JP7379415B2 - Method for producing catechin conjugate - Google Patents
Method for producing catechin conjugate Download PDFInfo
- Publication number
- JP7379415B2 JP7379415B2 JP2021092256A JP2021092256A JP7379415B2 JP 7379415 B2 JP7379415 B2 JP 7379415B2 JP 2021092256 A JP2021092256 A JP 2021092256A JP 2021092256 A JP2021092256 A JP 2021092256A JP 7379415 B2 JP7379415 B2 JP 7379415B2
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- JP
- Japan
- Prior art keywords
- compound
- catechin
- group
- reaction
- mol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 235000005487 catechin Nutrition 0.000 title claims description 36
- ADRVNXBAWSRFAJ-UHFFFAOYSA-N catechin Natural products OC1Cc2cc(O)cc(O)c2OC1c3ccc(O)c(O)c3 ADRVNXBAWSRFAJ-UHFFFAOYSA-N 0.000 title claims description 36
- 229950001002 cianidanol Drugs 0.000 title claims description 33
- PFTAWBLQPZVEMU-DZGCQCFKSA-N (+)-catechin Chemical compound C1([C@H]2OC3=CC(O)=CC(O)=C3C[C@@H]2O)=CC=C(O)C(O)=C1 PFTAWBLQPZVEMU-DZGCQCFKSA-N 0.000 title claims description 29
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 44
- -1 catechin compound Chemical group 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 239000002585 base Substances 0.000 claims description 14
- 150000001766 catechin derivatives Chemical class 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 150000001340 alkali metals Chemical group 0.000 claims description 4
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 3
- 150000001342 alkaline earth metals Chemical group 0.000 claims description 3
- 125000002367 glucuronosyl group Chemical group 0.000 claims description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 43
- 239000002904 solvent Substances 0.000 description 30
- 239000000203 mixture Substances 0.000 description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 23
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 230000015572 biosynthetic process Effects 0.000 description 19
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000012300 argon atmosphere Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000012156 elution solvent Substances 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 235000019253 formic acid Nutrition 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 6
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 6
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- 150000001765 catechin Chemical class 0.000 description 5
- 229940125797 compound 12 Drugs 0.000 description 5
- 230000021615 conjugation Effects 0.000 description 5
- 150000004673 fluoride salts Chemical class 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- 235000013824 polyphenols Nutrition 0.000 description 5
- 238000002953 preparative HPLC Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- PFTAWBLQPZVEMU-ZFWWWQNUSA-N (+)-epicatechin Natural products C1([C@@H]2OC3=CC(O)=CC(O)=C3C[C@@H]2O)=CC=C(O)C(O)=C1 PFTAWBLQPZVEMU-ZFWWWQNUSA-N 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 4
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 4
- GIWQSPITLQVMSG-UHFFFAOYSA-N 1,2-dimethylimidazole Chemical compound CC1=NC=CN1C GIWQSPITLQVMSG-UHFFFAOYSA-N 0.000 description 4
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical class FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 239000002841 Lewis acid Substances 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229940126543 compound 14 Drugs 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 229940097043 glucuronic acid Drugs 0.000 description 4
- 150000008282 halocarbons Chemical class 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 150000007517 lewis acids Chemical class 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- PFTAWBLQPZVEMU-UKRRQHHQSA-N (-)-epicatechin Chemical compound C1([C@H]2OC3=CC(O)=CC(O)=C3C[C@H]2O)=CC=C(O)C(O)=C1 PFTAWBLQPZVEMU-UKRRQHHQSA-N 0.000 description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 3
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 3
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 3
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940125758 compound 15 Drugs 0.000 description 3
- 229940126142 compound 16 Drugs 0.000 description 3
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 3
- 239000004210 ether based solvent Substances 0.000 description 3
- 230000023611 glucuronidation Effects 0.000 description 3
- 229930182480 glucuronide Natural products 0.000 description 3
- 150000008134 glucuronides Chemical class 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- 230000011987 methylation Effects 0.000 description 3
- 238000007069 methylation reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 230000019635 sulfation Effects 0.000 description 3
- 238000005670 sulfation reaction Methods 0.000 description 3
- 125000005270 trialkylamine group Chemical group 0.000 description 3
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 3
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- WZKSXHQDXQKIQJ-UHFFFAOYSA-N F[C](F)F Chemical compound F[C](F)F WZKSXHQDXQKIQJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical group OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- YNLAOSYQHBDIKW-UHFFFAOYSA-M diethylaluminium chloride Chemical compound CC[Al](Cl)CC YNLAOSYQHBDIKW-UHFFFAOYSA-M 0.000 description 2
- 235000012734 epicatechin Nutrition 0.000 description 2
- LPTRNLNOHUVQMS-UHFFFAOYSA-N epicatechin Natural products Cc1cc(O)cc2OC(C(O)Cc12)c1ccc(O)c(O)c1 LPTRNLNOHUVQMS-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- 150000002206 flavan-3-ols Chemical group 0.000 description 2
- 150000004687 hexahydrates Chemical class 0.000 description 2
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910000000 metal hydroxide Inorganic materials 0.000 description 2
- 150000004692 metal hydroxides Chemical class 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- DICCNWCUKCYGNF-QYESYBIKSA-N methyl alpha-D-glucopyranuronate Chemical compound COC(=O)[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O DICCNWCUKCYGNF-QYESYBIKSA-N 0.000 description 2
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 2
- 239000012022 methylating agents Substances 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 2
- 238000012924 normal-phase thin-layer chromatography Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 150000004686 pentahydrates Chemical class 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- 229930013915 (+)-catechin Natural products 0.000 description 1
- 235000007219 (+)-catechin Nutrition 0.000 description 1
- 235000007246 (+)-epicatechin Nutrition 0.000 description 1
- 235000007331 (-)-catechin Nutrition 0.000 description 1
- 229930013799 (-)-catechin Natural products 0.000 description 1
- PFTAWBLQPZVEMU-HIFRSBDPSA-N (-)-catechin Chemical compound C1([C@@H]2OC3=CC(O)=CC(O)=C3C[C@H]2O)=CC=C(O)C(O)=C1 PFTAWBLQPZVEMU-HIFRSBDPSA-N 0.000 description 1
- 235000007355 (-)-epicatechin Nutrition 0.000 description 1
- 229930013783 (-)-epicatechin Natural products 0.000 description 1
- MFQWRQASGSRKAJ-UHFFFAOYSA-N 1,1,1-trichloro-2-chlorosulfonyloxyethane Chemical compound ClC(Cl)(Cl)COS(Cl)(=O)=O MFQWRQASGSRKAJ-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- FOMUQBCOZUHIAR-UHFFFAOYSA-N 1-chlorosulfonyloxy-2,2-dimethylpropane Chemical compound CC(C)(C)COS(Cl)(=O)=O FOMUQBCOZUHIAR-UHFFFAOYSA-N 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical compound OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- DDFHBQSCUXNBSA-UHFFFAOYSA-N 5-(5-carboxythiophen-2-yl)thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC=C1C1=CC=C(C(O)=O)S1 DDFHBQSCUXNBSA-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- CITFYDYEWQIEPX-UHFFFAOYSA-N Flavanol Natural products O1C2=CC(OCC=C(C)C)=CC(O)=C2C(=O)C(O)C1C1=CC=C(O)C=C1 CITFYDYEWQIEPX-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- NUGPIZCTELGDOS-QHCPKHFHSA-N N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclopentanecarboxamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CC[C@@H](C=1C=NC=CC=1)NC(=O)C1CCCC1)C NUGPIZCTELGDOS-QHCPKHFHSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 241001122767 Theaceae Species 0.000 description 1
- IBUZGVQIKARDAF-RGDJUOJXSA-N [(2r,3r,4s,5r,6s)-3,4,5-triacetyloxy-6-(2,2,2-trichloroethanimidoyl)oxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1O[C@@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O IBUZGVQIKARDAF-RGDJUOJXSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004403 catechin group Chemical group 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- CXQWRCVTCMQVQX-UHFFFAOYSA-N cis-dihydroquercetin Natural products O1C2=CC(O)=CC(O)=C2C(=O)C(O)C1C1=CC=C(O)C(O)=C1 CXQWRCVTCMQVQX-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000011987 flavanols Nutrition 0.000 description 1
- 150000004674 formic acids Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- KWNIVSQDHXVNAL-HKLXJQGRSA-N methyl (2s,3s,4s,5r,6r)-3,4,5-triacetyloxy-6-(2,2,2-trichloroethanimidoyl)oxyoxane-2-carboxylate Chemical compound COC(=O)[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O KWNIVSQDHXVNAL-HKLXJQGRSA-N 0.000 description 1
- GWTNLHGTLIBHHZ-SVNGYHJRSA-N methyl (2s,3s,4s,5r,6r)-3,4,5-triacetyloxy-6-bromooxane-2-carboxylate Chemical compound COC(=O)[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O GWTNLHGTLIBHHZ-SVNGYHJRSA-N 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002715 modification method Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- IARSSOVWSJAVSZ-UHFFFAOYSA-N tris(dimethylamino)sulfanium Chemical compound CN(C)[S+](N(C)C)N(C)C IARSSOVWSJAVSZ-UHFFFAOYSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
- C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/06—Benzopyran radicals
- C07H17/065—Benzo[b]pyrans
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Description
本発明はカテキン抱合体の製造方法及びその製造中間体に関する。 The present invention relates to a method for producing a catechin conjugate and an intermediate for producing the same.
茶葉に含まれるカテキン類は、コレステロール上昇抑制作用、体脂肪燃焼作用等、様々な優れた生理活性機能を有することが知られている。 Catechins contained in tea leaves are known to have various excellent physiologically active functions, such as suppressing cholesterol rise and burning body fat.
体内に吸収されたカテキン類は、遊離の状態の他、グルクロン酸抱合体、硫酸抱合体、メチル抱合体等の抱合体として存在することが知られている。したがって、斯かる抱合体の体内動態や生物学的活性を検証することはカテキン類の有用性を探る上でも重要である。しかしながら、斯かる代謝物を血液や尿等の体液から直接単離することによっては当該化合物を十分な量で得ることは困難であり、それらを化学的に合成することが求められる。 It is known that catechins absorbed into the body exist not only in a free state but also as conjugates such as glucuronide conjugates, sulfate conjugates, and methyl conjugates. Therefore, it is important to examine the pharmacokinetics and biological activity of such conjugates in exploring the usefulness of catechins. However, it is difficult to obtain a sufficient amount of such metabolites by directly isolating them from body fluids such as blood or urine, and it is necessary to synthesize them chemically.
カテキン又はエピカテキンの抱合体を化学的に合成する手法としては、カテキン類を過剰量の抱合試薬で非選択的に処理し、得られた生成物を分離する方法の他、安価なバルク出発材料を使用し、カップリングによってカテキン骨格を構築する全合成法（例えば、非特許文献１、特許文献１）や、カテキン又はエピカテキンを出発原料としてフェノール基水酸基を選択的に保護し、特定部位を抱合化する半合成法が存在する。全合成法では合成工程数が長いことに加え、不斉中心の構築も必要になるという課題があり、半合成法では水酸基の選択的保護及び脱保護が課題になる。
例えば、非特許文献２、３や特許文献２には、カテキンＡ環の水酸基をメチル基もしくはアシル基で保護することによりカテキンＡ環を修飾する方法が開示されている。しかしながら、これらのＡ環修飾法は、Ａ環のいずれか一方の水酸基の選択的保護に適するとは云えず、また脱保護する際の選択性も良いとは云えない。
Methods for chemically synthesizing conjugates of catechin or epicatechin include a method in which catechins are treated non-selectively with an excess amount of a conjugation reagent and the resulting product is separated, as well as a method using cheap bulk starting materials. A total synthesis method in which a catechin skeleton is constructed by coupling using catechin (e.g., Non-Patent Document 1, Patent Document 1), or a method in which catechin or epicatechin is used as a starting material to selectively protect the phenolic hydroxyl group and a specific site is protected. Semi-synthetic methods of conjugation exist. The total synthetic method requires a long number of synthesis steps and also requires the construction of an asymmetric center, while the semi-synthetic method poses the problem of selective protection and deprotection of hydroxyl groups.
For example, Non-Patent Documents 2 and 3 and Patent Document 2 disclose methods of modifying the catechin A ring by protecting the hydroxyl group of the catechin A ring with a methyl group or an acyl group. However, these A ring modification methods cannot be said to be suitable for selectively protecting either one of the hydroxyl groups of the A ring, nor can they be said to have good selectivity during deprotection.
本発明は、半合成法により、効率良くカテキン抱合体を製造する方法、及びその製造中間体を提供することに関する。 The present invention relates to a method for efficiently producing a catechin conjugate by a semi-synthetic method, and to providing an intermediate for the production.
本発明者らは、カテキンやエピカテキンカテキン等のカテキン化合物からカテキン抱合体を化学合成すべく検討したところ、以下に示すように、Ｂ環のフェノール性水酸基をベンジルオキシカルボニル基（Ｃｂｚ）で保護した後に、ｔｅｒｔ－ブチルジメチルシリル（ＴＢＳ）化剤を反応させると、Ａ環のフェノール性水酸基のいずれか一方のみをＴＢＳ化することができ、斯かるシリル化カテキン誘導体（ＩＩＩ）を経由して抱合反応を用いることにより、カテキン化合物の５位又は７位の水酸基を効率よく抱合化できることを見出した。 The present inventors investigated the chemical synthesis of catechin conjugates from catechin compounds such as catechin and epicatechin-catechin, and found that the phenolic hydroxyl group of ring B was protected with a benzyloxycarbonyl group (Cbz) as shown below. After that, by reacting with a tert-butyldimethylsilylation agent (TBS), only one of the phenolic hydroxyl groups of the A ring can be converted to TBS, and via the silylated catechin derivative (III), It has been found that by using a conjugation reaction, the 5- or 7-position hydroxyl group of a catechin compound can be efficiently conjugated.
〔式中、Ｒ１ａ及びＲ２ａはいずれか一方が水素原子で他方がＴＢＳ基を示し、Ｒ１ｂ及びＲ２ｂはいずれか一方がＣｂｚ基で他方がＴＢＳ基を示し、Ｒ１ｃ及びＲ２ｃはいずれか一方がＣｂｚ基で他方が水素原子を示し、Ｒ１ｄ及びＲ２ｄはいずれか一方が水素原子で他方がメチル基、グルクロノシル基、グルコシル基又は－ＳＯ３Ｍ（ここで、Ｍは水素原子、アルカリ金属原子、アルカリ土類金属原子又はアンモニウムを示す）を示す。また、Ｒ１ｂ及びＲ２ｂはＲ１ａ及びＲ２ａに、Ｒ１ｃ及びＲ２ｃはＲ１ｂ及びＲ２ｂに、Ｒ１ｄ及びＲ２ｄはＲ１ｃ及びＲ２ｃに、それぞれ対応する。〕 [In the formula, one of R 1a and R 2a is a hydrogen atom and the other is a TBS group, one of R 1b and R 2b is a Cbz group and the other is a TBS group, and R 1c and R 2c are One of them is a Cbz group and the other is a hydrogen atom, and one of R 1d and R 2d is a hydrogen atom and the other is a methyl group, glucuronosyl group, glucosyl group, or -SO 3 M (here, M is a hydrogen atom) , an alkali metal atom, an alkaline earth metal atom, or ammonium). Further, R 1b and R 2b correspond to R 1a and R 2a , R 1c and R 2c correspond to R 1b and R 2b , and R 1d and R 2d correspond to R 1c and R 2c , respectively. ]
すなわち、本発明は、以下の１）～３）に係るものである。
１）上記式（Ｉ）で表されるカテキン化合物の３′位又は４′位の水酸基をＣｂｚ化して式（ＩＩ）で表される化合物とし、次いで塩基の存在下ＴＢＳ化剤を反応させる、式（ＩＩＩ）で表されるシリル化カテキン誘導体の製造方法。
２）１）の方法により得られた式（ＩＩＩ）で表されるシリル化カテキン誘導体の水酸基をＣｂｚ化して式（ＩＶ）で表されるシリル化カテキン保護誘導体とし、次いで、ＴＢＳ基を脱離して式（Ｖ）で表される化合物とし、次いで、硫酸化、メチル化、グルクロン酸化及びグルコシル化から選ばれる抱合反応に付し、続いて保護基を脱離する、式（ＶＩ）で表されるカテキン抱合体の製造方法。
３）上記一般式（ＩＩＩ）で表されるシリル化カテキン誘導体又は一般式（ＩＶ）で表されるシリル化カテキン保護誘導体。
That is, the present invention relates to the following 1) to 3).
1) Cbz-forming the 3'- or 4'-position hydroxyl group of the catechin compound represented by formula (I) to obtain a compound represented by formula (II), and then reacting with a TBS-forming agent in the presence of a base. A method for producing a silylated catechin derivative represented by formula (III).
2) The hydroxyl group of the silylated catechin derivative represented by formula (III) obtained by the method of 1) is converted into a silylated catechin protected derivative represented by formula (IV) by Cbzation, and then the TBS group is removed. to form a compound represented by formula (V), which is then subjected to a conjugation reaction selected from sulfation, methylation, glucuronidation, and glucosylation, and then the protecting group is removed, and the compound represented by formula (VI) is A method for producing a catechin conjugate.
3) A silylated catechin derivative represented by the above general formula (III) or a silylated catechin protected derivative represented by the general formula (IV).
本発明のカテキン抱合体及びその製造中間体を簡易に効率よく製造することができる。 The catechin conjugate of the present invention and its production intermediate can be produced easily and efficiently.
以下に、本発明のカテキン抱合体の製造法について、各工程ごとに説明する。
本発明のカテキン抱合体の製造方法において、出発原料として用いられる下記式（Ｉ）：
Below, each step of the method for producing a catechin conjugate of the present invention will be explained.
In the method for producing a catechin conjugate of the present invention, the following formula (I) used as a starting material:
また、慣例に従い、フラバノール骨格の二つのベンゼン環をＡ環及びＢ環（カテコール部分）とし、両者を結ぶ３つの炭素原子と酸素原子から構成される環をＣ環と呼ぶ。
Further, according to custom, the two benzene rings of the flavanol skeleton are referred to as ring A and ring B (catechol moiety), and the ring consisting of three carbon atoms and an oxygen atom connecting the two is referred to as ring C.
１．工程－１
本工程は、カテキン化合物（Ｉ）の３´位又は４´位の水酸基をベンジルオキシカルボニル（「Ｃｂｚ」と略記する）化する工程である。 This step is a step in which the hydroxyl group at the 3'-position or 4'-position of the catechin compound (I) is converted to benzyloxycarbonyl (abbreviated as "Cbz").
本工程におけるＣｂｚ化は、現在公知のあらゆる方法を採用することができる。
Ｃｂｚ化試薬としては、例えば、クロロギ酸ベンジル（塩化ベンジルオキシカルボニル（Ｚ－Ｃｌ））を用いるＳｃｈｏｔｔｅｎ－Ｂａｕｍａｎｎ法のほか、ｐ－ニトロフェニルエステル（Ｚ－ＯＮｐ）、Ｎ－ヒドロキシスクシンイミドエステル（Ｚ－ＯＮＳｕ）を挙げることができるが、好ましくはクロロギ酸ベンジルである。
Ｃｂｚ化試薬の使用量は、化合物（Ｉ）１モルに対して、Ｃｂｚ化試薬の使用量は、収率を向上する点から通常１．５モル以上、好ましくは１．７モル以上、より好ましくは１．９モル以上、さらに好ましくは２．０モル以上である。また、Ｃｂｚ化試薬の使用量は、Ｂ環の水酸基を優先的にＣｂｚ化する点から、化合物（Ｉ）１モルに対して、、通常２．５モル以下、好ましくは２．４モル以下、より好ましくは２．２モル以下、さらに好ましくは２．１モル以下である。さらに、Ｃｂｚ化試薬の使用量は、化合物（Ｉ）１モルに対して、通常１．５～２．５モル、好ましくは１．７～２．４モル、さらに好ましくは１．９～２．２モル、さらに好ましくは２．０～２．１モルである。
For Cbz conversion in this step, any currently known method can be employed.
Examples of Cbzation reagents include the Schotten-Baumann method using benzyl chloroformate (benzyloxycarbonyl chloride (Z-Cl)), p-nitrophenyl ester (Z-ONp), N-hydroxysuccinimide ester (Z- ONSu), preferably benzyl chloroformate.
The amount of Cbzation reagent used is usually 1.5 mol or more, preferably 1.7 mol or more, more preferably 1.5 mol or more, and more preferably 1.5 mol or more, per 1 mol of compound (I). is 1.9 mol or more, more preferably 2.0 mol or more. In addition, the amount of the Cbz-forming reagent to be used is usually 2.5 mol or less, preferably 2.4 mol or less, per 1 mol of compound (I), from the viewpoint of preferentially Cbz-forming the hydroxyl group of the B ring. More preferably it is 2.2 mol or less, and still more preferably 2.1 mol or less. Further, the amount of the Cbzation reagent to be used is generally 1.5 to 2.5 mol, preferably 1.7 to 2.4 mol, and more preferably 1.9 to 2.5 mol, per 1 mol of compound (I). The amount is 2 mol, more preferably 2.0 to 2.1 mol.
反応溶媒としては、ジクロロメタン、クロロホルム等の不活性ハロゲン化炭化水素系溶媒；トルエン等の不活性炭化水素系溶媒；エーテル、テトラヒドロフラン等の不活性エーテル系溶媒；ジメチルホルムアミド、ジメチルアセトアミドのようなアミド類；アセトニトリルのようなニトリル類等を挙げることができる。 Reaction solvents include inert halogenated hydrocarbon solvents such as dichloromethane and chloroform; inert hydrocarbon solvents such as toluene; inert ether solvents such as ether and tetrahydrofuran; amides such as dimethylformamide and dimethylacetamide. ; Examples include nitriles such as acetonitrile.
反応は、塩基の存在下に行われ、用いられる塩基としては、トリアルキルアミン（例えば、トリメチルアミン、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン等）、ピリジン、キノリン、ピペリジン、イミダゾール、ピコリン、４－ジメチルアミノピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルモルホリン、１，５－ジアザビシクロ［４．３．０］ノナ－５－エン（ＤＢＮ）、１，４－ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）等の有機塩基、炭酸カリウム等の無機塩基等が挙げられる。
塩基の使用量は、化合物（Ｉ）１モルに対して、通常１．５～２．５モル、好ましくは１．７～２．４モル、さらに好ましくは１．９０～２．２モル、さらに好ましくは２．００～２．１０モルである。
The reaction is carried out in the presence of a base, and the bases used include trialkylamines (for example, trimethylamine, triethylamine, N,N-diisopropylethylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, 4-dimethylamino Pyridine, N,N-dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO ), organic bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and inorganic bases such as potassium carbonate.
The amount of the base to be used is usually 1.5 to 2.5 mol, preferably 1.7 to 2.4 mol, more preferably 1.90 to 2.2 mol, and more preferably 1.90 to 2.2 mol, per 1 mol of compound (I). Preferably it is 2.00 to 2.10 mol.
反応温度としては、－２０～６０℃の範囲であり、０℃～室温の範囲が好ましい。
反応時間は、通常０．５～５時間程度であり、１～２時間程度が好ましい。
The reaction temperature ranges from -20 to 60°C, preferably from 0°C to room temperature.
The reaction time is usually about 0.5 to 5 hours, preferably about 1 to 2 hours.
２．工程－２
〔式中、Ｒ１ａ及びＲ２ａはいずれか一方が水素原子で他方がＴＢＳ基を示す。〕 [In the formula, one of R 1a and R 2a represents a hydrogen atom and the other represents a TBS group. ]
続いて、上記工程で得られた化合物（ＩＩ）のＡ環のフェノール性水酸基をｔｅｒｔ－ブチルジメチルシリル（「ＴＢＳ」と略記する）化し、シリル化カテキン誘導体（ＩＩＩ）を得る。当該誘導体（ＩＩＩ）は、文献未記載の新規化合物である。
ＴＢＳ化は、化合物（ＩＩ）を塩基の存在下でＴＢＳ化剤と反応させることにより行われる。
Subsequently, the phenolic hydroxyl group of the A ring of compound (II) obtained in the above step is converted to tert-butyldimethylsilyl (abbreviated as "TBS") to obtain a silylated catechin derivative (III). The derivative (III) is a new compound that has not been described in any literature.
TBS formation is carried out by reacting compound (II) with a TBS formation agent in the presence of a base.
溶媒としては、反応に悪影響を及ぼさないものであればよく、例えば、非プロトン性極性溶媒、ハロゲン化炭化水素系溶媒、或いはこれらの混合溶媒等が挙げられる。非プロトン性極性溶媒としては、例えばテトラヒドロフラン、アセトン、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド等が挙げられ、ハロゲン化炭化水素系溶媒としては、例えばジクロロメタン等が挙げられる。より好ましくはＮ，Ｎ－ジメチルホルムアミド、ジクロロメタンである。 The solvent may be any solvent that does not adversely affect the reaction, and examples thereof include aprotic polar solvents, halogenated hydrocarbon solvents, and mixed solvents thereof. Examples of the aprotic polar solvent include tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide, and examples of the halogenated hydrocarbon solvent include dichloromethane. More preferred are N,N-dimethylformamide and dichloromethane.
塩基としては、例えば、トリアルキルアミン（例えば、トリメチルアミン、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン等）、ピリジン、キノリン、ピペリジン、イミダゾール、ピコリン、４－ジメチルアミノピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルモルホリン、１，５－ジアザビシクロ［４．３．０］ノナ－５－エン（ＤＢＮ）、１，４－ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）等の有機塩基が挙げられ、イミダゾール、ピリジン等が挙げられ、好ましくはトリアルキルアミン、より好ましくはトリエチルアミンが挙げられる。 Examples of the base include trialkylamines (eg, trimethylamine, triethylamine, N,N-diisopropylethylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, 4-dimethylaminopyridine, N,N-dimethylaniline, N- Methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4 0] undec-7-ene (DBU), imidazole, pyridine and the like, preferably trialkylamine, more preferably triethylamine.
塩基の使用量は、化合物（ＩＩ）１モルに対して、通常０．５～２．４モル、好ましくは０．８～２．１モル、さらに好ましくは１．２～１．７モルである。 The amount of the base used is usually 0.5 to 2.4 mol, preferably 0.8 to 2.1 mol, more preferably 1.2 to 1.7 mol, per 1 mol of compound (II). .
ＴＢＳ化剤としては、例えばｔｅｒｔ－ブチルジメチルシリルクロリド（ＴＢＳ－Ｃｌ）、ｔｅｒｔ－ブチルジメチルシリルトリフルオロメタンスルホネート（ＴＢＳ－ＯＴｆ）等が挙げられるが、ｔｅｒｔ－ブチルジメチルシリルクロリドを用いるのが好ましい。
ＴＢＳ化剤の使用量は、反応効率の点から、化合物（ＩＩ）１モルに対して、０．５モル以上、好ましくは１モル以上、さらに好ましくは２モル以上、さらに好ましくは２．５モル以上である。また、ＴＢＳ化剤の使用量は、反応精度の点から、化合物（ＩＩ）１モルに対して、７モル以下、好ましくは５モル以下、さらに好ましくは４モル以下、さらに好ましくは３．５モル以下である。ＴＢＳ化剤の使用量は、Ａ環のフェノール性水酸基のいずれか一方をＴＢＳ化する点から、化合物（ＩＩ）１モルに対して、通常０．５～７モル、好ましくは１～５モル、さらに好ましくは２～４モル、さらに好ましくは２．５～３．５モルである。
Examples of the TBS-forming agent include tert-butyldimethylsilyl chloride (TBS-Cl), tert-butyldimethylsilyl trifluoromethanesulfonate (TBS-OTf), and it is preferable to use tert-butyldimethylsilyl chloride.
From the viewpoint of reaction efficiency, the amount of TBS-forming agent used is 0.5 mol or more, preferably 1 mol or more, more preferably 2 mol or more, and even more preferably 2.5 mol, per 1 mol of compound (II). That's all. In addition, from the viewpoint of reaction accuracy, the amount of the TBS forming agent to be used is 7 mol or less, preferably 5 mol or less, more preferably 4 mol or less, still more preferably 3.5 mol, per 1 mol of compound (II). It is as follows. The amount of the TBS-forming agent to be used is usually 0.5 to 7 mol, preferably 1 to 5 mol, per 1 mol of compound (II), in order to convert either one of the phenolic hydroxyl groups of the A ring into TBS. The amount is more preferably 2 to 4 mol, and even more preferably 2.5 to 3.5 mol.
反応温度は特に限定されず、通常、冷却下、室温下及び加熱下のいずれでも反応が行われる。好ましくは０～６０℃、さらに好ましくは１０～４０℃、さらに好ましくは２０～３０℃程度の温度条件下、２～３時間、好ましくは０．５～１．５時間反応させるのがよい。 The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature of 0 to 60°C, more preferably 10 to 40°C, even more preferably 20 to 30°C, for 2 to 3 hours, preferably 0.5 to 1.5 hours.
得られたシリル化カテキン誘導体（ＩＩＩ）は、オクタデシルシリル化シリカゲル（ＯＤＳ）等を充填したカラムを用いた分取ＨＰＬＣにより、５位ＴＢＳ化体と７位ＴＢＳ化体を分離することができる。 The obtained silylated catechin derivative (III) can be separated into a 5-position TBS derivative and a 7-position TBS derivative by preparative HPLC using a column packed with octadecylsilylated silica gel (ODS) or the like.
３．工程－３
〔式中、Ｒ１ａ及びＲ２ａはいずれか一方が水素原子で他方がＴＢＳ基を示し、Ｒ１ｂ及びＲ２ｂはいずれか一方がＣｂｚ基で他方がＴＢＳ基を示し、Ｒ１ｂ及びＲ２ｂはＲ１ａ及びＲ２ａにそれぞれ対応する。〕 [In the formula, one of R 1a and R 2a is a hydrogen atom and the other is a TBS group, one of R 1b and R 2b is a Cbz group and the other is a TBS group, and R 1b and R 2b are Corresponding to R 1a and R 2a , respectively. ]
続いて、上記工程で得られたシリル化カテキン誘導体（ＩＩＩ）の残余の水酸基をＣｂｚ化し、シリル化カテキン保護誘導体（ＩＶ）を得る。当該誘導体（ＩＶ）も文献未記載の新規化合物である。
Ｃｂｚ化は、工程－１で示した方法と同様の方法を採用することができる。
Subsequently, the remaining hydroxyl groups of the silylated catechin derivative (III) obtained in the above step are converted to Cbz to obtain the silylated catechin protected derivative (IV). The derivative (IV) is also a new compound that has not been described in any literature.
For Cbz conversion, a method similar to the method shown in Step-1 can be adopted.
４．工程－４
〔式中、Ｒ１ｂ及びＲ２ｂはいずれか一方がＣｂｚ基で他方がＴＢＳ基を示し、Ｒ１ｃ及びＲ２ｃはいずれか一方がＣｂｚ基で他方が水素原子を示し、Ｒ１ｃ及びＲ２ｃはＲ１ｂ及びＲ２ｂにそれぞれ対応する。〕 [In the formula, one of R 1b and R 2b represents a Cbz group and the other represents a TBS group; one of R 1c and R 2c represents a Cbz group and the other represents a hydrogen atom; R 1c and R 2c are Corresponding to R 1b and R 2b , respectively. ]
上記工程で得られたシリル化カテキン保護誘導体（ＩＶ）のＴＢＳ基を脱離し、化合物（Ｖ）を得る。
ＴＢＳ基の脱離は、公知の方法によって行うことができ、例えば有機溶媒中でフッ化物の塩、又はフッ化水素の付加体を作用させる方法が汎用される。
フッ化物の塩としては、例えばフッ化テトラ－ｎ－ブチルアンモニウム（ＴＢＡＦ）、ジフルオロトリメチルケイ酸トリス（ジメチルアミノ）スルホニウム（ＴＡＳＦ）等が挙げられ、フッ化水素の付加体としては、例えばフッ化水素ピリジン、フッ化アンモニウム等が挙げられる。
The TBS group of the silylated catechin protected derivative (IV) obtained in the above step is removed to obtain compound (V).
The TBS group can be removed by a known method, for example, a commonly used method is to use a fluoride salt or a hydrogen fluoride adduct in an organic solvent.
Examples of fluoride salts include tetra-n-butylammonium fluoride (TBAF), tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF), and examples of hydrogen fluoride adducts include fluoride. Examples include hydrogen pyridine and ammonium fluoride.
フッ化物の塩又はフッ化水素付加体の使用量は、化合物（ＩＶ）１モルに対して、好ましくは０．５～５モル、より好ましくは１～３モル、より好ましくは１．５～２．５モルである。 The amount of the fluoride salt or hydrogen fluoride adduct to be used is preferably 0.5 to 5 mol, more preferably 1 to 3 mol, more preferably 1.5 to 2 mol, per 1 mol of compound (IV). .5 mol.
この反応で使用される溶媒としては、例えば、テトラヒドロフランや１，４－ジオキサン等のエーテル系溶媒、クロロホルムやジクロロメタンや１、１－ジクロロエタンやクロロベンゼン等のハロゲン化炭化水素系溶媒、アセトンやアセトニトリルやＮ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド等の極性溶媒が例示される。 Examples of the solvent used in this reaction include ether solvents such as tetrahydrofuran and 1,4-dioxane, halogenated hydrocarbon solvents such as chloroform, dichloromethane, 1,1-dichloroethane, and chlorobenzene, acetone, acetonitrile, and N , N-dimethylformamide, dimethylsulfoxide and the like.
フッ化物の塩を用いた反応は、化合物（ＩＶ）とフッ化物の塩を溶媒中で攪拌し、０～４０℃、好ましくは２０～３０℃で、１～６０分間、好ましくは５～２０分間反応させるのがよい。 In the reaction using a fluoride salt, compound (IV) and a fluoride salt are stirred in a solvent at 0 to 40°C, preferably 20 to 30°C, for 1 to 60 minutes, preferably 5 to 20 minutes. It is better to react.
５．工程－５
〔式中、Ｒ１ｃ及びＲ２ｃはいずれか一方がＣｂｚ基で他方が水素原子を示し、Ｒ１ｄ及びＲ２ｄはいずれか一方が水素原子で他方がメチル基、グルクロノシル基、グルコシル基又は－ＳＯ３Ｍ（ここで、Ｍは水素原子、アルカリ金属原子、アルカリ土類金属原子又はアンモニウムを示す）を示し、Ｒ１ｄ及びＲ２ｄはＲ１ｃ及びＲ２ｃにそれぞれ対応する。〕 [In the formula, one of R 1c and R 2c is a Cbz group and the other is a hydrogen atom, and one of R 1d and R 2d is a hydrogen atom and the other is a methyl group, glucuronosyl group, glucosyl group, or -SO 3 M (here, M represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, or ammonium), and R 1d and R 2d correspond to R 1c and R 2c , respectively. ]
化合物（Ｖ）の抱合体化は、硫酸化、メチル化、グルクロン酸化又はグルコシル化のいずれかであり、化合物（Ｖ）に対して、公知の硫酸供与体、メチル供与体、グルクロン酸供与体又はグルコース供与体を反応させることにより行われる。
硫酸供与体としては、例えばネオペンチルクロロスルファート、トリクロロエチルクロロスルファート、２，２，２－トリクロロエトキシ－スルフリル－１，２－ジメチルイミダゾリウムトリフレート（2,2,2-trichloroethoxy-sulfuryl-1,2-dimethylimidazolium triflate；ＳＤＩＳ）等が挙げられる。
グルクロン酸供与体としては、２，３，４－トリ－Ｏ－アセチル－α－Ｄ－メチルグルクロノピラノシル－１－（Ｎ－フェニル）－２，２，２－トリフルオロアセトイミダート、２，３，４－トリ－Ｏ－アセチル－α－Ｄ－メチルグルコピラノシル－１－（Ｎ－４－メトキシフェニル）－２，２，２－トリフルオロアセトイミダート、２，３，４－トリ－Ｏ－アセチル－α－Ｄ－メチルグルクロノピラノシル－１－Ｏ－（２，２，２－トリクロロアセトイミダート）、アセトブロモ－α－Ｄ－グルクロン酸メチルエステル等が挙げられる。
グルコース供与体としては、２，３，４，６－テトラ－Ｏ－アセチル－α－Ｄ－グルコピラノシル－１－（Ｎ－フェニル）－２，２，２－トリフルオロアセトイミダート、２，３，４，６－テトラ－Ｏ－アセチル－α－Ｄ－グルクロピラノシル－１－Ｏ－（２，２，２－トリクロロアセトイミダート）、α－アセトブロモグルコース等が挙げられる。
メチル供与としては、例えば、ヨウ化メチル、ジメチル硫酸、ｐ－トルエンスルホン酸メチルエステル、メタンスルホン酸メチルエステル等のメチル化剤が挙げられる。
Conjugation of compound (V) is sulfation, methylation, glucuronidation or glucosylation, and compound (V) is conjugated with a known sulfate donor, methyl donor, glucuronide donor or This is done by reacting a glucose donor.
Examples of the sulfuric acid donor include neopentyl chlorosulfate, trichloroethyl chlorosulfate, 2,2,2-trichloroethoxy-sulfuryl-1,2-dimethylimidazolium triflate (2,2,2-trichloroethoxy-sulfuryl- 1,2-dimethylimidazolium triflate (SDIS) and the like.
As the glucuronic acid donor, 2,3,4-tri-O-acetyl-α-D-methylglucuronopyranosyl-1-(N-phenyl)-2,2,2-trifluoroacetimidate, 2,3,4-tri-O-acetyl-α-D-methylglucopyranosyl-1-(N-4-methoxyphenyl)-2,2,2-trifluoroacetimidate, 2,3,4 -tri-O-acetyl-α-D-methylglucuronopyranosyl-1-O-(2,2,2-trichloroacetimidate), acetobromo-α-D-glucuronic acid methyl ester, and the like.
As glucose donors, 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl-1-(N-phenyl)-2,2,2-trifluoroacetimidate, 2,3, Examples include 4,6-tetra-O-acetyl-α-D-gluclopyranosyl-1-O-(2,2,2-trichloroacetimidate) and α-acetobromoglucose.
Examples of methyl donors include methylating agents such as methyl iodide, dimethyl sulfate, p-toluenesulfonic acid methyl ester, and methanesulfonic acid methyl ester.
例えば、硫酸化は、硫酸供与体としてＳＤＩＳを用いる方法が好ましく、エーテル系、塩素系、非プロトン性又はその混合溶媒中、塩基の存在下、カテキン保護誘導体（Ｖ）とＳＤＩＳを撹拌することにより行われる。塩基としては、トリエチルアミン、Ｎ、Ｎ―ジイソプロピルエチルアミン、ピリジン、イミダゾール、キノリン、ピコリン、１－メチルイミダゾール、１，２－ジメチルイミダゾール、４－ジメチルアミノピリジン、Ｎ，Ｎ－ジメチルアニリン、Ｎ－メチルモルホリン、１，５－ジアザビシクロ［４．３．０］ノナ－５－エン（ＤＢＮ）、１，４－ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）等の３級アミンが挙げられ、好ましくは１，２－ジメチルイミダゾールが挙げられる。
反応温度は、通常２３～２７℃程度であり、反応時間は、通常１～１２時間程度である。
For example, sulfation is preferably carried out by stirring the catechin protected derivative (V) and SDIS in an ether, chlorine, aprotic or mixed solvent in the presence of a base. It will be done. As a base, triethylamine, N,N-diisopropylethylamine, pyridine, imidazole, quinoline, picoline, 1-methylimidazole, 1,2-dimethylimidazole, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylmorpholine , 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0 ] Examples include tertiary amines such as undec-7-ene (DBU), preferably 1,2-dimethylimidazole.
The reaction temperature is usually about 23 to 27°C, and the reaction time is usually about 1 to 12 hours.
グルクロン酸化は、グルクロン酸供与体として２，３，４－トリ－Ｏ－アセチル－１－Ｏ－（トリクロロアセトイミドイル）－α－Ｄ－グルクロン酸メチルを用いる方法が好ましく、エーテル系、塩素系、非プロトン性又はその混合溶媒中、ルイス酸とモレキュラーシーブス４Ａの存在下、カテキン保護誘導体（Ｖ）と２，３，４－トリ－Ｏ－アセチル－１－Ｏ－（トリクロロアセトイミドイル）－α－Ｄ－グルクロン酸メチルを撹拌することにより行われる。ルイス酸としては、塩化アルミニウム（III）、ジエチルアルミニウムクロリド、塩化ニッケル（II）（６水和物）、塩化スズ（IV）（５水和物）、塩化チタン（IV）、塩化亜鉛、トリフルオロボラン－エーテル錯体が挙げられ、好ましくはトリフルオロボラン－エーテル錯体が挙げられる。反応温度は、通常２３～２７℃程度であり、反応時間は、通常１～２４時間程度である。 For glucuronidation, a method using methyl 2,3,4-tri-O-acetyl-1-O-(trichloroacetimidoyl)-α-D-glucuronate as a glucuronic acid donor is preferred; , catechin protected derivative (V) and 2,3,4-tri-O-acetyl-1-O-(trichloroacetimidoyl)- in an aprotic or mixed solvent, in the presence of a Lewis acid and molecular sieves 4A. This is carried out by stirring methyl α-D-glucuronate. Lewis acids include aluminum (III) chloride, diethylaluminum chloride, nickel (II) chloride (hexahydrate), tin (IV) chloride (pentahydrate), titanium (IV) chloride, zinc chloride, and trifluorocarbon. Examples include ran-ether complexes, and preferably trifluoroborane-ether complexes. The reaction temperature is usually about 23 to 27°C, and the reaction time is usually about 1 to 24 hours.
グルコシル化は、グルコシル供与体として２，３，４，６－テトラ－Ｏ－アセチル－β－Ｄ－グルコピラノシル２，２，２－トリクロロアセトイミダートを用いる方法が好ましく、エーテル系、塩素系、非プロトン性又はその混合溶媒中、ルイス酸とモレキュラーシーブス４Ａの存在下、カテキン保護誘導体（Ｖ）と２，３，４，６－テトラ－Ｏ－アセチル－β－Ｄ－グルコピラノシル２，２，２－トリクロロアセトイミダートを撹拌することにより行われる。ルイス酸としては、塩化アルミニウム（III）、ジエチルアルミニウムクロリド、塩化ニッケル（II）（６水和物）、塩化スズ（IV）（５水和物）、塩化チタン（IV）、塩化亜鉛、トリフルオロボラン－エーテル錯体が挙げられ、好ましくはトリフルオロボラン－エーテル錯体が挙げられる。反応温度は、通常２３～２７℃程度であり、反応時間は、通常１～２４時間程度である。 For glucosylation, a method using 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl 2,2,2-trichloroacetimidate as a glucosyl donor is preferred; In a protic or mixed solvent, in the presence of a Lewis acid and molecular sieves 4A, catechin protected derivative (V) and 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl 2,2,2- This is done by stirring trichloroacetimidate. Lewis acids include aluminum (III) chloride, diethylaluminum chloride, nickel (II) chloride (hexahydrate), tin (IV) chloride (pentahydrate), titanium (IV) chloride, zinc chloride, and trifluorocarbon. Examples include ran-ether complexes, and preferably trifluoroborane-ether complexes. The reaction temperature is usually about 23 to 27°C, and the reaction time is usually about 1 to 24 hours.
メチル化は、例えば非プロトン性極性溶媒中、０℃～室温で化合物（Ｖ）とメチル化剤及び塩基とを反応させることにより行うことができる。
ここで、メチル化剤としては、ヨードメタン、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、トリメチルシリルジアゾメタン等を用いるのが好ましく、より好ましくはヨードメタン、硫酸ジメチル、トリフルオロメタンスルホン酸メチルである。非プロトン性極性溶媒とは、Ｎ、Ｎ－ジメチルホルムアミド、ジメチルスルホキシドもしくはヘキサメチルリン酸トリアミド、又はこれらの混合物及びこれらと不活性溶媒（例えばテトラヒドロフラン、１．２－ジメトキシエタン等）との混合物が挙げられる。
塩基としては、例えばナトリウム、カリウムのようなアルカリ金属；ナトリウムメトキシド、ナトリウムエトキシド、カリウム第３級ブトキシドのようなアルカリ金属アルコキシド；炭酸ナトリウム、炭酸カリウムのような炭酸塩；重炭酸ナトリウム、重炭酸カリウムのような重炭酸塩；水酸化ナトリウム、水酸化カリウムのような金属水酸化物；水素化ナトリウム、水素化カリウムのような金属水素化物等が使用できる。
Methylation can be carried out, for example, by reacting compound (V) with a methylating agent and a base in an aprotic polar solvent at 0° C. to room temperature.
Here, as the methylating agent, it is preferable to use iodomethane, dimethyl sulfate, methyl trifluoromethanesulfonate, diazomethane, trimethylsilyldiazomethane, etc., and more preferably iodomethane, dimethyl sulfate, and methyl trifluoromethanesulfonate. Aprotic polar solvents include N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, or mixtures thereof and mixtures thereof with inert solvents (e.g., tetrahydrofuran, 1,2-dimethoxyethane, etc.). Can be mentioned.
Bases include, for example, alkali metals such as sodium and potassium; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; carbonates such as sodium carbonate and potassium carbonate; sodium bicarbonate and bicarbonate; Bicarbonates such as potassium carbonate; metal hydroxides such as sodium hydroxide and potassium hydroxide; metal hydrides such as sodium hydride and potassium hydride, etc. can be used.
斯くして得られる、カテキン保護誘導体（Ｖ）と硫酸供与体、メチル供与体、グルクロン酸供与体又はグルコース供与体との反応生成物については、必要に応じて、各供与体に由来するエステル残基等の保護基を脱離すること、併せてＢ環及びＣ環のＣｂｚ基を脱離することにより、カテキン抱合体（ＶＩ）を得る。 The reaction products of the catechin protected derivative (V) and the sulfuric acid donor, methyl donor, glucuronic acid donor or glucose donor obtained in this way may be treated with ester residues derived from each donor as necessary. The catechin conjugate (VI) is obtained by removing the protective group such as Cbz group and the Cbz group of the B ring and C ring.
エステル残基等の保護基の脱離手段としては、例えば加水分解反応が挙げられる。加水分解反応は、酸又は塩基の存在下、反応生成物と水とを適宜溶媒中で接触させることにより実施することができる。ここで、使用可能な酸としては、例えば、塩酸、臭化水素酸、硫酸、リン酸等の無機酸や、酢酸、トリフルオロ酢酸、ギ酸、ｐ－トルエンスルホン酸等の有機酸が挙げられる。塩基としては、例えば、水酸化ナトリウム、水酸化バリウム等の金属水酸化物、炭酸ナトリウム、炭酸カリウム等の炭酸塩、更には酢酸ナトリウム等が挙げられる。
溶媒としては、例えば、エタノール、エチレングリコールジメチルエーテル、テトラヒドロフラン、ジオキサンなどの水混和性有機溶媒が水と共に用いられる。
反応は、通常、約０～１００℃、好ましくは室温～５０℃で、０．５～３時間、好ましくは０．５～２時間行われる。
Examples of means for removing protective groups such as ester residues include hydrolysis reaction. The hydrolysis reaction can be carried out by bringing the reaction product into contact with water in an appropriate solvent in the presence of an acid or a base. Examples of acids that can be used include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid, trifluoroacetic acid, formic acid, and p-toluenesulfonic acid. Examples of the base include metal hydroxides such as sodium hydroxide and barium hydroxide, carbonates such as sodium carbonate and potassium carbonate, and sodium acetate.
As the solvent, for example, water-miscible organic solvents such as ethanol, ethylene glycol dimethyl ether, tetrahydrofuran, and dioxane are used together with water.
The reaction is usually carried out at about 0 to 100°C, preferably room temperature to 50°C, for 0.5 to 3 hours, preferably 0.5 to 2 hours.
また、Ｂ環及びＣ環のＣｂｚ基の脱離手段としては、水素化触媒存在下で加水素分解することにより、行うことができる。 Further, the Cbz groups of the B ring and C ring can be eliminated by hydrogenolysis in the presence of a hydrogenation catalyst.
反応は、水素源（水素、ギ酸又はギ酸アンモニウム等のギ酸類等）の存在下において、適当な溶媒中、水素化触媒の存在下で、カテキン保護誘導体（Ｖ）と硫酸供与体、メチル供与体、グルクロン酸供与体又はグルコース供与体との反応生成物を撹拌することにより行われる。
溶媒としては、ジエチルエーテル、テトラヒドロフラン、ジオキサン等のエーテル系溶媒、メタノール、エタノール等のアルコール系溶媒、ギ酸、酢酸等の酸性溶媒及びこれらの混合溶媒等が挙げられる。
In the presence of a hydrogen source (hydrogen, formic acid or formic acids such as ammonium formate), in an appropriate solvent, in the presence of a hydrogenation catalyst, the catechin protected derivative (V), a sulfuric acid donor, a methyl donor, etc. , by stirring the reaction product with a glucuronic acid donor or a glucose donor.
Examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran, and dioxane, alcohol solvents such as methanol and ethanol, acidic solvents such as formic acid and acetic acid, and mixed solvents thereof.
水素化触媒としては、水酸化パラジウム（ＩＩ）／炭素（Ｐｄ（ＯＨ）２／Ｃ）、パラジウム／炭素（Ｐｄ／Ｃ）等のパラジウム触媒、ラネーニッケル等の水素担持金属触媒等が挙げられる。 Examples of hydrogenation catalysts include palladium catalysts such as palladium (II) hydroxide/carbon (Pd(OH) 2 /C) and palladium/carbon (Pd/C), hydrogen-supported metal catalysts such as Raney nickel, and the like.
水素化触媒の使用量は、化合物（ＶＩ）の仕込質量に対して、通常１～３００質量％、好ましくは５～２００質量％、さらに好ましくは１０～１５０質量％、さらに好ましくは１５～１００質量％、さらに好ましくは２０～５０質量％である。 The amount of hydrogenation catalyst used is usually 1 to 300% by mass, preferably 5 to 200% by mass, more preferably 10 to 150% by mass, and even more preferably 15 to 100% by mass, based on the charged mass of compound (VI). %, more preferably 20 to 50% by mass.
反応温度は、通常２３～２７℃程度であり、反応時間は、通常６～２４時間程度である。 The reaction temperature is usually about 23 to 27°C, and the reaction time is usually about 6 to 24 hours.
尚、本発明の各反応における目的物の単離は、必要に応じて、有機合成化学で常用される精製法、例えば濾過、洗浄、乾燥、再結晶、各種クロマトグラフィー、蒸留等により行うことができる。 The target product in each reaction of the present invention can be isolated, if necessary, by purification methods commonly used in organic synthetic chemistry, such as filtration, washing, drying, recrystallization, various chromatography, distillation, etc. can.
実施例１ 硫酸抱合体の製造
（１）化合物６の合成
Example 1 Production of sulfuric acid conjugate (1) Synthesis of compound 6
アルゴン雰囲気下、５００ｍＬ丸底フラスコに化合物１（５ｇ，１７ｍｍｏｌ）をとり、脱水アセトン（１６７ｍＬ）を加え撹拌し、澄明な溶液を得た。続いて、トリエチルアミン（４．８ｍＬ，３４ｍｍｏｌ）とクロロギ酸ベンジル（４．８ｍＬ，３４ ｍｍｏｌ）を氷浴で冷却下、順次加え、１時間撹拌した。反応後、濾過し、アセトン（８０ｍＬ）で洗浄、得られた有機層をエバポレーターにて溶媒を減圧蒸留した。得られた残渣をシリカゲルクロマトグラフィー（溶出溶媒：クロロホルム－メタノール（２０：１，ｖ／ｖ））により精製し、白いアモルファスとして化合物６（７．５ｇ, １３ｍｍｏｌ, ８０％）を得た。 Compound 1 (5 g, 17 mmol) was placed in a 500 mL round bottom flask under an argon atmosphere, and dehydrated acetone (167 mL) was added and stirred to obtain a clear solution. Subsequently, triethylamine (4.8 mL, 34 mmol) and benzyl chloroformate (4.8 mL, 34 mmol) were added one after another under cooling in an ice bath, and the mixture was stirred for 1 hour. After the reaction, the organic layer was filtered and washed with acetone (80 mL), and the solvent was distilled off under reduced pressure using an evaporator. The obtained residue was purified by silica gel chromatography (elution solvent: chloroform-methanol (20:1, v/v)) to obtain Compound 6 (7.5 g, 13 mmol, 80%) as a white amorphous.
１Ｈ－ＮＭＲ（６００ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ７．５６（ｄ，Ｊ＝２．０Ｈｚ,１Ｈ），７．５０（ｄｄ，Ｊ＝８．３，１．８Ｈｚ，１Ｈ），７．４６－７．４４（ｍ，４Ｈ），７．４１－７．３６（ｍ，７Ｈ），６．０４（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），５．９５（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），５．２７（ｓ，２Ｈ），５．２６（ｓ，２Ｈ），５．０７－５．０７（ｍ，１Ｈ），４．３２－４．３２（ｍ，１Ｈ），２．９１（ｄｄ，Ｊ＝１７，４．５，Ｈｚ，１Ｈ），２．７９（ｄｄ，Ｊ＝１６．４，２．５Ｈｚ，１Ｈ） 1 H-NMR (600MHz, acetone-d6) δ7.56 (d, J=2.0Hz, 1H), 7.50 (dd, J=8.3, 1.8Hz, 1H), 7.46-7 .44 (m, 4H), 7.41-7.36 (m, 7H), 6.04 (d, J = 2.3Hz, 1H), 5.95 (d, J = 2.3Hz, 1H) , 5.27 (s, 2H), 5.26 (s, 2H), 5.07-5.07 (m, 1H), 4.32-4.32 (m, 1H), 2.91 (dd , J=17,4.5,Hz,1H),2.79(dd,J=16.4,2.5Hz,1H)
１３Ｃ－ＮＭＲ（１５０ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ１５７．６４，１５７．６２，１５６．６６，１５３．４６，１５３．４０，１４２．９７，１４２．６１，１４０．２０，１３６．１４，１２９．４４，１２９．４１，１２９．１８，１２６．２７，１２３．３７，１２２．６５，９９．５９，９６．３８，９５．６８，７９．１８，７８．７２，７１．１２，６６．４０，２９．１２ 13C -NMR (150MHz, acetone-d6) δ157.64, 157.62, 156.66, 153.46, 153.40, 142.97, 142.61, 140.20, 136.14, 129.44 , 129.41, 129.18, 126.27, 123.37, 122.65, 99.59, 96.38, 95.68, 79.18, 78.72, 71.12, 66.40, 29 .12
（２） （４－（（２′Ｒ，３′Ｒ）－５′－（（ｔｅｒｔ－Ｂｕｔｙｌｄｉｍｅｔｈｙｌｓｉｌｙｌ）ｏｘｙ）－３′，７′－ｄｉｈｙｄｒｏｘｙｃｈｒｏｍａｎ－２′－ｙｌ）－１，２－ｐｈｅｎｙｌｅｎｅ）ｄｉｂｅｎｚｙｌ ｂｉｓｃａｒｂｏｎａｔｅ（化合物７）及び（４－（（２′Ｒ，３′Ｒ）－７′－（（ｔｅｒｔ－ｂｕｔｙｌｄｉｍｅｔｈｙｌｓｉｌｙｌ）ｏｘｙ）－３′，５′－ｄｉｈｙｄｒｏｘｙｃｈｒｏｍａｎ－２′－ｙｌ）－１，２－ｐｈｅｎｙｌｅｎｅ）ｄｉｂｅｎｚｙｌ ｂｉｓｃａｒｂｏｎａｔｅ（化合物８）の合成 (2) (4-((2'R,3'R)-5'-((tert-Butyldimethylsilyl)oxy)-3',7'-dihydroxychroman-2'-yl)-1,2-phenylene)dibenzyl biscarbonate (compound 7) and (4-((2'R,3'R)-7'-((tert-butyldimethylsilyl)oxy)-3',5'-dihydroxychroman-2'-yl)-1,2- Synthesis of phenylene dibenzyl biscarbonate (compound 8)
アルゴン雰囲気下、２０ｍＬ丸底フラスコに化合物６（１００ｍｇ，０．１８ｍｍｏｌ）とをとり、脱水ジクロロメタン（４ｍＬ）を加え撹拌し、澄明な溶液を得た。続いて、トリエチルアミン（３８μＬ，０．２７ｍｍｏｌ）とｔ－ブチルジメチルシリルクロリド（８４ｍｇ,０．５５ｍｍｏｌ）を室温で順次加え、１時間撹拌した。反応後、酢酸エチル（１０ｍＬ）で希釈した後、水を加えることで反応を停止した。引き続き、酢酸エチルにて３回抽出、得られた有機層を飽和食塩水により洗浄、無水硫酸ナトリウムで乾燥後、エバポレーターにて溶媒を減圧蒸留した。得られた残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン－酢酸エチル（５：２，ｖ／ｖ））により精製し、白いアモルファスとして化合物７（７６ｍｇ，０．１１ｍｍｏｌ，６１％）と化合物８（２９ｍｇ，０．０４ｍｍｏｌ，２４％）を得た。 Compound 6 (100 mg, 0.18 mmol) was placed in a 20 mL round bottom flask under an argon atmosphere, and dehydrated dichloromethane (4 mL) was added and stirred to obtain a clear solution. Subsequently, triethylamine (38 μL, 0.27 mmol) and t-butyldimethylsilyl chloride (84 mg, 0.55 mmol) were sequentially added at room temperature, and the mixture was stirred for 1 hour. After the reaction, the reaction mixture was diluted with ethyl acetate (10 mL) and water was added to stop the reaction. Subsequently, the organic layer was extracted three times with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled under reduced pressure using an evaporator. The obtained residue was purified by silica gel chromatography (elution solvent: hexane-ethyl acetate (5:2, v/v)), and compound 7 (76 mg, 0.11 mmol, 61%) and compound 8 (29 mg) were obtained as white amorphous. , 0.04 mmol, 24%).
化合物７：
１Ｈ－ＮＭＲ（６００ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ７．５４（ｄ，Ｊ＝１．８Ｈｚ，１Ｈ），７．５０（ｄｄ，Ｊ＝８．６，１．８Ｈｚ，１Ｈ），７．４４－７．４６（ｍ，４Ｈ），７．３６－７．４１（ｍ，７Ｈ），６．０７（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），６．０５（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ），５．２７（ｓ，２Ｈ），５．２６（ｓ，２Ｈ），５．０８（ｓ，１Ｈ），４．３２－４．３４（ｍ，１Ｈ），４．０７（ｄ，Ｊ＝５．７Ｈｚ，１Ｈ），２．９２（ｄｄ，Ｊ＝１６，４．４Ｈｚ，１Ｈ），２．７９（ｄｄ，Ｊ＝１６，２．７Ｈｚ，１Ｈ），１．０１（ｓ，９Ｈ），０．２４（ｓ，６Ｈ）
Compound 7:
1 H-NMR (600MHz, acetone-d6) δ7.54 (d, J=1.8Hz, 1H), 7.50 (dd, J=8.6, 1.8Hz, 1H), 7.44-7 .46 (m, 4H), 7.36-7.41 (m, 7H), 6.07 (d, J=2.3Hz, 1H), 6.05 (d, J=2.2Hz, 1H) , 5.27 (s, 2H), 5.26 (s, 2H), 5.08 (s, 1H), 4.32-4.34 (m, 1H), 4.07 (d, J=5 .7Hz, 1H), 2.92 (dd, J=16, 4.4Hz, 1H), 2.79 (dd, J=16, 2.7Hz, 1H), 1.01 (s, 9H), 0 .24 (s, 6H)
１３Ｃ－ＮＭＲ（１５０ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ１５７．４７，１５６．７９，１５６．０１，１５３．４６，１５３．４１，１４２．９９，１４２．６５，１４０．０８，１３６．１４，１２９．４５，１２９．４２，１２９．１９，１２６．２９，１２３．４０，１２２．６５，１０３．６０，１００．２２，９７．４３，７８．７５，７１．１３，６６．３５，２６．１３，１８．８２，－４．４０，－４．１２ 13C -NMR (150MHz, acetone-d6) δ157.47, 156.79, 156.01, 153.46, 153.41, 142.99, 142.65, 140.08, 136.14, 129.45 , 129.42, 129.19, 126.29, 123.40, 122.65, 103.60, 100.22, 97.43, 78.75, 71.13, 66.35, 26.13, 18 .82, -4.40, -4.12
化合物８：
１Ｈ－ＮＭＲ（６００ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ７．５６（ｄ，Ｊ＝１．８Ｈｚ，１Ｈ），７．５１（ｄｄ，Ｊ＝８．４，１．６Ｈｚ，１Ｈ），７．４４－７．４６（ｍ，４Ｈ），７．３６－７．４１（ｍ，７Ｈ），６．０８（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ），５．９７（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ），５．２７（ｓ，２Ｈ），５．２６（ｓ，２Ｈ），５．１０（ｓ，１Ｈ），４．３４－４．３７（ｍ，１Ｈ），４．０７（ｄ，Ｊ＝５．５Ｈｚ１Ｈ），２．９４（ｄｄ，Ｊ＝１６，４．５Ｈｚ，１Ｈ），２．８０－２．８３（ｍ，１Ｈ），０．９７（ｓ，９Ｈ），０．１９（ｓ，６Ｈ）
Compound 8:
1 H-NMR (600MHz, acetone-d6) δ7.56 (d, J=1.8Hz, 1H), 7.51 (dd, J=8.4, 1.6Hz, 1H), 7.44-7 .46 (m, 4H), 7.36-7.41 (m, 7H), 6.08 (d, J=2.2Hz, 1H), 5.97 (d, J=2.2Hz, 1H) , 5.27 (s, 2H), 5.26 (s, 2H), 5.10 (s, 1H), 4.34-4.37 (m, 1H), 4.07 (d, J=5 .5Hz 1H), 2.94 (dd, J=16, 4.5Hz, 1H), 2.80-2.83 (m, 1H), 0.97 (s, 9H), 0.19 (s, 6H) )
１３Ｃ－ＮＭＲ（１５０ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ１５７．４８，１５６．６１，１５５．６６，１５３．４６，１５３．４１，１４３．００，１４２．６４，１４０．０８，１３６．１５，１２９．４５，１２９．４２，１２９．４１，１２６．２４，１２３．４０，１２２．６５，１０１．８６，１００．７６，１００．３７，７８．７６，７１．１３，６６．２３，２６．０３，１８．７４，－４．２５０，－４．２７ 13C -NMR (150MHz, acetone-d6) δ157.48, 156.61, 155.66, 153.46, 153.41, 143.00, 142.64, 140.08, 136.15, 129.45 , 129.42, 129.41, 126.24, 123.40, 122.65, 101.86, 100.76, 100.37, 78.76, 71.13, 66.23, 26.03, 18 .74, -4.250, -4.27
（３） （４－（（２′Ｒ，３′Ｒ）－３′，７′－Ｂｉｓ（（（ｂｅｎｚｙｌｏｘｙ）ｃａｒｂｏｎｙｌ）ｏｘｙ）－５′－（（ｔｅｒｔ－ｂｕｔｙｌｄｉｍｅｔｈｙｌｓｉｌｙｌ）ｏｘｙ）ｃｈｒｏｍａｎ－２′－ｙｌ）－１，２－ｐｈｅｎｙｌｅｎｅ）ｄｉｂｅｎｚｙｌ ｂｉｓｃａｒｂｏｎａｔｅ（化合物９）及び（４－（（２′Ｒ，３′Ｒ）－３′，５′－Ｂｉｓ（（（ｂｅｎｚｙｌｏｘｙ）ｃａｒｂｏｎｙｌ）ｏｘｙ）－７′－（（ｔｅｒｔ－ｂｕｔｙｌｄｉｍｅｔｈｙｌｓｉｌｙｌ）ｏｘｙ）ｃｈｒｏｍａｎ－２′－ｙｌ）－１，２－ｐｈｅｎｙｌｅｎｅ）ｄｉｂｅｎｚｙｌ ｂｉｓｃａｒｂｏｎａｔｅ（化合物１１）の合成 (3) (4-((2'R,3'R)-3',7'-Bis((benzyloxy)carbonyl)oxy)-5'-((tert-butyldimethylsilyl)oxy)chroman-2'- yl)-1,2-phenylene)dibenzyl biscarbonate (compound 9) and (4-((2′R,3′R)-3′,5′-Bis((benzyloxy)carbonyl)oxy)-7′- Synthesis of ((tert-butyldimethylsilyl)oxy)chroman-2'-yl)-1,2-phenylene)dibenzyl biscarbonate (compound 11)
（３－１）化合物９の合成
アルゴン雰囲気下、１００ｍＬ丸底フラスコに化合物７（１．８ｇ，２．６７ｍｍｏｌ）とＮ，Ｎ－ジメチルアミノピリジン（０．９８２ｇ，８．０３ｍｍｏｌ）をとり、脱水ジクロロメタン（２７ｍＬ）を加え撹拌し、澄明な溶液を得た。続いて、トリエチルアミン（１．１ｍＬ，８．０３ｍｍｏｌ）とクロロギ酸ベンジル（１．８９ｍＬ，１３ｍｍｏｌ）を氷浴で冷却下、順次加え、１時間撹拌した。反応後、酢酸エチル（５４ｍＬ）で希釈した後、水を加えることで反応を停止した。引き続き、酢酸エチルにて３回抽出、得られた有機層を飽和食塩水により洗浄、無水硫酸ナトリウムで乾燥後、エバポレーターにて溶媒を減圧蒸留した。得られた残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン－酢酸エチル（３：１，ｖ／ｖ））により精製し、白いアモルファスとして化合物９（１．４４ｇ，１．５２ｍｍｏｌ，５７％）を得た。
(3-1) Synthesis of Compound 9 Under an argon atmosphere, compound 7 (1.8 g, 2.67 mmol) and N,N-dimethylaminopyridine (0.982 g, 8.03 mmol) were placed in a 100 mL round bottom flask and dehydrated. Dichloromethane (27 mL) was added and stirred to obtain a clear solution. Subsequently, triethylamine (1.1 mL, 8.03 mmol) and benzyl chloroformate (1.89 mL, 13 mmol) were sequentially added under cooling in an ice bath, and the mixture was stirred for 1 hour. After the reaction, the reaction mixture was diluted with ethyl acetate (54 mL) and water was added to stop the reaction. Subsequently, the organic layer was extracted three times with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled under reduced pressure using an evaporator. The obtained residue was purified by silica gel chromatography (elution solvent: hexane-ethyl acetate (3:1, v/v)) to obtain Compound 9 (1.44 g, 1.52 mmol, 57%) as a white amorphous. .
１Ｈ－ＮＭＲ（６００ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ７．５８（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ），７．５１（ｄｄ，Ｊ＝８．７，１．９Ｈｚ，１Ｈ），７．２５－７．４８（ｍ，２１Ｈ），６．５１（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ），６．４３（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ），５．４９－５．５０（ｍ，１Ｈ），５．４２（ｓ，１Ｈ），５．２７（ｓ，４Ｈ），５．２５（ｓ，２Ｈ），４．９９（ｓ，２Ｈ），３．１７（ｄｄ，Ｊ＝１７，４．３Ｈｚ，１Ｈ），３．１０（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），１．０１（ｓ，９Ｈ），０．２６（ｓ，３Ｈ），０．２３（ｓ，３Ｈ） 1 H-NMR (600MHz, acetone-d6) δ7.58 (d, J=1.9Hz, 1H), 7.51 (dd, J=8.7, 1.9Hz, 1H), 7.25-7 .48 (m, 21H), 6.51 (d, J = 2.2Hz, 1H), 6.43 (d, J = 2.2Hz, 1H), 5.49-5.50 (m, 1H) , 5.42 (s, 1H), 5.27 (s, 4H), 5.25 (s, 2H), 4.99 (s, 2H), 3.17 (dd, J=17, 4.3Hz , 1H), 3.10 (d, J=16Hz, 1H), 1.01 (s, 9H), 0.26 (s, 3H), 0.23 (s, 3H)
１３Ｃ－ＮＭＲ（１５０ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ１５６．０２，１５５．５４，１５５．０５，１５３．９８，１５３．３２，１５１．３８，１４３．２８，１４３．１４，１３７．９１，１３６．４５，１３６．３１，１３６．０９，１３６．０８，１２９．４４，１２９．４２，１２９．３７，１２９．２７，１２９．２３，１２９．１８，１２９．０５，１２８．９１，１２５．９４，１２３．８７，１２２．４２，１０９．０６，１０５．６７，１０３．６７，７６．９９，７１．９５，７１．１９，７０．７４，７０．０９，２６．０４，１８．７９，－４．２０，－４．２２ 13C -NMR (150MHz, acetone-d6) δ156.02, 155.54, 155.05, 153.98, 153.32, 151.38, 143.28, 143.14, 137.91, 136.45 , 136.31, 136.09, 136.08, 129.44, 129.42, 129.37, 129.27, 129.23, 129.18, 129.05, 128.91, 125.94, 123 .87, 122.42, 109.06, 105.67, 103.67, 76.99, 71.95, 71.19, 70.74, 70.09, 26.04, 18.79, -4. 20, -4.22
（３－２）化合物１１の合成
アルゴン雰囲気下、５０ｍL丸底フラスコに化合物８（６６０ｍｇ，０．９８ｍｍｏｌ）とＮ，Ｎ－ジメチルアミノピリジン（３６０ｍｇ，２．９４ｍｍｏｌ）をとり、脱水ジクロロメタン（１０ｍＬ）を加え撹拌し、澄明な溶液を得た。続いて、トリエチルアミン（４１１μＬ、０．９８ｍｍｏｌ）とクロロギ酸ベンジル（６９２μＬ，４．９０ｍｍｏｌ）を氷浴で冷却下、順次加え、１時間撹拌した。反応後、酢酸エチル（２０ｍＬ）で希釈した後、水を加えることで反応を停止した。引き続き、酢酸エチルにて３回抽出、得られた有機層を飽和食塩水により洗浄、無水硫酸ナトリウムで乾燥後、エバポレーターにて溶媒を減圧蒸留した。得られた残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン－酢酸エチル（３：１，ｖ／ｖ））により精製し、白いアモルファスとして化合物１１（６７８ｍｇ，０．７２ｍｍｏｌ，７４％）を得た。
(3-2) Synthesis of Compound 11 Under an argon atmosphere, compound 8 (660 mg, 0.98 mmol) and N,N-dimethylaminopyridine (360 mg, 2.94 mmol) were placed in a 50 mL round bottom flask, and dehydrated dichloromethane (10 mL) was added. was added and stirred to obtain a clear solution. Subsequently, triethylamine (411 μL, 0.98 mmol) and benzyl chloroformate (692 μL, 4.90 mmol) were sequentially added under cooling in an ice bath, and the mixture was stirred for 1 hour. After the reaction, the reaction mixture was diluted with ethyl acetate (20 mL) and water was added to stop the reaction. Subsequently, the organic layer was extracted three times with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled under reduced pressure using an evaporator. The obtained residue was purified by silica gel chromatography (elution solvent: hexane-ethyl acetate (3:1, v/v)) to obtain Compound 11 (678 mg, 0.72 mmol, 74%) as a white amorphous.
１Ｈ－ＮＭＲ（６００ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ７．５８（ｄ，Ｊ＝１．７Ｈｚ，１Ｈ），７．５１（ｄｄ，Ｊ＝８．４，１．６Ｈｚ，１Ｈ），７．２５－７．４８（ｍ，２１Ｈ），６．４６（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ），６．４４（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ），５．４５（ｍ，１Ｈ），５．４０（ｓ，１Ｈ），５．２９（ｓ，２Ｈ），５．２８（ｓ，２Ｈ），５．２５（ｓ，２Ｈ），４．９９（ｓ，２Ｈ），３．１２（ｄｄ，Ｊ＝１７，４．３Ｈｚ，１Ｈ），２．９４（ｄ，Ｊ＝１６Ｈｚ，１Ｈ），０．９９（ｓ，９Ｈ），０．２３（ｓ，６Ｈ） 1 H-NMR (600MHz, acetone-d6) δ7.58 (d, J=1.7Hz, 1H), 7.51 (dd, J=8.4, 1.6Hz, 1H), 7.25-7 .48 (m, 21H), 6.46 (d, J = 2.2Hz, 1H), 6.44 (d, J = 2.2Hz, 1H), 5.45 (m, 1H), 5.40 (s, 1H), 5.29 (s, 2H), 5.28 (s, 2H), 5.25 (s, 2H), 4.99 (s, 2H), 3.12 (dd, J= 17, 4.3Hz, 1H), 2.94 (d, J=16Hz, 1H), 0.99 (s, 9H), 0.23 (s, 6H)
１３Ｃ－ＮＭＲ（１５０ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ１５６．０８，１５５．８９，１５５．０４，１５３．５０，１５３．３３，１５３．３１，１５１．３６，１４３．２９，１４３．２０，１３７．８０，１３６．４６，１３６．３０，１３６．１０，１３６．０９，１２９．４６，１２９．４５，１２９．４３，１２９．２８，１２９．２０，１２９．１８，１２９．０４，１２８．８６，１２６．０２，１２３．８８，１２２．４５，１０８．０１，１０６．７０，１０６．１８，７７．０５，７１．５７，７１．２１，７０．９６，７０．１３，２６．１７，２５．９３，１８．７０，－４３９，－４．４２． 13C -NMR (150MHz, acetone-d6) δ156.08, 155.89, 155.04, 153.50, 153.33, 153.31, 151.36, 143.29, 143.20, 137.80 , 136.46, 136.30, 136.10, 136.09, 129.46, 129.45, 129.43, 129.28, 129.20, 129.18, 129.04, 128.86, 126 .02, 123.88, 122.45, 108.01, 106.70, 106.18, 77.05, 71.57, 71.21, 70.96, 70.13, 26.17, 25.93 , 18.70, -439, -4.42.
（４）化合物１０及び化合物１２の合成 (4) Synthesis of compound 10 and compound 12
（４－１）化合物１０の合成
アルゴン雰囲気下、１００ｍＬ丸底フラスコに化合物９（１．４ｇ，１．４８ｍｍｏｌ）をとり、水含有テトラヒドロフラン（２０ｍＬ）を加え撹拌し、澄明な溶液を得た。続いて、酢酸（４３０μＬ，７．４４ｍｍｏｌ）とフッ化テトラ－ｎ－ブチルアンモニウムテトラヒドロフラン溶液（３ｍＬ，２．９７ｍｍｏｌ）を室温で順次加え、１０分間撹拌した。反応後、酢酸エチル（４０ｍＬ）で希釈した後、塩化アンモニウム水溶液を加えることで反応を停止した。引き続き、酢酸エチルにて３回抽出、得られた有機層を飽和食塩水により洗浄、無水硫酸ナトリウムで乾燥後、エバポレーターにて溶媒を減圧蒸留した。得られた残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン－酢酸エチル（１：１，ｖ／ｖ））により精製し、白いアモルファスとして化合物１０（１．０９ｇ，１．３２ｍｍｏｌ，８９％）を得た。
(4-1) Synthesis of Compound 10 Under an argon atmosphere, Compound 9 (1.4 g, 1.48 mmol) was placed in a 100 mL round bottom flask, and water-containing tetrahydrofuran (20 mL) was added and stirred to obtain a clear solution. Subsequently, acetic acid (430 μL, 7.44 mmol) and a tetra-n-butylammonium fluoride tetrahydrofuran solution (3 mL, 2.97 mmol) were sequentially added at room temperature, and the mixture was stirred for 10 minutes. After the reaction, the reaction mixture was diluted with ethyl acetate (40 mL), and then an aqueous ammonium chloride solution was added to stop the reaction. Subsequently, the organic layer was extracted three times with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled under reduced pressure using an evaporator. The obtained residue was purified by silica gel chromatography (elution solvent: hexane-ethyl acetate (1:1, v/v)) to obtain compound 10 (1.09 g, 1.32 mmol, 89%) as a white amorphous. .
１Ｈ－ＮＭＲ（６００ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ７．５９（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ），７．５２（ｄｄ，Ｊ＝８．６，１．８Ｈｚ，１Ｈ），７．２５－７．４８（ｍ，２１Ｈ），６．３９（ｍ，２Ｈ），５．４９－５．５０（ｍ，１Ｈ），５．４１（ｓ，１Ｈ），５．２７（ｓ，２Ｈ），５．２６（ｓ，２Ｈ），５．２５（ｓ，２Ｈ），５．００（ｓ，２Ｈ），３．１６（ｄｄ，Ｊ＝１８，４．３Ｈｚ，１Ｈ），３．０７（ｄ，Ｊ＝１６Ｈｚ，１Ｈ） 1 H-NMR (600MHz, acetone-d6) δ7.59 (d, J=1.9Hz, 1H), 7.52 (dd, J=8.6, 1.8Hz, 1H), 7.25-7 .48 (m, 21H), 6.39 (m, 2H), 5.49-5.50 (m, 1H), 5.41 (s, 1H), 5.27 (s, 2H), 5. 26 (s, 2H), 5.25 (s, 2H), 5.00 (s, 2H), 3.16 (dd, J = 18, 4.3Hz, 1H), 3.07 (d, J = 16Hz, 1H)
１３Ｃ－ＮＭＲ（１５０ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ１５７．２１，１５６．００，１５５．１１，１５４．０８，１５３．３３，１５１．５２，１４３．２８，１４３．１１，１３８．０４，１３６．５０，１３６．３７，１３６．１０，１２９．４５，１２９．４２，１２９．３７，１２９．２７，１２９．２３，１２９．１９，１２９．０２，１２８．８４，１２５．９５，１２３．８４，１２２．４４，１０５．０６，１０１．８２，１０１．６９，７６．９９，７２．０２，７１．２０，７０．６７，７０．０５，２６．４２ 13C -NMR (150MHz, acetone-d6) δ157.21, 156.00, 155.11, 154.08, 153.33, 151.52, 143.28, 143.11, 138.04, 136.50 , 136.37, 136.10, 129.45, 129.42, 129.37, 129.27, 129.23, 129.19, 129.02, 128.84, 125.95, 123.84, 122 .44, 105.06, 101.82, 101.69, 76.99, 72.02, 71.20, 70.67, 70.05, 26.42
（４－２）化合物１２の合成
アルゴン雰囲気下、５０ｍＬ丸底フラスコに化合物１１（６５０ｍｇ，０．６９ｍｍｏｌ）をとり、水含有テトラヒドロフラン（１０ｍＬ）を加え撹拌し、澄明な溶液を得た。続いて、酢酸（２００μＬ，３．４５ｍｍｏｌ）とフッ化テトラ－ｎ－ブチルアンモニウムテトラヒドロフラン溶液（１．３８ｍＬ，１．３８ｍｍｏｌ）を室温で順次加え、１０分間撹拌した。反応後、酢酸エチル（２０ｍＬ）で希釈した後、塩化アンモニウム水溶液を加えることで反応を停止した。引き続き、酢酸エチルにて３回抽出、得られた有機層を飽和食塩水により洗浄、無水硫酸ナトリウムで乾燥後、エバポレーターにて溶媒を減圧蒸留した。得られた残渣をシリカゲルクロマトグラフィー（溶出溶媒：ヘキサン－酢酸エチル（２：１，ｖ／ｖ））により精製し、白いアモルファスとして化合物１２（５５１ｍｇ，０．６７ｍｍｏｌ，９７％）を得た。
(4-2) Synthesis of Compound 12 Under an argon atmosphere, Compound 11 (650 mg, 0.69 mmol) was placed in a 50 mL round bottom flask, and water-containing tetrahydrofuran (10 mL) was added and stirred to obtain a clear solution. Subsequently, acetic acid (200 μL, 3.45 mmol) and tetra-n-butylammonium fluoride tetrahydrofuran solution (1.38 mL, 1.38 mmol) were sequentially added at room temperature and stirred for 10 minutes. After the reaction, the reaction mixture was diluted with ethyl acetate (20 mL) and then an aqueous ammonium chloride solution was added to stop the reaction. Subsequently, the organic layer was extracted three times with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled under reduced pressure using an evaporator. The obtained residue was purified by silica gel chromatography (elution solvent: hexane-ethyl acetate (2:1, v/v)) to obtain Compound 12 (551 mg, 0.67 mmol, 97%) as a white amorphous.
１Ｈ－ＮＭＲ（６００ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ７．５７（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ），７．５１（ｄｄ，Ｊ＝８．４，１．８Ｈｚ，１Ｈ），７．２５－７．４８（ｍ，２１Ｈ），６．４０（ｍ，２Ｈ），５．４１－５．４２（ｍ，１Ｈ），５．３８（ｓ，１Ｈ），５．２９（ｓ，２Ｈ），５．２７（ｓ，２Ｈ），５．２５（ｓ，２Ｈ），４．９９（ｓ，２Ｈ），３．０８（ｄｄ，Ｊ＝１７，４．３Ｈｚ，１Ｈ），２．９０（ｄ，Ｊ＝１５Ｈｚ，１Ｈ） 1 H-NMR (600MHz, acetone-d6) δ7.57 (d, J=1.9Hz, 1H), 7.51 (dd, J=8.4, 1.8Hz, 1H), 7.25-7 .48 (m, 21H), 6.40 (m, 2H), 5.41-5.42 (m, 1H), 5.38 (s, 1H), 5.29 (s, 2H), 5. 27 (s, 2H), 5.25 (s, 2H), 4.99 (s, 2H), 3.08 (dd, J = 17, 4.3Hz, 1H), 2.90 (d, J = 15Hz, 1H)
１３Ｃ－ＮＭＲ（１５０ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ１５７．８４，１５６．１８，１５５．０５，１５３．５８，１５３．３３，１５１．５３，１４３．２７，１４３．１７，１３７．９４，１３６．４８，１３６．３５，１３６．１０，１３６．０８，１２９．４５，１２９．４３，１２９．２８，１２９．１９，１２９．１８，１２９．０２，１２８．８３，１２６．０３，１２３．８７，１２２．４５，１０３．９１，１０３．５２，１０２．０１，７７．０１，７１．７２，７１．２０，７０．９０，７０．０９，２６．０８ 13C -NMR (150MHz, acetone-d6) δ157.84, 156.18, 155.05, 153.58, 153.33, 151.53, 143.27, 143.17, 137.94, 136.48 , 136.35, 136.10, 136.08, 129.45, 129.43, 129.28, 129.19, 129.18, 129.02, 128.83, 126.03, 123.87, 122 .45, 103.91, 103.52, 102.01, 77.01, 71.72, 71.20, 70.90, 70.09, 26.08
（５）化合物１３及び化合物１４の合成 (5) Synthesis of compound 13 and compound 14
（５－１）化合物１３の合成
アルゴン雰囲気下、５０ｍＬ丸底フラスコに化合物１０（１００ｍｇ，０．１２ｍｍｏｌ）とＳＤＩＳ（１１１ｍｇ，０．２４ｍｍｏｌ）をとり、脱水ジクロロメタン（５ｍＬ）を加え撹拌し、澄明な溶液を得た。続いて、１，２－ジメチルイミダゾール（２５ｍｇ，０．２４ｍｍｏｌ）を室温で加え、５時間撹拌した。反応後、酢酸エチル（１０ｍＬ）で希釈した後、水を加えることで反応を停止した。引き続き、酢酸エチルにて３回抽出、得られた有機層を飽和食塩水により洗浄、無水硫酸ナトリウムで乾燥後、エバポレーターにて溶媒を減圧蒸留した。得られた残渣を分取薄層クロマトグラフィー（溶出溶媒：ヘキサン－酢酸エチル（３：１，ｖ／ｖ））により精製し、白いアモルファスとして化合物１３（８２ｍｇ，０．０８ｍｍｏｌ，６６％）を得た。
(5-1) Synthesis of Compound 13 Under an argon atmosphere, compound 10 (100 mg, 0.12 mmol) and SDIS (111 mg, 0.24 mmol) were placed in a 50 mL round-bottomed flask, and dehydrated dichloromethane (5 mL) was added thereto and stirred. A solution was obtained. Subsequently, 1,2-dimethylimidazole (25 mg, 0.24 mmol) was added at room temperature and stirred for 5 hours. After the reaction, the reaction mixture was diluted with ethyl acetate (10 mL) and water was added to stop the reaction. Subsequently, the organic layer was extracted three times with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled under reduced pressure using an evaporator. The obtained residue was purified by preparative thin layer chromatography (elution solvent: hexane-ethyl acetate (3:1, v/v)) to obtain Compound 13 (82 mg, 0.08 mmol, 66%) as a white amorphous. Ta.
１Ｈ－ＮＭＲ（６００ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ７．５９（ｄ，Ｊ＝１．８Ｈｚ，１Ｈ），７．５３（ｄｄ，Ｊ＝８．５，１．９Ｈｚ，１Ｈ），７．２４－７．４８（ｍ，２１Ｈ），７．１３（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ），７．００（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ），５．５９（ｍ，２Ｈ），５．２５－５．３０（ｍ，８Ｈ），４．９９（ｍ，２Ｈ），３．４５（ｄｄ，Ｊ＝１７，４．１Ｈｚ，１Ｈ），３．４０（ｄ，Ｊ＝１７Ｈｚ，１Ｈ） 1 H-NMR (600MHz, acetone-d6) δ7.59 (d, J=1.8Hz, 1H), 7.53 (dd, J=8.5, 1.9Hz, 1H), 7.24-7 .48 (m, 21H), 7.13 (d, J = 2.2Hz, 1H), 7.00 (d, J = 2.2Hz, 1H), 5.59 (m, 2H), 5.25 -5.30 (m, 8H), 4.99 (m, 2H), 3.45 (dd, J=17, 4.1Hz, 1H), 3.40 (d, J=17Hz, 1H)
１３Ｃ－ＮＭＲ（１５０ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ１５６．４４，１５４．８８，１５３．７２，１５３．３２，１５３．３０，１５１．３１，１４９．４５，１４３．３５，１４３．３２，１３７．２３，１３６．３７，１３６．１０，１３６．０８，１３６．０７，１２９．５１，１２９．４７，１２９．３６，１２９．２９，１２９．２１，１２９．０８，１２８．８８，１２６．００，１２３．９９，１２２．４６，１１１．８２，１１０．３６，１０８．７２，９３．６４，８１．６５，７７．４７，７１．２３，７１．１８，７０．８２，７０．２６，２６．７１ 13C -NMR (150MHz, acetone-d6) δ156.44, 154.88, 153.72, 153.32, 153.30, 151.31, 149.45, 143.35, 143.32, 137.23 , 136.37, 136.10, 136.08, 136.07, 129.51, 129.47, 129.36, 129.29, 129.21, 129.08, 128.88, 126.00, 123 .99,122.46,111.82,110.36,108.72,93.64,81.65,77.47,71.23,71.18,70.82,70.26,26.71
（５－２）化合物１４の合成
アルゴン雰囲気下、５０ｍＬ丸底フラスコに化合物１２（４２０ｍｇ，０．５０ｍｍｏｌ）とＳＤＩＳ（４６３ｍｇ，１．０１ｍｍｏｌ）をとり、脱水ジクロロメタン（２１ｍＬ）を加え撹拌し、澄明な溶液を得た。続いて、１，２－ジメチルイミダゾール（９８ｍｇ，１．０１ｍｍｏｌ）を室温で加え、２時間撹拌した。反応後、酢酸エチル（４２ｍＬ）で希釈した後、水を加えることで反応を停止した。引き続き、酢酸エチルにて３回抽出、得られた有機層を飽和食塩水により洗浄、無水硫酸ナトリウムで乾燥後、エバポレーターにて溶媒を減圧蒸留した。得られた残渣を分取薄層クロマトグラフィー（溶出溶媒：ヘキサン－酢酸エチル（２：１，ｖ／ｖ））により精製し、白いアモルファスとして化合物１４（４３４ｍｇ，０．６２ｍｍｏｌ，８２％）を得た。
(5-2) Synthesis of Compound 14 Under an argon atmosphere, compound 12 (420 mg, 0.50 mmol) and SDIS (463 mg, 1.01 mmol) were placed in a 50 mL round-bottomed flask, and dehydrated dichloromethane (21 mL) was added thereto and stirred. A solution was obtained. Subsequently, 1,2-dimethylimidazole (98 mg, 1.01 mmol) was added at room temperature and stirred for 2 hours. After the reaction, the reaction mixture was diluted with ethyl acetate (42 mL) and water was added to stop the reaction. Subsequently, the organic layer was extracted three times with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled under reduced pressure using an evaporator. The obtained residue was purified by preparative thin layer chromatography (elution solvent: hexane-ethyl acetate (2:1, v/v)) to obtain Compound 14 (434 mg, 0.62 mmol, 82%) as a white amorphous. Ta.
１Ｈ－ＮＭＲ（６００ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ７．５８（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ），７．５２（ｄｄ，Ｊ＝８．４，１．８Ｈｚ，１Ｈ），７．２４－７．４９（ｍ，２１Ｈ），７．１４（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），７．１１（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），５．５１－５．５３（ｍ，１Ｈ），５．３２（ｓ，２Ｈ），５．２８（ｓ，２Ｈ），５．２７（ｓ，２Ｈ），５．２６（ｓ，２Ｈ），３．２４（ｄｄ，Ｊ＝１７，４．１Ｈｚ，１ｈ），３．０７（ｄ，Ｊ＝１６Ｈｚ，１ｈ） 1 H-NMR (600MHz, acetone-d6) δ7.58 (d, J=1.9Hz, 1H), 7.52 (dd, J=8.4, 1.8Hz, 1H), 7.24-7 .49 (m, 21H), 7.14 (d, J = 2.3Hz, 1H), 7.11 (d, J = 2.3Hz, 1H), 5.51-5.53 (m, 1H) , 5.32 (s, 2H), 5.28 (s, 2H), 5.27 (s, 2H), 5.26 (s, 2H), 3.24 (dd, J=17, 4.1Hz , 1h), 3.07 (d, J=16Hz, 1h)
１３Ｃ－ＮＭＲ（１５０ＭＨｚ，ａｃｅｔｏｎｅ－ｄ６）δ１５６．３６，１５４．８８，１５３．３２，１５３．３０，１５３．１８，１５１．３４，１４９．４１，１４３．３４，１３７．２１，１３６．３７，１３６．０９，１３６．０７，１３６．０３，１２９．５５，１２９．５０，１２９．４６,１２９．２９,１２９．２１,１２９．０７,１２８．８６,１２６．００,１２３．９９，１２２．４５，１１３．４３，１０９．１１，１０８．７２，９３．６５，８１．３６，７７．４８，７１．３９，７１．２４，７０．８８，７０．２４，２６．４１． 13C -NMR (150MHz, acetone-d6) δ156.36, 154.88, 153.32, 153.30, 153.18, 151.34, 149.41, 143.34, 137.21, 136.37 , 136.09, 136.07, 136.03, 129.55, 129.50, 129.46, 129.29, 129.21, 129.07, 128.86, 126.00, 123.99, 122 .45, 113.43, 109.11, 108.72, 93.65, 81.36, 77.48, 71.39, 71.24, 70.88, 70.24, 26.41.
（６）（２Ｒ，３Ｒ）－２－（３′，４′－Ｄｉｈｙｄｒｏｘｙｐｈｅｎｙｌ）－３，７－ｄｉｈｙｄｒｏｘｙｃｈｒｏｍａｎ－５－ｙｌ ａｍｍｏｎｉｕｍ ｓｕｌｆａｔｅ（化合物２）及び（２Ｒ，３Ｒ）－２－（３′，４′－Ｄｉｈｙｄｒｏｘｙｐｈｅｎｙｌ）－３，５－ｄｉｈｙｄｒｏｘｙｃｈｒｏｍａｎ－７－ｙｌ ａｍｍｏｎｉｕｍ ｓｕｌｆａｔｅ（化合物３）の合成 (6) (2R,3R)-2-(3',4'-Dihydroxyphenyl)-3,7-dihydroxychroman-5-yl ammonium sulfate (compound 2) and (2R,3R)-2-(3',4 Synthesis of '-Dihydroxyphenyl)-3,5-dihydroxychroman-7-yl ammonium sulfate (Compound 3)
（６－１）化合物２の合成
アルゴン雰囲気下、５０ｍＬ丸底フラスコに化合物１３（８０ｍｇ，７７μｍｏｌ）とギ酸アンモニウム（４９ｍｇ，０．７７ｍｍｏｌ）をとり、テトラヒドロフラン－メタノール混合液（８ｍＬ，３：１）を加え撹拌し、澄明な溶液を得た。続いて、パラジウム炭素（２０ｍｇ）を室温で加え、フラスコ内を水素置換し、１６時間激しく撹拌した。反応後、パラジウム炭素を濾過、テトラヒドロフラン－メタノール混合液（３２ｍＬ，３：１）で洗浄、得られた有機層をエバポレーターにて溶媒を減圧蒸留した。得られた残渣を分取逆相薄層クロマトグラフィー（溶出溶媒：水－メタノール（９：１，ｖ／ｖ））により精製し、白色個体を得た。得られた個体を分取ＨＰＬＣにより精製し、白色個体として化合物２（２６ｍｇ，６７μｍｏｌ，８７％）を得た。
(6-1) Synthesis of Compound 2 Under an argon atmosphere, compound 13 (80 mg, 77 μmol) and ammonium formate (49 mg, 0.77 mmol) were placed in a 50 mL round bottom flask, and a mixture of tetrahydrofuran and methanol (8 mL, 3:1) was added. was added and stirred to obtain a clear solution. Subsequently, palladium on carbon (20 mg) was added at room temperature, the inside of the flask was replaced with hydrogen, and the mixture was vigorously stirred for 16 hours. After the reaction, the palladium on carbon was filtered, washed with a tetrahydrofuran-methanol mixture (32 mL, 3:1), and the solvent was distilled off under reduced pressure from the resulting organic layer using an evaporator. The obtained residue was purified by preparative reverse phase thin layer chromatography (elution solvent: water-methanol (9:1, v/v)) to obtain a white solid. The obtained solid was purified by preparative HPLC to obtain Compound 2 (26 mg, 67 μmol, 87%) as a white solid.
[分取条件]
分取カラム：Ｌ－ｃｏｌｕｍｎＯＤＳ,ｓｉｚｅ２０ｍｍｘ２５９ｍｍ５μｍ
溶離液：Ａ（１０ｍＭ酢酸酸アンモニウム水溶液）、Ｂ（アセトニトリル）
流速：２０ｍＬ／ｍｉｎ
注入量：５００μＬ
温度：４０℃
検出波長：２８０ｎｍ
グラジエント条件Ｂ（％）：１０％（５分）、１０→３０％（８分）
[Preparative conditions]
Preparative column: L-column ODS, size 20mm x 259mm 5μm
Eluent: A (10mM ammonium acetate aqueous solution), B (acetonitrile)
Flow rate: 20mL/min
Injection volume: 500μL
Temperature: 40℃
Detection wavelength: 280nm
Gradient condition B (%): 10% (5 minutes), 10 → 30% (8 minutes)
１Ｈ－ＮＭＲ（６００ＭＨｚ，ＤＭＳＯ－ｄ６）δ６．８９（ｓ，１Ｈ），６．６５（ｓ，２Ｈ），６．５３（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ），５．９３（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），４．７２（ｓ，１Ｈ），３．９７－３．９９（ｍ，１Ｈ），２．７８（ｄｄ，Ｊ＝１６，４．４Ｈｚ，１Ｈ），２．５８（ｄｄ，Ｊ＝１６，３．２Ｈｚ，１Ｈ） 1H -NMR (600MHz, DMSO-d6) δ6.89 (s, 1H), 6.65 (s, 2H), 6.53 (d, J = 2.2Hz, 1H), 5.93 (d, J=2.3Hz, 1H), 4.72 (s, 1H), 3.97-3.99 (m, 1H), 2.78 (dd, J=16, 4.4Hz, 1H), 2. 58 (dd, J=16, 3.2Hz, 1H)
ＨＲＭＳｃａｌｃｄ．ｆｏｒＣ１５Ｈ１５Ｏ９Ｓ＋［Ｍ＋Ｈ］＋：３７１．０４３１；ｆｏｕｎｄ：３７1．０４３８ HRMScalcd. forC 15 H 15 O 9 S + [M+H] + :371.0431; found:371.0438
（６－２）化合物３の合成
アルゴン雰囲気下、５０ｍＬ丸底フラスコに化合物１４（７３ｍｇ，７０μｍｏｌ）とギ酸アンモニウム（４５ｍｇ，０．７０ｍｍｏｌ）をとり、テトラヒドロフラン－メタノール混合液（８ｍＬ，３：１）を加え撹拌し、澄明な溶液を得た。続いて、パラジウム炭素（２０ｍｇ）を室温で加え、フラスコ内を水素置換し、１６時間激しく撹拌した。反応後、パラジウム炭素を濾過、テトラヒドロフラン－メタノール混合液（３２ｍＬ，３：１）で洗浄、得られた有機層をエバポレーターにて溶媒を減圧蒸留した。得られた残渣を分取逆相薄層クロマトグラフィー（溶出溶媒：水－メタノール（９：１，ｖ／ｖ））により精製し、白色個体を得た。得られた個体を分取ＨＰＬＣにより精製し、白色個体として化合物３（１７ｍｇ，４４μｍｏｌ，６３％）を得た。
(6-2) Synthesis of Compound 3 Under an argon atmosphere, compound 14 (73 mg, 70 μmol) and ammonium formate (45 mg, 0.70 mmol) were placed in a 50 mL round bottom flask, and a mixture of tetrahydrofuran and methanol (8 mL, 3:1) was added. was added and stirred to obtain a clear solution. Subsequently, palladium on carbon (20 mg) was added at room temperature, the inside of the flask was replaced with hydrogen, and the mixture was vigorously stirred for 16 hours. After the reaction, the palladium on carbon was filtered, washed with a tetrahydrofuran-methanol mixture (32 mL, 3:1), and the solvent was distilled off under reduced pressure from the resulting organic layer using an evaporator. The obtained residue was purified by preparative reverse phase thin layer chromatography (elution solvent: water-methanol (9:1, v/v)) to obtain a white solid. The obtained solid was purified by preparative HPLC to obtain Compound 3 (17 mg, 44 μmol, 63%) as a white solid.
[分取条件]
分取カラム：Ｌ－ｃｏｌｕｍｎＯＤＳ,ｓｉｚｅ２０ｍｍｘ２５９ｍｍ５μｍ
溶離液：Ａ（１０ｍＭ酢酸アンモニウム水溶液）、Ｂ（アセトニトリル）
流速：２０ｍＬ／ｍｉｎ
注入量：５００μＬ
温度：４０℃
検出波長：２８０ｎｍ
グラジエント条件Ｂ（％）：１０％（５分）、１０→２０％（１２分）
[Preparative conditions]
Preparative column: L-column ODS, size 20mm x 259mm 5μm
Eluent: A (10mM ammonium acetate aqueous solution), B (acetonitrile)
Flow rate: 20mL/min
Injection volume: 500μL
Temperature: 40℃
Detection wavelength: 280nm
Gradient condition B (%): 10% (5 minutes), 10 → 20% (12 minutes)
１Ｈ－ＮＭＲ（６００ＭＨｚ，ＤＭＳＯ－ｄ６）δ６．９１（ｓ，１Ｈ），６．６６（ｓ，２Ｈ），６．３１（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），６．１２（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），４．７６（ｓ，１Ｈ），４．０（ｍ，１Ｈ），２．７２（ｄｄ，Ｊ＝１６，４．３Ｈｚ，１Ｈ），２．５５（ｄｄ，Ｊ＝１６，２．６Ｈｚ，１Ｈ） 1H -NMR (600MHz, DMSO-d6) δ6.91 (s, 1H), 6.66 (s, 2H), 6.31 (d, J = 2.0Hz, 1H), 6.12 (d, J = 2.0Hz, 1H), 4.76 (s, 1H), 4.0 (m, 1H), 2.72 (dd, J = 16, 4.3Hz, 1H), 2.55 (dd, J=16, 2.6Hz, 1H)
ＨＲＭＳｃａｌｃｄ．ｆｏｒＣ１５Ｈ１５Ｏ９Ｓ＋［Ｍ＋Ｈ］＋：３７１．０４３１；ｆｏｕｎｄ：３７１．０４４２． HRMScalcd. forC 15 H 15 O 9 S + [M+H] + :371.0431; found: 371.0442.
実施例２ グルクロン酸抱合体の製造
（１）化合物１５及び化合物１６の合成
Example 2 Production of glucuronide conjugate (1) Synthesis of compound 15 and compound 16
（１－１）化合物１５の合成
アルゴン雰囲気下、５０ｍＬ丸底フラスコに化合物１０（１５０ｍｇ，０．１８ｍｍｏｌ）、２，３，４－トリ－Ｏ－アセチル－１－Ｏ－（トリクロロアセトイミドイル）－α－Ｄ－グルクロン酸メチル（６０ｍｇ，０．５４ｍｍｏｌ）、そしてモレキュラーシーブス４Å（７５０ｍｇ）をとり、脱水ジクロロメタン（１０ｍＬ）を加え撹拌し、澄明な溶液を得た。続いて、トリフルオロボランエーテル錯体（４６０μＬ，３．６３ｍｍｏｌ）を０℃で加えた後、室温まで昇温し、１６時間撹拌した。反応後、酢酸エチル（２０ｍＬ）で希釈した後、水を加えることで反応を停止した。引き続き、酢酸エチルにて３回抽出、得られた有機層を飽和食塩水により洗浄、無水硫酸ナトリウムで乾燥後、エバポレーターにて溶媒を減圧蒸留した。得られた残渣を分取順相薄層クロマトグラフィー（溶出溶媒：ヘキサン－酢酸エチル（２：１，ｖ／ｖ））により粗精製し、白いアモルファスとして混合物（１０３ｍｇ）を得た。
(1-1) Synthesis of Compound 15 Under an argon atmosphere, compound 10 (150 mg, 0.18 mmol) and 2,3,4-tri-O-acetyl-1-O-(trichloroacetimidoyl) were placed in a 50 mL round bottom flask. Methyl -α-D-glucuronate (60 mg, 0.54 mmol) and molecular sieves 4 Å (750 mg) were taken, and dehydrated dichloromethane (10 mL) was added and stirred to obtain a clear solution. Subsequently, trifluoroborane ether complex (460 μL, 3.63 mmol) was added at 0° C., then the mixture was heated to room temperature and stirred for 16 hours. After the reaction, the reaction mixture was diluted with ethyl acetate (20 mL) and water was added to stop the reaction. Subsequently, the organic layer was extracted three times with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled under reduced pressure using an evaporator. The obtained residue was roughly purified by preparative normal phase thin layer chromatography (elution solvent: hexane-ethyl acetate (2:1, v/v)) to obtain a mixture (103 mg) as a white amorphous.
（１－２）化合物１６の合成
アルゴン雰囲気下、５０ｍＬ丸底フラスコに化合物１２（１５０ｍｇ，０．１８ｍｍｏｌ）、２，３，４－トリ－Ｏ－アセチル－１－Ｏ－（トリクロロアセトイミドイル）－α－Ｄ－グルクロン酸メチル（２６０ｍｇ，０．５４ｍｍｏｌ）、そしてモレキュラーシーブス４Å（７５０ｍｇ）をとり、脱水ジクロロメタン（１０ｍＬ）を加え撹拌し、澄明な溶液を得た。続いて、トリフルオロボランエーテル錯体（４６０μＬ，３．６３ｍｍｏｌ）を０℃で加えた後、室温まで昇温し、１６時間撹拌した。反応後、酢酸エチル（２０ｍＬ）で希釈した後、水を加えることで反応を停止した。引き続き、酢酸エチルにて３回抽出、得られた有機層を飽和食塩水により洗浄、無水硫酸ナトリウムで乾燥後、エバポレーターにて溶媒を減圧蒸留した。得られた残渣を分取順相薄層クロマトグラフィー（溶出溶媒：ヘキサン－酢酸エチル（２：１，ｖ／ｖ））により粗精製し、白いアモルファスとして混合物（１５３ｍｇ）を得た。
(1-2) Synthesis of Compound 16 Under argon atmosphere, compound 12 (150 mg, 0.18 mmol), 2,3,4-tri-O-acetyl-1-O-(trichloroacetimidoyl) was placed in a 50 mL round bottom flask. Methyl -α-D-glucuronate (260 mg, 0.54 mmol) and molecular sieves 4 Å (750 mg) were taken, and dehydrated dichloromethane (10 mL) was added and stirred to obtain a clear solution. Subsequently, trifluoroborane ether complex (460 μL, 3.63 mmol) was added at 0° C., then the mixture was heated to room temperature and stirred for 16 hours. After the reaction, the reaction mixture was diluted with ethyl acetate (20 mL) and water was added to stop the reaction. Subsequently, the organic layer was extracted three times with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled under reduced pressure using an evaporator. The obtained residue was roughly purified by preparative normal phase thin layer chromatography (elution solvent: hexane-ethyl acetate (2:1, v/v)) to obtain a mixture (153 mg) as a white amorphous.
（２）（２Ｒ，３Ｒ，４Ｒ，５Ｓ，６Ｒ）－６－（（（２′Ｒ，３′Ｒ）－２－（３″，４″－Ｄｉｈｙｄｒｏｘｙｐｈｅｎｙｌ）－３′，７′－ｄｉｈｙｄｒｏｘｙｃｈｒｏｍａｎ－５′－ｙｌ）ｏｘｙ）－３，４，５－ｔｒｉｈｙｄｒｏｘｙｔｅｔｒａｈｙｄｒｏ－２Ｈ－ｐｙｒａｎ－２－ｃａｒｂｏｘｙｌｉｃ ａｃｉｄ（化合物４）及び（２Ｒ，３Ｒ，４Ｒ，５Ｓ，６Ｒ）－６－（（（２′Ｒ，３′Ｒ）－２－（３″，４″－Ｄｉｈｙｄｒｏｘｙｐｈｅｎｙｌ）－３′，５′－ｄｉｈｙｄｒｏｘｙｃｈｒｏｍａｎ－７′－ｙｌ）ｏｘｙ）－３，４，５－ｔｒｉｈｙｄｒｏｘｙｔｅｔｒａｈｙｄｒｏ－２Ｈ－ｐｙｒａｎ－２－ｃａｒｂｏｘｙｌｉｃ ａｃｉｄ（化合物５）の合成 (2)(2R,3R,4R,5S,6R)-6-(((2'R,3'R)-2-(3'',4''-Dihydroxyphenyl)-3',7'-dihydroxychroman-5 '-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (compound 4) and (2R,3R,4R,5S,6R)-6-(((2'R,3 'R)-2-(3'',4''-Dihydroxyphenyl)-3',5'-dihydroxychroman-7'-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (compound 5) Synthesis
（２－１）化合物４の合成
アルゴン雰囲気下、２０ｍＬ丸底フラスコに化合物１５の合成で得られた混合物（１０３ｍｇ）をとり、テトラヒドロフラン－メタノール混合液（４ｍＬ，３：１）を加え撹拌し、澄明な溶液を得た。続いて、パラジウム炭素（３３ｍｇ）を室温で加え、フラスコ内を水素置換し、３時間激しく撹拌した。反応後、パラジウム炭素を濾過、テトラヒドロフランーメタノール混合液（３２ｍＬ，３：１）で洗浄、得られた有機層をエバポレーターにて溶媒を減圧蒸留した。引き続き、脱水メタノール（１０ｍＬ）とナトリウムメトキシドメタノール溶液（３９７μＬ，１．９８ｍｍｏｌ）を氷浴で冷却下、順次加え、３０分間撹拌した。撹拌後、精製水（３．９７ｍＬ）を加え、さらに室温で３０分間撹拌した。その後、エバポレーターにて溶媒を減圧蒸留し、得られた残渣を分取ＨＰＬＣにより精製し、白色個体として化合物４（１７ｍｇ，３６μｍｏｌ，２０％（３行程収率））を得た。
(2-1) Synthesis of Compound 4 Under an argon atmosphere, the mixture obtained in the synthesis of Compound 15 (103 mg) was placed in a 20 mL round bottom flask, and a tetrahydrofuran-methanol mixture (4 mL, 3:1) was added and stirred. A clear solution was obtained. Subsequently, palladium on carbon (33 mg) was added at room temperature, the inside of the flask was replaced with hydrogen, and the mixture was vigorously stirred for 3 hours. After the reaction, the palladium on carbon was filtered, washed with a tetrahydrofuran-methanol mixture (32 mL, 3:1), and the solvent was distilled off under reduced pressure from the resulting organic layer using an evaporator. Subsequently, dehydrated methanol (10 mL) and sodium methoxide methanol solution (397 μL, 1.98 mmol) were sequentially added while cooling in an ice bath, and the mixture was stirred for 30 minutes. After stirring, purified water (3.97 mL) was added, and the mixture was further stirred at room temperature for 30 minutes. Thereafter, the solvent was distilled under reduced pressure using an evaporator, and the resulting residue was purified by preparative HPLC to obtain Compound 4 (17 mg, 36 μmol, 20% (3-step yield)) as a white solid.
[分取条件]
分取カラム：Ｌ－ｃｏｌｕｍｎＯＤＳ,ｓｉｚｅ２０ｍｍｘ２５９ｍｍ５μｍ
溶離液：Ａ（０．１％ギ酸水溶液）、Ｂ（アセトニトリル）
流速：２０ｍＬ／ｍｉｎ
注入量：５００μＬ
温度：４０℃
検出波長：２８０ｎｍ
グラジエント条件Ｂ（％）：３→１０％（５分）、１０％（１０分）
[Preparative conditions]
Preparative column: L-column ODS, size 20mm x 259mm 5μm
Eluent: A (0.1% formic acid aqueous solution), B (acetonitrile)
Flow rate: 20mL/min
Injection volume: 500μL
Temperature: 40℃
Detection wavelength: 280nm
Gradient condition B (%): 3 → 10% (5 minutes), 10% (10 minutes)
１Ｈ－ＮＭＲ（６００ＭＨｚ，Ｄ２Ｏ－ａｃｅｔｏｎｅ－ｄ６（１：９））δ７．００（ｄ，Ｊ＝１．８Ｈｚ，１Ｈ），６．７８（ｄｄ，Ｊ＝８．１，１．７Ｈｚ，１Ｈ），６．７５（ｄ，Ｊ＝８．１Ｈｚ，１Ｈ），６．４９（ｄ，Ｊ＝２．１Ｈｚ，１Ｈ），６．００（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ），４．８３（ｓ，１Ｈ），４．８０ｄ，Ｊ＝７．２Ｈｚ，１Ｈ），４．１６（ｍ，１Ｈ），３．７０（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），３．５２－３．５５（ｍ，３Ｈ），２．９０（ｄｄ，Ｊ＝１６，３．１Ｈｚ，１Ｈ），２．８４（ｄｄ，Ｊ＝１６，４．３Ｈｚ，１Ｈ） 1 H-NMR (600 MHz, D 2 O-acetone-d6 (1:9)) δ7.00 (d, J = 1.8 Hz, 1H), 6.78 (dd, J = 8.1, 1.7 Hz , 1H), 6.75 (d, J = 8.1Hz, 1H), 6.49 (d, J = 2.1Hz, 1H), 6.00 (d, J = 2.2Hz, 1H), 4 .83 (s, 1H), 4.80d, J = 7.2Hz, 1H), 4.16 (m, 1H), 3.70 (d, J = 8.5Hz, 1H), 3.52-3 .55 (m, 3H), 2.90 (dd, J=16, 3.1Hz, 1H), 2.84 (dd, J=16, 4.3Hz, 1H)
ＨＲＭＳｃａｌｃｄ．ｆｏｒＣ２１Ｈ２２Ｏ１２Ｎａ＋［Ｍ＋Ｎａ］＋：４８９．１００３；ｆｏｕｎｄ：４８９．１００４． HRMScalcd. forC 21 H 22 O 12 Na + [M+Na] + :489.1003; found: 489.1004.
（２－２）化合物５の合成
アルゴン雰囲気下、２０ｍＬL丸底フラスコに化合物１６の合成で得られた混合物（１５３ｍｇ）をとり、テトラヒドロフラン－メタノール混合液（４ｍＬ，３：１）を加え撹拌し、澄明な溶液を得た。続いて、パラジウム炭素（５０ｍｇ）を室温で加え、フラスコ内を水素置換し、３時間激しく撹拌した。反応後、パラジウム炭素を濾過、テトラヒドロフランーメタノール混合液（３２ｍＬ，３：１）で洗浄、得られた有機層をエバポレーターにて溶媒を減圧蒸留した。引き続き、脱水メタノール（１０ｍＬ）とナトリウムメトキシドメタノール溶液（５９１μＬ，２．９４ｍｍｏｌ）を氷浴で冷却下、順次加え、３０分間撹拌した。撹拌後、精製水（５．９１ｍＬ）を加え、さらに室温で３０分間撹拌した。その後、エバポレーターにて溶媒を減圧蒸留し、得られた残渣を分取ＨＰＬＣにより精製し、白色個体として化合物５（１０ｍｇ，２１μｍｏｌ，１２％（３行程収率））を得た。
(2-2) Synthesis of compound 5 Under an argon atmosphere, the mixture obtained in the synthesis of compound 16 (153 mg) was placed in a 20 mL round bottom flask, and a tetrahydrofuran-methanol mixture (4 mL, 3:1) was added and stirred. A clear solution was obtained. Subsequently, palladium on carbon (50 mg) was added at room temperature, the inside of the flask was replaced with hydrogen, and the mixture was vigorously stirred for 3 hours. After the reaction, the palladium on carbon was filtered, washed with a tetrahydrofuran-methanol mixture (32 mL, 3:1), and the solvent was distilled off under reduced pressure from the resulting organic layer using an evaporator. Subsequently, dehydrated methanol (10 mL) and sodium methoxide methanol solution (591 μL, 2.94 mmol) were sequentially added while cooling in an ice bath, and the mixture was stirred for 30 minutes. After stirring, purified water (5.91 mL) was added, and the mixture was further stirred at room temperature for 30 minutes. Thereafter, the solvent was distilled under reduced pressure using an evaporator, and the resulting residue was purified by preparative HPLC to obtain Compound 5 (10 mg, 21 μmol, 12% (3-step yield)) as a white solid.
[分取条件]
分取カラム：Ｌ－ｃｏｌｕｍｎＯＤＳ,ｓｉｚｅ２０ｍｍｘ２５９ｍｍ５μｍ
溶離液：Ａ（０．１％ギ酸水溶液）、Ｂ（アセトニトリル）
流速：２０ｍＬ／ｍｉｎ
注入量：５００μＬ
温度：４０℃
検出波長：２８０ｎｍ
グラジエント条件Ｂ（％）：３→１０％（５分）、１０％（１５分）
[Preparative conditions]
Preparative column: L-column ODS, size 20mm x 259mm 5μm
Eluent: A (0.1% formic acid aqueous solution), B (acetonitrile)
Flow rate: 20mL/min
Injection volume: 500μL
Temperature: 40℃
Detection wavelength: 280nm
Gradient condition B (%): 3 → 10% (5 minutes), 10% (15 minutes)
１Ｈ－ＮＭＲ（６００ＭＨｚ，Ｄ２Ｏ－ａｃｅｔｏｎｅ－ｄ６（９：１））δ６．８９（ｓ，１Ｈ），６．７８（ｍ，２Ｈ），６．１８（ｓ，１Ｈ），６．１６（ｓ，１Ｈ），４．８７（ｄ，Ｊ＝６．９Ｈｚ，１Ｈ），４．７９（ｓ，１Ｈ），４．１８（ｓ，１Ｈ），３．６８（ｍ，１Ｈ），３．４１－３．４６（ｍ，３Ｈ），２．７８（ｄｄ，Ｊ＝１６，３．１Ｈｚ，１Ｈ），２．６４（ｄ，Ｊ＝１６Ｈｚ，１Ｈ） 1 H-NMR (600 MHz, D 2 O-acetone-d6 (9:1)) δ6.89 (s, 1H), 6.78 (m, 2H), 6.18 (s, 1H), 6.16 (s, 1H), 4.87 (d, J=6.9Hz, 1H), 4.79 (s, 1H), 4.18 (s, 1H), 3.68 (m, 1H), 3. 41-3.46 (m, 3H), 2.78 (dd, J=16, 3.1Hz, 1H), 2.64 (d, J=16Hz, 1H)
ＨＲＭＳｃａｌｃｄ．ｆｏｒＣ２１Ｈ２２Ｏ１２Ｎａ＋［Ｍ＋Ｎａ］＋：４８９．１００３；ｆｏｕｎｄ：４８９．１０２０． HRMScalcd. forC 21 H 22 O 12 Na + [M+Na] + :489.1003; found: 489.1020.
比較例
本発明の工程－２において、ｔ－ブチルジメチルシリルクロリドに代えて、表１に示す試薬を用いてＡ環の水酸基保護を検討したが、アリル化試薬の場合、反応性が低く目的の化合物が得られなかった。一方で、ｔ－ブチルジメチルシリルクロリドでは、５置換体ならびに７置換体が良好な収率で得られた。
Comparative Example In Step-2 of the present invention, protection of the hydroxyl group of the A ring was investigated using the reagents shown in Table 1 instead of t-butyldimethylsilyl chloride, but in the case of the allylating reagent, the reactivity was low and the target No compound was obtained. On the other hand, with t-butyldimethylsilyl chloride, penta-substituted and hepta-substituted products were obtained in good yields.
Claims (2)
で表されるシリル化カテキン誘導体とし、次いで、その水酸基をベンジルオキシカルボニル化して、下記式（ＩＶ）：
で表されるシリル化カテキン保護誘導体とし、次いで、ＴＢＳ基を脱離して下記式（Ｖ）：
で表される化合物とし、次いで、硫酸化、メチル化、グルクロン酸化及びグルコシル化から選ばれる抱合反応に付し、続いて保護基を脱離する、下記式（ＶＩ）：
で表されるカテキン抱合体の製造方法。 The following formula (I):
A silylated catechin derivative represented by the following formula (IV) is obtained, and the hydroxyl group is then benzyloxycarbonylated to obtain the following formula (IV):
A silylated catechin protected derivative represented by is obtained, and then the TBS group is removed to obtain the following formula (V):
A compound represented by the following formula (VI):
A method for producing a catechin conjugate represented by
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| JP2009007272A (en) | 2007-06-27 | 2009-01-15 | Toyama Prefecture | New method for producing 3-o-substituted catechin derivative |
| CN104327034A (en) | 2014-09-30 | 2015-02-04 | 浙江大学 | Selective preparation method for 5-site and 7-site ester catechin molecules |
| CN111233810A (en) | 2020-01-18 | 2020-06-05 | 安徽农业大学 | Preparation method and application of hydroxycinnamoyl ester type catechin |
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| JP2009007272A (en) | 2007-06-27 | 2009-01-15 | Toyama Prefecture | New method for producing 3-o-substituted catechin derivative |
| CN104327034A (en) | 2014-09-30 | 2015-02-04 | 浙江大学 | Selective preparation method for 5-site and 7-site ester catechin molecules |
| CN111233810A (en) | 2020-01-18 | 2020-06-05 | 安徽农业大学 | Preparation method and application of hydroxycinnamoyl ester type catechin |
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| Title |
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| DOCAMPO-PALACIOS, Maite L. et al.，Efficient Chemical Synthesis of (Epi)catechin Glucuronides: Brain-Targeted Metabolites for Treatment，ACS Omega，2020年11月12日，Volume 5, Issue 46，pp. 30095-30110 |
| VAN DYK, Martha S. et al.，Selective O-methylation of polyhydroxyflavan-3-ols via benzyl carbonates，Tetrahedron Letters，1990年，Volume 31, Issue 18，pp. 2643-2646 |
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