 167.1, 144.3, 136.4, 128.4, 127.99, 127.95, 122.4, 66.0, 55.7, 48.1, 47.1, 44.2, 42.7, 41.6, 40.3, 39.8, 38.6, 38.2, 37.0, 32.4, 31.9, 31.3, 28.5, 28.1, 27.2, 26.9, 26.1, 25.8, 23.6, 23.3, 19.1, 17.0, 16.8, 15.1.
MS (ESI-TOF) [M + H] + 560.4106.
［実施例３］
（化合物（２ｃ）の製造）
化合物（２ｂ）２．９１ｇを酢酸２００ｍＬに溶かし、酢酸ナトリウム４６９ｍｇと塩化パラジウム二ナトリウム１．６８ｇを加えて、室温で３日間撹拌した。反応液を氷水に注ぎ、析出した結晶をろ過した。結晶を６０℃で一晩減圧乾燥し、３．５６ｇの結晶を得た。得られた結晶３．５６ｇをジクロロメタン１３０ｍＬに溶かし、無水酢酸１．３ｍＬ、トリエチルアミン１．８ｍＬ、ジメチルアミノピリジン３２．１ｍｇを加えて、室温で1時間撹拌した。次いで、反応液に水を加えて水洗し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。濃縮物をテトラヒドロフラン１００ｍＬに溶かし、ピリジン０．５ｍＬを加え、室温で１５分撹拌した。その後反応液を−４０℃に冷却し、四酢酸鉛２．９２ｇを酢酸５０ｍＬに溶かした溶液を滴下した後、室温で一晩撹拌した。次いで、１Ｎ水酸化ナトリウム水溶液５０ｍＬに水素化ホウ素ナトリウム２４９ｍｇを溶かした溶液を調製し、反応液に滴下して室温でさらに１０分撹拌した。次いで、反応液を酢酸エチルで希釈し、セライトでろ過後、水洗し、無水硫酸ナトリウムで乾燥した後、減圧濃縮し、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝８：１）で精製して、２．７ｇの化合物（２ｃ）を無色固体として得た（収率７９％）。
得られた化合物（２ｃ）の物性を確認したところ、以下のようであった。
[Example 3]
(Production of Compound (2c))
2.91 g of compound (2b) was dissolved in 200 mL of acetic acid, 469 mg of sodium acetate and 1.68 g of disodium palladium chloride were added, and the mixture was stirred at room temperature for 3 days. The reaction solution was poured into ice water, and the precipitated crystals were filtered. The crystals were dried under reduced pressure at 60 ° C. overnight to obtain 3.56 g of crystals. 3.56 g of the obtained crystals were dissolved in 130 mL of dichloromethane, 1.3 mL of acetic anhydride, 1.8 mL of triethylamine, and 32.1 mg of dimethylaminopyridine were added, and the mixture was stirred at room temperature for 1 hour. Next, water was added to the reaction solution, which was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The concentrate was dissolved in 100 mL of tetrahydrofuran, 0.5 mL of pyridine was added, and the mixture was stirred at room temperature for 15 minutes. Thereafter, the reaction solution was cooled to −40 ° C., a solution prepared by dissolving 2.92 g of lead tetraacetate in 50 mL of acetic acid was added dropwise, and the mixture was stirred overnight at room temperature. Next, a solution in which 249 mg of sodium borohydride was dissolved in 50 mL of 1N sodium hydroxide aqueous solution was prepared, added dropwise to the reaction solution, and further stirred at room temperature for 10 minutes. Next, the reaction solution was diluted with ethyl acetate, filtered through celite, washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1), 2.7 g of compound (2c) was obtained as a colorless solid (yield 79%).
When the physical property of the obtained compound (2c) was confirmed, it was as follows.
1H-NMR (400MHz, CDCl3) δppm: 7.35-7.31 (5H, m), 5.19 (1H, t, J = 3.7 Hz), 5.19 (1H, d, J = 12.4 Hz), 5.09 (1H, d, J = 12.4 Hz), 4.21 (1H, d, J = 11.0 Hz), 4.15 (1H, d, J = 11.0 Hz), 2.80-2.76 (1H, m), 2.56-2.47 (1H, m), 2.18 (3H, s), 2.06 (3H, s), 1.18 (3H, s), 1.14 (3H, s), 1.12 (3H, s), 1.01 (3H, s), 0.99 (3H, s), 0.74 (3H, s).
13C-NMR (100MHz, CDCl3) δppm: 176.8, 170.8, 170.4, 169.6, 144.3, 136.3, 128.4, 127.99, 127.97, 122.2, 68.1, 66.0, 48.5, 48.2, 46.7, 44.3, 43.9, 42.8, 41.7, 39.8, 38.3, 37.2, 36.0, 32.0, 31.4, 28.6, 28.2, 27.0, 26.1, 25.8, 23.7, 21.0, 20.3, 20.1, 19.44, 19.40, 16.8, 15.5.
MS (ESI-TOF) [M + H]+ 660.4276.
1 H-NMR (400MHz, CDCl 3 ) δppm: 7.35-7.31 (5H, m), 5.19 (1H, t, J = 3.7 Hz), 5.19 (1H, d, J = 12.4 Hz), 5.09 (1H, d , J = 12.4 Hz), 4.21 (1H, d, J = 11.0 Hz), 4.15 (1H, d, J = 11.0 Hz), 2.80-2.76 (1H, m), 2.56-2.47 (1H, m), 2.18 (3H, s), 2.06 (3H, s), 1.18 (3H, s), 1.14 (3H, s), 1.12 (3H, s), 1.01 (3H, s), 0.99 (3H, s), 0.74 ( 3H, s).
13 C-NMR (100 MHz, CDCl 3 ) δppm: 176.8, 170.8, 170.4, 169.6, 144.3, 136.3, 128.4, 127.99, 127.97, 122.2, 68.1, 66.0, 48.5, 48.2, 46.7, 44.3, 43.9, 42.8, 41.7, 39.8, 38.3, 37.2, 36.0, 32.0, 31.4, 28.6, 28.2, 27.0, 26.1, 25.8, 23.7, 21.0, 20.3, 20.1, 19.44, 19.40, 16.8, 15.5.
MS (ESI-TOF) [M + H] + 660.4276.
［実施例４］
（化合物（２ｄ）の製造）
化合物（２ｃ）２．７０ｇをメタノール４１ｍＬに溶かし、炭酸ナトリウム１．９５ｇを加え室温で一夜撹拌した。反応液に水を加え、酢酸エチルで抽出し、飽和塩化ナトリウム水溶液で洗浄して、無水硫酸ナトリウムで乾燥した後、減圧濃縮し、２．１０ｇの化合物（２ｄ）を白色結晶として得た（収率８９％）。
得られた化合物（２ｄ）の物性を確認したところ、以下のようであった。
[Example 4]
(Production of Compound (2d))
2.70 g of compound (2c) was dissolved in 41 mL of methanol, 1.95 g of sodium carbonate was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.10 g of compound (2d) as white crystals (yield). Rate 89%).
When the physical property of the obtained compound (2d) was confirmed, it was as follows.
融点；194-197℃.
1H-NMR (400MHz, CDCl3) δppm: 7.36-7.31 (5H, m), 5.18 (1H, t, J = 3.2 Hz), 5.18 (1H, d, J = 12.4 Hz), 5.08 (1H, d, J = 12.4 Hz), 3.63 (1H, d, J = 11.2 Hz), 3.52 (1H, d, J = 11.2 Hz), 3.15-3.11 (1H, m), 2.10-2.03 (1H, m), 1.14 (3H, s), 1.11 (3H, s), 1.09 (3H, s), 1.04 (3H, s), 0.99 (3H, s), 0.74 (3H, s).
13C-NMR (100MHz, CDCl3) δppm: 176.8, 166.5, 144.4, 136.3, 128.4, 128.0, 127.9, 122.2, 67.6, 66.0, 49.8, 48.2, 47.0, 44.9, 44.3, 42.8, 41.7, 39.8, 38.3, 38.1, 36.8, 32.2, 32.0, 31.4, 28.6, 28.2, 27.0, 26.1, 26.0, 23.7, 19.0, 18.6, 17.4, 16.9, 15.4.
MS (ESI-TOF) [M + H]+ 576.4053.
Melting point: 194-197 ° C.
1 H-NMR (400MHz, CDCl 3 ) δppm: 7.36-7.31 (5H, m), 5.18 (1H, t, J = 3.2 Hz), 5.18 (1H, d, J = 12.4 Hz), 5.08 (1H, d , J = 12.4 Hz), 3.63 (1H, d, J = 11.2 Hz), 3.52 (1H, d, J = 11.2 Hz), 3.15-3.11 (1H, m), 2.10-2.03 (1H, m), 1.14 (3H, s), 1.11 (3H, s), 1.09 (3H, s), 1.04 (3H, s), 0.99 (3H, s), 0.74 (3H, s).
13 C-NMR (100 MHz, CDCl 3 ) δppm: 176.8, 166.5, 144.4, 136.3, 128.4, 128.0, 127.9, 122.2, 67.6, 66.0, 49.8, 48.2, 47.0, 44.9, 44.3, 42.8, 41.7, 39.8, 38.3, 38.1, 36.8, 32.2, 32.0, 31.4, 28.6, 28.2, 27.0, 26.1, 26.0, 23.7, 19.0, 18.6, 17.4, 16.9, 15.4.
MS (ESI-TOF) [M + H] + 576.4053.
［実施例５］
（化合物（２ｅ）の製造）
水１５ｍＬに酢酸アンモニウム３．６１ｇとトリクロロチタンの塩酸水溶液１１ｍＬを加え、化合物（２ｄ）１．０ｇをテトラヒドロフラン１５ｍＬに溶かしたものを室温で滴下し、一夜撹拌した。次いで、反応液をクロロホルムで抽出し、無水硫酸ナトリウムで乾燥した後、減圧濃縮し、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝８：１）で精製し、８２０ｍｇの化合物（２ｅ）を白色結晶として得た（収率８４％）。
得られた化合物（２ｅ）の物性を確認したところ、以下のようであった。
[Example 5]
(Production of Compound (2e))
A solution of 3.61 g of ammonium acetate and 11 mL of an aqueous hydrochloric acid solution of trichlorotitanium in 15 mL of water was added dropwise in a solution of 1.0 g of compound (2d) in 15 mL of tetrahydrofuran at room temperature and stirred overnight. Next, the reaction solution was extracted with chloroform, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to give 820 mg of compound (2e) as white crystals. Obtained (yield 84%).
When the physical property of the obtained compound (2e) was confirmed, it was as follows.
融点；174-176℃.
1H-NMR (400MHz, CDCl3) δppm: 7.36-7.31 (5H, m), 5.19 (1H, d, J = 12.2 Hz), 5.18 (1H, t, J = 4.3 Hz), 5.08 (1H, d, J = 12.4 Hz), 3.65 (1H, dd, J = 10.6, 4.8 Hz), 3.43 (1H, dd, J = 11.5, 5.1 Hz), 2.66-2.61 (1H, m), 2.42 (1H, t, J = 6.2 Hz), 2.30-2.26 (1H, m), 1.17 (3H, s), 1.14 (3H, s), 1.14 (3H, s), 1.04 (3H, s), 1.02 (3H, s), 0.75 (3H, s).
13C-NMR (100MHz,CDCl3) δppm: 218.9, 176.8, 144.4, 136.4, 128.4, 127.97, 127.95, 122.1, 67.0, 66.0, 52.4, 49.3, 48.2, 46.8, 44.3, 42.8, 41.7, 39.9, 39.0, 38.3, 36.5, 35.3, 32.1, 32.0, 31.4, 28.6, 28.2, 27.0, 26.2, 26.0, 23.7, 19.3, 16.95, 16.94, 15.5.
MS (ESI-TOF) [M + Na]+ 583.3763.
Melting point: 174-176 ° C.
1 H-NMR (400MHz, CDCl 3 ) δppm: 7.36-7.31 (5H, m), 5.19 (1H, d, J = 12.2 Hz), 5.18 (1H, t, J = 4.3 Hz), 5.08 (1H, d , J = 12.4 Hz), 3.65 (1H, dd, J = 10.6, 4.8 Hz), 3.43 (1H, dd, J = 11.5, 5.1 Hz), 2.66-2.61 (1H, m), 2.42 (1H, t, J = 6.2 Hz), 2.30-2.26 (1H, m), 1.17 (3H, s), 1.14 (3H, s), 1.14 (3H, s), 1.04 (3H, s), 1.02 (3H, s), 0.75 (3H, s).
13 C-NMR (100 MHz, CDCl 3 ) δppm: 218.9, 176.8, 144.4, 136.4, 128.4, 127.97, 127.95, 122.1, 67.0, 66.0, 52.4, 49.3, 48.2, 46.8, 44.3, 42.8, 41.7, 39.9, 39.0, 38.3, 36.5, 35.3, 32.1, 32.0, 31.4, 28.6, 28.2, 27.0, 26.2, 26.0, 23.7, 19.3, 16.95, 16.94, 15.5.
MS (ESI-TOF) [M + Na] + 583.3763.
［実施例６］
（化合物（３）の製造）
化合物（２ｅ）８２０ｍｇをメタノール１５ｍＬに溶かし、炭酸ナトリウム６２０ｍｇを加えて、室温で３日間撹拌した。次いで、反応液に５％塩酸を加え、酢酸エチルで抽出し、飽和塩化ナトリウム水溶液で洗浄して、無水硫酸ナトリウムで乾燥した後、減圧濃縮し、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２０：１）で精製し、５９０ｍｇの化合物（３）を白色結晶として得た（収率７６％ ）。
得られた化合物（３）の物性を確認したところ、以下のようであった。
[Example 6]
(Production of Compound (3))
820 mg of compound (2e) was dissolved in 15 mL of methanol, 620 mg of sodium carbonate was added, and the mixture was stirred at room temperature for 3 days. Next, 5% hydrochloric acid was added to the reaction solution, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and silica gel column chromatography (hexane: ethyl acetate = 20: In 1), 590 mg of compound (3) was obtained as white crystals (yield 76%).
It was as follows when the physical property of the obtained compound (3) was confirmed.
融点；133-135℃.
1H-NMR (400MHz, CDCl3) δppm: 7.37-7.30 (5H, m), 5.19 (1H, t, J = 3.9 Hz), 5.19 (1H, d, J = 12.4 Hz), 5.09 (1H, d, J = 12.4 Hz), 2.47-2.44 (1H, m), 2.33-2.30 (2H, m),1.15 (3H, s), 1.14 (3H, s), 1.12 (3H, s), 1.03 (3H, s), 1.01 (3H, d, J = 6.3 Hz), 0.75 (3H, s).
13C-NMR (100MHz, CDCl3) δppm: 213.4, 176.8, 144.5, 136.4, 128.4, 127.97, 127.95, 122.3, 66.0, 53.6, 48.2, 45.3, 44.8, 44.3, 42.8, 41.7, 40.4, 39.6, 38.3, 37.5, 36.6, 32.0, 31.6, 31.4, 28.6, 28.2, 27.0, 26.2, 25.9, 24.1, 22.1, 16.9, 13.5, 11.8.
MS (ESI-TOF) [M + H]+ 531.3859.
Melting point: 133-135 ° C.
1 H-NMR (400MHz, CDCl 3 ) δppm: 7.37-7.30 (5H, m), 5.19 (1H, t, J = 3.9 Hz), 5.19 (1H, d, J = 12.4 Hz), 5.09 (1H, d , J = 12.4 Hz), 2.47-2.44 (1H, m), 2.33-2.30 (2H, m), 1.15 (3H, s), 1.14 (3H, s), 1.12 (3H, s), 1.03 (3H, s), 1.01 (3H, d, J = 6.3 Hz), 0.75 (3H, s).
13 C-NMR (100 MHz, CDCl 3 ) δppm: 213.4, 176.8, 144.5, 136.4, 128.4, 127.97, 127.95, 122.3, 66.0, 53.6, 48.2, 45.3, 44.8, 44.3, 42.8, 41.7, 40.4, 39.6, 38.3, 37.5, 36.6, 32.0, 31.6, 31.4, 28.6, 28.2, 27.0, 26.2, 25.9, 24.1, 22.1, 16.9, 13.5, 11.8.
MS (ESI-TOF) [M + H] + 531.3859.
［実施例７］
（化合物（４）の製造）
化合物（３）１００ｍｇをテトラヒドロフラン２ｍＬに溶かし、−７８℃に冷却して、リチウムビストリメチルシリルアミドのテトラヒドロフラン溶液（１Ｍ）を０．２ｍＬ滴下し、−７８℃で３０分撹拌後、３０分かけて０℃まで昇温した。次いで、反応液を再度−７８℃に冷却し、クロロトリメチルシラン０．０７ｍＬを滴下し、室温に戻して１．５時間撹拌した。次いで、反応液に飽和炭酸水素ナトリウム溶液を加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。濃縮物をテトラヒドロフラン１ｍＬとアセトニトリル２ｍＬに溶解し、酢酸パラジウム４２．４ｍｇを加えて、室温で２４時間撹拌した。次いで、反応液を濾過した後、減圧濃縮し、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１５：１）で精製し、１６０ｍｇの化合物（４）を無色固体として得た（収率８９％）。
得られた化合物（４）の物性を確認したところ、以下のようであった。
[Example 7]
(Production of Compound (4))
100 mg of compound (3) is dissolved in 2 mL of tetrahydrofuran, cooled to −78 ° C., 0.2 mL of a tetrahydrofuran solution (1M) of lithium bistrimethylsilylamide is added dropwise, stirred at −78 ° C. for 30 minutes, and then added over 30 minutes. The temperature was raised to ° C. Next, the reaction solution was cooled again to −78 ° C., 0.07 mL of chlorotrimethylsilane was added dropwise, and the mixture was returned to room temperature and stirred for 1.5 hours. Subsequently, a saturated sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was dissolved in 1 mL of tetrahydrofuran and 2 mL of acetonitrile, 42.4 mg of palladium acetate was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was then filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to give 160 mg of compound (4) as a colorless solid (yield 89%).
It was as follows when the physical property of the obtained compound (4) was confirmed.
1H-NMR (400MHz, CDCl3) δppm: 7.37-7.32 (5H, m), 7.04 (1H, d, J = 10.2 Hz), 5.77 (1H, d, J = 10.2 Hz), 5.23 (1H, t, J = 3.2 Hz), 5.20 (1H, d, J = 12.2 Hz), 5.09 (1H, d, J = 12.2 Hz), 2.37-2.34 (1H, m), 2.15-2.09 (1H, m), 1.17 (3H, s), 1.152 (3H, d, J = 6.8Hz), 1.148 (3H, s), 1.139 (3H, s), 1.06 (3H, s), 0.75 (3H, s).
13C-NMR (100MHz, CDCl3) δppm: 202.1, 176.7, 159.1, 144.9, 136.3, 128.4, 127.99, 127.97, 125.4, 121.8, 66.0, 51.5, 48.4, 44.3, 42.7, 42.2, 42.0, 40.52, 40.45, 39.5, 38.3, 32.1, 31.8, 31.4, 28.6, 28.2, 26.9, 26.0, 25.9, 23.8, 21.1, 17.4, 15.7, 12.5.
MS (ESI-TOF) [M + H]+ 529.3698.
1 H-NMR (400MHz, CDCl 3 ) δppm: 7.37-7.32 (5H, m), 7.04 (1H, d, J = 10.2 Hz), 5.77 (1H, d, J = 10.2 Hz), 5.23 (1H, t , J = 3.2 Hz), 5.20 (1H, d, J = 12.2 Hz), 5.09 (1H, d, J = 12.2 Hz), 2.37-2.34 (1H, m), 2.15-2.09 (1H, m), 1.17 (3H, s), 1.152 (3H, d, J = 6.8Hz), 1.148 (3H, s), 1.139 (3H, s), 1.06 (3H, s), 0.75 (3H, s).
13 C-NMR (100 MHz, CDCl 3 ) δppm: 202.1, 176.7, 159.1, 144.9, 136.3, 128.4, 127.99, 127.97, 125.4, 121.8, 66.0, 51.5, 48.4, 44.3, 42.7, 42.2, 42.0, 40.52, 40.45, 39.5, 38.3, 32.1, 31.8, 31.4, 28.6, 28.2, 26.9, 26.0, 25.9, 23.8, 21.1, 17.4, 15.7, 12.5.
MS (ESI-TOF) [M + H] + 529.3698.
［実施例８］
（化合物（５）の製造）
化合物（４）３００ｍｇをテトラヒドロフラン６ｍＬに溶かし、−７８℃に冷却して、リチウムビストリメチルシリルアミドのテトラヒドロフラン溶液（１Ｍ）を６ｍＬ滴下し、−７８℃で３０分撹拌後、３０分かけて０℃まで昇温した。次いで、反応液を再度−７８℃に冷却し、重水素化ヨードメタン１．２ｍＬを滴下して、室温に戻して３時間撹拌した。次いで、反応液に飽和炭酸水素ナトリウム溶液を加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥した後、減圧濃縮し、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２０：１）で精製し、２９０ｍｇの化合物（５）を無色固体として得た（収率９３％）。
得られた化合物（５）の物性を確認したところ、以下のようであった。
[Example 8]
(Production of Compound (5))
300 mg of compound (4) is dissolved in 6 mL of tetrahydrofuran, cooled to −78 ° C., 6 mL of a tetrahydrofuran solution (1M) of lithium bistrimethylsilylamide is added dropwise, stirred at −78 ° C. for 30 minutes, and then until 0 ° C. over 30 minutes. The temperature rose. Next, the reaction solution was cooled again to −78 ° C., 1.2 mL of deuterated iodomethane was added dropwise, and the mixture was returned to room temperature and stirred for 3 hours. Next, a saturated sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1), and 290 mg of Compound (5) was obtained as a colorless solid (yield 93%).
When the physical property of the obtained compound (5) was confirmed, it was as follows.
1H-NMR (400MHz, CDCl3) δppm: 7.35-7.31 (5H, m), 7.04 (1H, d, J = 10.0 Hz), 5.80 (1H, d, J = 10.0 Hz), 5.23 (1H, t, J = 3.4 Hz), 5.20 (1H, d, J = 12.2 Hz), 5.09 (1H, d, J = 12.2 Hz), 1.18 (3H, s), 1.15 (3H, s), 1.14 (3H, s), 1.10 (3H, s), 1.04 (3H, s), 0.75 (3H, s).
13C-NMR (100MHz,CDCl3) δppm: 205.2 176.7, 159.0, 144.7, 136.3, 128.4, 127.99, 127.97, 124.9, 121.7, 66.0, 53.4, 48.3, 44.4, 44.2, 42.6, 41.9, 41.8, 40.6, 39.4, 38.2, 32.5, 32.0, 31.4, 28.6, 28.2, 26.9, 26.1, 25.9, 23.5, 21.6, 19.0, 18.8, 17.4.
MS (ESI-TOF) [M + H]+ 546.4013.
1 H-NMR (400MHz, CDCl 3 ) δppm: 7.35-7.31 (5H, m), 7.04 (1H, d, J = 10.0 Hz), 5.80 (1H, d, J = 10.0 Hz), 5.23 (1H, t , J = 3.4 Hz), 5.20 (1H, d, J = 12.2 Hz), 5.09 (1H, d, J = 12.2 Hz), 1.18 (3H, s), 1.15 (3H, s), 1.14 (3H, s ), 1.10 (3H, s), 1.04 (3H, s), 0.75 (3H, s).
13 C-NMR (100 MHz, CDCl 3 ) δppm: 205.2 176.7, 159.0, 144.7, 136.3, 128.4, 127.99, 127.97, 124.9, 121.7, 66.0, 53.4, 48.3, 44.4, 44.2, 42.6, 41.9, 41.8, 40.6, 39.4 , 38.2, 32.5, 32.0, 31.4, 28.6, 28.2, 26.9, 26.1, 25.9, 23.5, 21.6, 19.0, 18.8, 17.4.
MS (ESI-TOF) [M + H] + 546.4013.
［実施例９］
（化合物（６ａ）の製造）
化合物（５）１４０ｍｇを酢酸エチル１ｍＬとエタノール１ｍＬの混合溶媒に溶かし、パラジウムカーボン４０ｍｇを加えて、水素雰囲気下１５時間撹拌した。次いで、反応液をろ過後、減圧濃縮し、１１４ｍｇの化合物（６ａ）を白色結晶として得た（収率９７％）。
得られた化合物（６ａ）の物性を確認したところ、以下のようであった。
[Example 9]
(Production of Compound (6a))
140 mg of compound (5) was dissolved in a mixed solvent of 1 mL of ethyl acetate and 1 mL of ethanol, 40 mg of palladium carbon was added, and the mixture was stirred under a hydrogen atmosphere for 15 hours. Then, the reaction solution was filtered and concentrated under reduced pressure to obtain 114 mg of the compound (6a) as white crystals (yield 97%).
When the physical property of the obtained compound (6a) was confirmed, it was as follows.
融点；265-267℃.
1H-NMR (400MHz, CDCl3) δppm: 5.25 (1H, t, J = 3.5 Hz), 2.58-2.54 (1H, m), 2.39-2.35 (1H, m), 1.14 (3H, s), 1.08 (3H, s), 1.01 (3H, s), 0.99 (3H, s), 0.95 (3H, s), 0.76 (3H, s).
13C-NMR (100MHz, CDCl3) δppm:. 217.7, 182.9, 144.2, 122.5, 55.3, 48.1, 47.3, 46.9, 44.1, 42.6, 41.7, 39.8, 39.4, 38.3, 36.7, 34.3, 32.2, 32.1, 31.1, 28.8, 28.2, 27.0, 26.2, 25.9, 23.7, 21.5, 19.7, 16.8, 15.3.
MS (ESI-TOF) [M + H]+ 458.3739.
Melting point: 265-267 ° C.
1 H-NMR (400MHz, CDCl 3 ) δppm: 5.25 (1H, t, J = 3.5 Hz), 2.58-2.54 (1H, m), 2.39-2.35 (1H, m), 1.14 (3H, s), 1.08 (3H, s), 1.01 (3H, s), 0.99 (3H, s), 0.95 (3H, s), 0.76 (3H, s).
13 C-NMR (100 MHz, CDCl 3 ) δppm: 217.7, 182.9, 144.2, 122.5, 55.3, 48.1, 47.3, 46.9, 44.1, 42.6, 41.7, 39.8, 39.4, 38.3, 36.7, 34.3, 32.2, 32.1, 31.1 , 28.8, 28.2, 27.0, 26.2, 25.9, 23.7, 21.5, 19.7, 16.8, 15.3.
MS (ESI-TOF) [M + H] + 458.3739.
［実施例１０］
（化合物（７ａ）の製造）
化合物（６ａ）４６ｍｇを、ジクロロメタン１ｍＬ、アセトニトリル１ｍＬ及びピリジン０．５ｍＬの混合溶媒に溶かし、ヨウ化銅１．９ｍｇとｔ−ブチルヒドロペルオキシド７０％溶液０．３ｍＬを加えて、４０℃で２４時間加熱撹拌した。次いで、反応液に５％塩酸を加え、クロロホルムで抽出し、５％塩酸で洗浄して、無水硫酸ナトリウムで乾燥した後、減圧濃縮後し、シリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：１）で精製し、３０ｍｇの化合物（７ａ）を白色結晶として得た（収率６３％）。
得られた化合物（７ａ）の物性を確認したところ、以下のようであった。
[Example 10]
(Production of Compound (7a))
Compound (6a) (46 mg) is dissolved in a mixed solvent of dichloromethane (1 mL), acetonitrile (1 mL) and pyridine (0.5 mL), and copper iodide (1.9 mg) and t-butyl hydroperoxide (70% solution) are added thereto at 40 ° C. for 24 hours. Stir with heating. Next, 5% hydrochloric acid was added to the reaction solution, extracted with chloroform, washed with 5% hydrochloric acid, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and silica gel column chromatography (chloroform: methanol = 100: 1). To obtain 30 mg of the compound (7a) as white crystals (yield 63%).
When the physical property of the obtained compound (7a) was confirmed, it was as follows.
融点；283-286℃.
1H-NMR (400MHz, CDCl3) δppm: 5.74 (1H, s), 3.00-2.94 (1H, m), 2.68-2.60 (1H, m), 2.45 (1H, s), 2.36-2.33 (1H, m), 2.24-2.20 (1H, m), 1.38 (3H, s), 1.28 (3H, s), 1.23 (3H, s), 1.17 (3H, s), 1.07 (3H, s), 0.86 (3H, s).
13C-NMR (100MHz, CDCl3) δppm: 217.1, 199.4, 181.7, 169.6, 128.4, 61.1, 55.4, 48.3, 47.6, 45.3, 43.9, 43.4, 41.0, 39.8, 37.8, 36.8, 34.3, 32.2, 31.9, 31.0, 28.6, 28.5, 26.6, 26.5, 23.4, 21.4, 18.9, 18.6, 15.7.
MS (ESI-TOF) [M + H]+ 472.3481.
Melting point: 283-286 ° C.
1 H-NMR (400MHz, CDCl 3 ) δppm: 5.74 (1H, s), 3.00-2.94 (1H, m), 2.68-2.60 (1H, m), 2.45 (1H, s), 2.36-2.33 (1H, m), 2.24-2.20 (1H, m), 1.38 (3H, s), 1.28 (3H, s), 1.23 (3H, s), 1.17 (3H, s), 1.07 (3H, s), 0.86 (3H , s).
13 C-NMR (100 MHz, CDCl 3 ) δppm: 217.1, 199.4, 181.7, 169.6, 128.4, 61.1, 55.4, 48.3, 47.6, 45.3, 43.9, 43.4, 41.0, 39.8, 37.8, 36.8, 34.3, 32.2, 31.9, 31.0, 28.6, 28.5, 26.6, 26.5, 23.4, 21.4, 18.9, 18.6, 15.7.
MS (ESI-TOF) [M + H] + 472.3481.
［実施例１１］
（標識化グリチルレチン酸（８ａ）の製造）
化合物（７ａ）５８ｍｇをテトラヒドロフラン１ｍＬとメタノール１ｍＬの混合溶媒に溶かし、水素化ホウ素ナトリウム１４ｍｇを加えて、室温で1時間撹拌した。次いで、反応液に５％塩酸を加え、酢酸エチルで抽出し、飽和塩化ナトリウム溶液で洗浄して、無水硫酸ナトリウムで乾燥した後、減圧濃縮し、シリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：１）で精製し、５０ｍｇの標識化グリチルレチン酸（８ａ）を白色結晶として得た（収率８６％）。
得られた標識化グリチルレチン酸（８ａ）の物性を確認したところ、以下のようであった。
[Example 11]
(Production of labeled glycyrrhetinic acid (8a))
58 mg of compound (7a) was dissolved in a mixed solvent of 1 mL of tetrahydrofuran and 1 mL of methanol, 14 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 1 hour. Next, 5% hydrochloric acid was added to the reaction solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and silica gel column chromatography (chloroform: methanol = 100: 1). To obtain 50 mg of labeled glycyrrhetinic acid (8a) as white crystals (yield 86%).
It was as follows when the physical property of the obtained labeled glycyrrhetic acid (8a) was confirmed.
融点；287-290℃.
1H-NMR (400MHz, CDCl3) δppm: 5.70 (1H, s), 3.23 (1H, dd, J = 10.7, 5.4 Hz), 2.79 (1H, dt, J = 13.4, 3.4 Hz), 2.35 (1H, s), 2.20-2.17 (1H, m), 1.37 (3H, s), 1.22 (3H, s), 1.14 (3H, s), 1.13 (3H, s), 0.84 (3H, s), 0.80 (3H, s).
13C-NMR (100MHz, CDCl3) δppm: 200.3, 181.1, 169.2, 128.4, 78.8, 61.8, 54.9, 48.3, 45.5, 43.8, 43.3, 41.0, 39.2, 38.9, 37.8, 37.1, 32.8, 31.9, 31.0, 28.6, 28.5, 27.3, 26.6, 26.5, 23.5, 18.8, 17.6, 16.4, 15.6.
MS (ESI-TOF) [M + H]+ 474.3637.
Melting point: 287-290 ° C.
1 H-NMR (400MHz, CDCl 3 ) δppm: 5.70 (1H, s), 3.23 (1H, dd, J = 10.7, 5.4 Hz), 2.79 (1H, dt, J = 13.4, 3.4 Hz), 2.35 (1H , s), 2.20-2.17 (1H, m), 1.37 (3H, s), 1.22 (3H, s), 1.14 (3H, s), 1.13 (3H, s), 0.84 (3H, s), 0.80 ( 3H, s).
13 C-NMR (100 MHz, CDCl 3 ) δppm: 200.3, 181.1, 169.2, 128.4, 78.8, 61.8, 54.9, 48.3, 45.5, 43.8, 43.3, 41.0, 39.2, 38.9, 37.8, 37.1, 32.8, 31.9, 31.0, 28.6, 28.5, 27.3, 26.6, 26.5, 23.5, 18.8, 17.6, 16.4, 15.6.
MS (ESI-TOF) [M + H] + 474.3637.
［実施例１２］
（化合物（６ｂ）の製造）
化合物（５）１００ｍｇをベンゼン１ｍＬとエタノール１ｍＬの混合溶媒に溶かし、クロロトリストリフェニルホスフィンロジウム８５ｍｇを加え、室温で水素雰囲気下２４時間撹拌した。次いで、反応液をろ過した後、減圧濃縮し、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１）で精製し、８６ｍｇの化合物（６ｂ）を無色固体として得た（収率９６％）。
得られた化合物（６ｂ）の物性を確認したところ、以下のようであった。
[Example 12]
(Production of Compound (6b))
100 mg of compound (5) was dissolved in a mixed solvent of 1 mL of benzene and 1 mL of ethanol, 85 mg of chlorotristriphenylphosphine rhodium was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 24 hours. Then, the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 86 mg of compound (6b) as a colorless solid (yield 96%).
When the physical property of the obtained compound (6b) was confirmed, it was as follows.
1H-NMR (400MHz, CDCl3) δppm: 7.29-7.24 (5H, m), 5.19 (1H, d, J = 12.4 Hz), 5.11 (1H, t, J = 3.9 Hz), 5.08 (1H, d, J = 12.4 Hz), 2.48 (1H, ddd, J = 17.1, 9.9, 6.0 Hz), 2.31-2.27 (1H, m), 1.07 (3H, s), 1.06 (3H, s), 1.00 (3H, s), 0.98 (3H, s), 0.93 (3H, s), 0.67 (3H, s).
13C-NMR (100MHz, CDCl3) δppm: 217.6, 176.7, 144.3, 136.3, 128.4, 128.0, 127.9, 122.3, 66.0, 55.3, 48.2, 47.3, 46.9, 44.3, 42.8, 41.7, 39.8, 39.4, 38.3, 36.7, 34.2, 32.2, 32.0, 31.4, 28.6, 28.2, 27.0, 26.2, 25.9, 23.7, 21.5, 19.7, 16.8, 15.3, 14.3.
1 H-NMR (400MHz, CDCl 3 ) δppm: 7.29-7.24 (5H, m), 5.19 (1H, d, J = 12.4 Hz), 5.11 (1H, t, J = 3.9 Hz), 5.08 (1H, d , J = 12.4 Hz), 2.48 (1H, ddd, J = 17.1, 9.9, 6.0 Hz), 2.31-2.27 (1H, m), 1.07 (3H, s), 1.06 (3H, s), 1.00 (3H, s), 0.98 (3H, s), 0.93 (3H, s), 0.67 (3H, s).
13 C-NMR (100 MHz, CDCl 3 ) δppm: 217.6, 176.7, 144.3, 136.3, 128.4, 128.0, 127.9, 122.3, 66.0, 55.3, 48.2, 47.3, 46.9, 44.3, 42.8, 41.7, 39.8, 39.4, 38.3, 36.7, 34.2, 32.2, 32.0, 31.4, 28.6, 28.2, 27.0, 26.2, 25.9, 23.7, 21.5, 19.7, 16.8, 15.3, 14.3.
［実施例１３］
（化合物（７ｂ）の製造）
化合物（６ｂ）９６ｍｇをジクロロメタン１ｍＬ、アセトニトリル１ｍＬ及びピリジン０．５ｍＬの混合溶媒に溶かし、ヨウ化銅１．７ｍｇとｔ−ブチルヒドロペルオキシド７０％溶液０．５ｍＬを加えて、室温で２４時間撹拌した。次いで、反応液に５％塩酸を加え、クロロホルムで抽出し、５％塩酸で洗浄して、無水硫酸ナトリウムで乾燥した後、減圧濃縮し、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１）で精製し、５０ｍｇの化合物（７ｂ）を無色固体として得た（収率５１％）。
得られた化合物（７ｂ）の物性を確認したところ、以下のようであった。
[Example 13]
(Production of Compound (7b))
96 mg of compound (6b) was dissolved in a mixed solvent of 1 mL of dichloromethane, 1 mL of acetonitrile and 0.5 mL of pyridine, 1.7 mg of copper iodide and 0.5 mL of a 70% solution of t-butyl hydroperoxide were added, and the mixture was stirred at room temperature for 24 hours. . Next, 5% hydrochloric acid was added to the reaction solution, extracted with chloroform, washed with 5% hydrochloric acid, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and silica gel column chromatography (hexane: ethyl acetate = 10: 1). To give 50 mg of compound (7b) as a colorless solid (yield 51%).
When the physical property of the obtained compound (7b) was confirmed, it was as follows.
1H-NMR (400MHz, CDCl3) δppm: 7.40-7.31 (5H, m), 5.58 (1H, s), 5.20 (1H, d, J = 12.2 Hz), 5.09 (1H, d, J = 12.2 Hz), 2.97-2.94 (1H, m), 2.65-2.61 (1H, m), 2.42 (1H, s), 2.37-2.33 (1H, m), 1.36 (3H, s), 1.27 (3H, s), 1.16 (3H, s), 1.15 (3H, s), 1.06 (3H, s), 0.75 (3H, s).
13C-NMR (100MHz, CDCl3) δppm: 216.9, 199.1, 176.0, 169.3, 136.0, 128.5, 128.3, 128.2, 128.1, 66.2, 61.0, 55.4, 48.2, 47.6, 45.2, 44.0, 43.3, 41.2, 39.8, 37.7, 36.7, 34.2, 32.2, 31.8, 31.2, 28.5, 28.3, 26.6, 26.4, 23.3, 21.4, 18.8, 18.6, 15.7.
1 H-NMR (400MHz, CDCl 3 ) δppm: 7.40-7.31 (5H, m), 5.58 (1H, s), 5.20 (1H, d, J = 12.2 Hz), 5.09 (1H, d, J = 12.2 Hz ), 2.97-2.94 (1H, m), 2.65-2.61 (1H, m), 2.42 (1H, s), 2.37-2.33 (1H, m), 1.36 (3H, s), 1.27 (3H, s), 1.16 (3H, s), 1.15 (3H, s), 1.06 (3H, s), 0.75 (3H, s).
13 C-NMR (100 MHz, CDCl 3 ) δppm: 216.9, 199.1, 176.0, 169.3, 136.0, 128.5, 128.3, 128.2, 128.1, 66.2, 61.0, 55.4, 48.2, 47.6, 45.2, 44.0, 43.3, 41.2, 39.8, 37.7, 36.7, 34.2, 32.2, 31.8, 31.2, 28.5, 28.3, 26.6, 26.4, 23.3, 21.4, 18.8, 18.6, 15.7.
［実施例１４］
（化合物９の製造）
化合物（７ｂ）５０ｍｇをテトラヒドロフラン１ｍＬとメタノール１ｍＬの混合溶媒に溶かし、水素化ホウ素ナトリウム１０ｍｇを加えて、室温で４時間撹拌した。次いで、反応液に５％塩酸を加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥した後、減圧濃縮し、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１）で精製し、４６ｍｇの化合物（９）を無色固体として得た（収率９１％）。
得られた化合物（９）の物性を確認したところ、以下のようであった。
[Example 14]
(Production of Compound 9)
50 mg of compound (7b) was dissolved in a mixed solvent of 1 mL of tetrahydrofuran and 1 mL of methanol, 10 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 4 hours. Next, 5% hydrochloric acid was added to the reaction solution, extracted with chloroform, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 46 mg of compound ( 9) was obtained as a colorless solid (91% yield).
It was as follows when the physical property of the obtained compound (9) was confirmed.
1H-NMR (400MHz, CDCl3) δppm: 7.36-7.33 (5H, m), 5.54 (1H, s), 5.19 (1H, d, J = 12.2 Hz), 5.08 (1H, d, J = 12.2 Hz), 3.22 (1H, dd, J = 10.9, 5.6 Hz), 2.78 (1H, dt, J = 13.4, 3.4 Hz), 2.31 (1H, s), 1.35 (3H, s), 1.16 (3H, s), 1.13 (3H, s), 1.11 (3H, s), 0.80 (3H, s), 0.73 (3H, s).
13C-NMR (100MHz, CDCl3) δppm: 199.9, 176.0, 168.8, 136.0, 128.5, 128.4, 128.2, 128.1, 78.7, 66.2, 61.8, 54.9, 48.2, 45.4, 44.0, 43.2, 41.1, 39.2, 38.9, 37.7, 37.1, 32.8, 31.8, 31.2, 28.4, 28.3, 27.3, 26.5, 26.5, 23.4, 18.7, 17.6, 16.4, 15.6.
1 H-NMR (400MHz, CDCl 3 ) δppm: 7.36-7.33 (5H, m), 5.54 (1H, s), 5.19 (1H, d, J = 12.2 Hz), 5.08 (1H, d, J = 12.2 Hz ), 3.22 (1H, dd, J = 10.9, 5.6 Hz), 2.78 (1H, dt, J = 13.4, 3.4 Hz), 2.31 (1H, s), 1.35 (3H, s), 1.16 (3H, s) , 1.13 (3H, s), 1.11 (3H, s), 0.80 (3H, s), 0.73 (3H, s).
13 C-NMR (100 MHz, CDCl 3 ) δppm: 199.9, 176.0, 168.8, 136.0, 128.5, 128.4, 128.2, 128.1, 78.7, 66.2, 61.8, 54.9, 48.2, 45.4, 44.0, 43.2, 41.1, 39.2, 38.9, 37.7, 37.1, 32.8, 31.8, 31.2, 28.4, 28.3, 27.3, 26.5, 26.5, 23.4, 18.7, 17.6, 16.4, 15.6.
本発明は、グリチルリチン及びグリチルレチン酸の薬理作用を発現する際の作用機序や生体内代謝の解析に利用可能である。特に医薬品開発に有用である。 INDUSTRIAL APPLICATION This invention can be utilized for the analysis of the action mechanism at the time of expressing the pharmacological action of glycyrrhizin and glycyrrhetinic acid, and in vivo metabolism. It is particularly useful for drug development.
Claims (17)
下記式（２ａ）で表される化合物に、ヒドロキシルアミン塩酸塩を作用させて下記式（２ｂ）で表される化合物とし、
下記式（２ｂ）で表される化合物に、酢酸ナトリウム及び塩化パラジウム二ナトリウムを作用させ、次いで無水酢酸を作用させ、次いで四酢酸鉛を作用させてから水素化ホウ素ナトリウムを作用させて下記式（２ｃ）で表される化合物とし、
下記式（２ｃ）で表される化合物に塩基を作用させて下記式（２ｄ）で表される化合物とし、
下記式（２ｄ）で表される化合物に、トリクロロチタン及び酢酸アンモニウムを作用させて下記式（２ｅ）で表される化合物とし、
下記式（２ｅ）で表される化合物に塩基を作用させて下記式（３）で表される化合物とし、
下記式（３）で表される化合物に、リチウムビストリメチルシリルアミドを作用させ、次いでクロロトリメチルシランを作用させ、次いで酢酸パラジウムを作用させて下記式（４）で表される化合物とし、
下記式（４）で表される化合物に、リチウムビストリメチルシリルアミドを作用させ、次いで一般式「ＣＤ３Ｌ」で表される化合物（「Ｌ」はハロゲン原子を表す）を作用させて下記式（５）で表される化合物とする、
ことを特徴とする下記式（５）で表される化合物の製造方法。
Hydroxylamine hydrochloride is allowed to act on the compound represented by the following formula (2a) to obtain a compound represented by the following formula (2b).
To the compound represented by the following formula (2b), sodium acetate and disodium palladium chloride are allowed to act, then acetic anhydride is allowed to act, then lead tetraacetate is allowed to act, and then sodium borohydride is allowed to act. A compound represented by 2c),
A base is allowed to act on the compound represented by the following formula (2c) to obtain a compound represented by the following formula (2d),
A compound represented by the following formula (2e) is prepared by allowing trichlorotitanium and ammonium acetate to act on the compound represented by the following formula (2d).
A base is allowed to act on the compound represented by the following formula (2e) to obtain a compound represented by the following formula (3),
Lithium bistrimethylsilylamide is allowed to act on the compound represented by the following formula (3), then chlorotrimethylsilane is allowed to act, and then palladium acetate is allowed to act to obtain a compound represented by the following formula (4).
Lithium bistrimethylsilylamide is allowed to act on a compound represented by the following formula (4), and then a compound represented by the general formula “CD 3 L” (“L” represents a halogen atom) is allowed to act on the compound represented by the following formula ( A compound represented by 5),
The manufacturing method of the compound represented by following formula (5) characterized by the above-mentioned.
下記式（６ａ）で表される化合物にヨウ化銅及びｔ−ブチルヒドロペルオキシドを作用させて下記式（７ａ）で表される化合物とし、
下記式（７ａ）で表される化合物に水素化ホウ素ナトリウムを作用させて下記式（８ａ）で表される標識化されたグリチルレチン酸とする、
ことを特徴とする標識化グリチルレチン酸の製造方法。
The compound represented by the following formula (6a) is allowed to act on copper iodide and t-butyl hydroperoxide to obtain a compound represented by the following formula (7a).
By allowing sodium borohydride to act on the compound represented by the following formula (7a), a labeled glycyrrhetinic acid represented by the following formula (8a) is obtained.
A method for producing a labeled glycyrrhetinic acid characterized by the above.
下記式（６ｂ）で表される化合物にヨウ化銅及びｔ−ブチルヒドロペルオキシドを作用させて下記式（７ｂ）で表される化合物とし、
下記式（７ｂ）で表される化合物に水素化ホウ素ナトリウムを作用させて下記式（９）で表される化合物とする、
ことを特徴とする下記式（９）で表される化合物の製造方法。
The compound represented by the following formula (6b) is allowed to act on copper iodide and t-butyl hydroperoxide to obtain a compound represented by the following formula (7b).
By allowing sodium borohydride to act on the compound represented by the following formula (7b), a compound represented by the following formula (9) is obtained.
The manufacturing method of the compound represented by following formula (9) characterized by the above-mentioned.
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |