JP2009542796A - ピロリジン置換フラボンのエナンチオ選択的合成 - Google Patents
ピロリジン置換フラボンのエナンチオ選択的合成 Download PDFInfo
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- JP2009542796A JP2009542796A JP2009518985A JP2009518985A JP2009542796A JP 2009542796 A JP2009542796 A JP 2009542796A JP 2009518985 A JP2009518985 A JP 2009518985A JP 2009518985 A JP2009518985 A JP 2009518985A JP 2009542796 A JP2009542796 A JP 2009542796A
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- 238000003786 synthesis reaction Methods 0.000 title abstract description 10
- 230000015572 biosynthetic process Effects 0.000 title abstract description 9
- 229930003944 flavone Natural products 0.000 title abstract description 4
- 235000011949 flavones Nutrition 0.000 title abstract description 4
- 150000002213 flavones Chemical class 0.000 title abstract 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 title 1
- 150000003839 salts Chemical group 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims description 65
- 238000000034 method Methods 0.000 claims description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 26
- -1 C 1 -C 4 -alkoxy Chemical group 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 239000011541 reaction mixture Substances 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000002585 base Substances 0.000 claims description 16
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 239000003638 chemical reducing agent Substances 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 10
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 claims description 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000007868 Raney catalyst Substances 0.000 claims description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 6
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 6
- 150000004696 coordination complex Chemical class 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 6
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 6
- 239000001119 stannous chloride Substances 0.000 claims description 6
- 235000011150 stannous chloride Nutrition 0.000 claims description 6
- 229940126062 Compound A Drugs 0.000 claims description 5
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 229940125782 compound 2 Drugs 0.000 claims description 5
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- BZQRBEVTLZHKEA-UHFFFAOYSA-L magnesium;trifluoromethanesulfonate Chemical compound [Mg+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F BZQRBEVTLZHKEA-UHFFFAOYSA-L 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- YHGHAFKDRXNDMC-LKFCYVNXSA-N (2r,3s)-1-methyl-5-oxo-3-(2,4,6-trimethoxyphenyl)pyrrolidine-2-carboxylic acid Chemical compound COC1=CC(OC)=CC(OC)=C1[C@H]1[C@H](C(O)=O)N(C)C(=O)C1 YHGHAFKDRXNDMC-LKFCYVNXSA-N 0.000 claims description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 239000012649 demethylating agent Substances 0.000 claims description 4
- FRXQVOYXWZGMLI-UHFFFAOYSA-N dimethyl 5-oxo-3-(2,4,6-trimethoxyphenyl)pyrrolidine-2,4-dicarboxylate Chemical compound COC(=O)C1NC(=O)C(C(=O)OC)C1C1=C(OC)C=C(OC)C=C1OC FRXQVOYXWZGMLI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 4
- YZPQGUSGVWCEFZ-JXMROGBWSA-N methyl (e)-2-nitro-3-(2,4,6-trimethoxyphenyl)prop-2-enoate Chemical compound COC(=O)C(\[N+]([O-])=O)=C/C1=C(OC)C=C(OC)C=C1OC YZPQGUSGVWCEFZ-JXMROGBWSA-N 0.000 claims description 4
- 239000002808 molecular sieve Substances 0.000 claims 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 claims description 4
- KFGFAPZWUZEIPL-UHFFFAOYSA-N trimethyl 3-nitro-2-(2,4,6-trimethoxyphenyl)propane-1,1,3-tricarboxylate Chemical compound COC(=O)C(C(=O)OC)C(C(C(=O)OC)[N+]([O-])=O)C1=C(OC)C=C(OC)C=C1OC KFGFAPZWUZEIPL-UHFFFAOYSA-N 0.000 claims description 4
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 claims description 4
- 229910015900 BF3 Inorganic materials 0.000 claims description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 3
- UYQMRAQWCFNNAV-NEPJUHHUSA-N [(2r,3s)-1-methyl-3-(2,4,6-trimethoxyphenyl)pyrrolidin-2-yl]methanol Chemical compound COC1=CC(OC)=CC(OC)=C1[C@H]1[C@H](CO)N(C)CC1 UYQMRAQWCFNNAV-NEPJUHHUSA-N 0.000 claims description 3
- RIYGVWPZTGPGKT-OLZOCXBDSA-N [(2r,3s)-3-(3-acetyl-2-hydroxy-4,6-dimethoxyphenyl)-1-methylpyrrolidin-2-yl]methyl acetate Chemical compound COC1=CC(OC)=C(C(C)=O)C(O)=C1[C@H]1[C@H](COC(C)=O)N(C)CC1 RIYGVWPZTGPGKT-OLZOCXBDSA-N 0.000 claims description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 3
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 3
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 3
- 239000012670 alkaline solution Substances 0.000 claims description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 230000001335 demethylating effect Effects 0.000 claims description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 3
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 3
- 239000012022 methylating agents Substances 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 238000012545 processing Methods 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 claims description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 2
- LJUQGASMPRMWIW-UHFFFAOYSA-N 5,6-dimethylbenzimidazole Chemical compound C1=C(C)C(C)=CC2=C1NC=N2 LJUQGASMPRMWIW-UHFFFAOYSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- MPCRDALPQLDDFX-UHFFFAOYSA-L Magnesium perchlorate Chemical compound [Mg+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O MPCRDALPQLDDFX-UHFFFAOYSA-L 0.000 claims description 2
- 238000006845 Michael addition reaction Methods 0.000 claims description 2
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 2
- ZKXWKVVCCTZOLD-UHFFFAOYSA-N copper;4-hydroxypent-3-en-2-one Chemical compound [Cu].CC(O)=CC(C)=O.CC(O)=CC(C)=O ZKXWKVVCCTZOLD-UHFFFAOYSA-N 0.000 claims description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- WGJJZRVGLPOKQT-UHFFFAOYSA-K lanthanum(3+);trifluoromethanesulfonate Chemical compound [La+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F WGJJZRVGLPOKQT-UHFFFAOYSA-K 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 2
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 2
- BLQJIBCZHWBKSL-UHFFFAOYSA-L magnesium iodide Chemical compound [Mg+2].[I-].[I-] BLQJIBCZHWBKSL-UHFFFAOYSA-L 0.000 claims description 2
- 229910001641 magnesium iodide Inorganic materials 0.000 claims description 2
- AKTIAGQCYPCKFX-FDGPNNRMSA-L magnesium;(z)-4-oxopent-2-en-2-olate Chemical compound [Mg+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O AKTIAGQCYPCKFX-FDGPNNRMSA-L 0.000 claims description 2
- LNUMNTDMTRECOT-UHFFFAOYSA-N methyl 5-oxo-3-(2,4,6-trimethoxyphenyl)pyrrolidine-2-carboxylate Chemical compound COC(=O)C1NC(=O)CC1C1=C(OC)C=C(OC)C=C1OC LNUMNTDMTRECOT-UHFFFAOYSA-N 0.000 claims description 2
- BMGNSKKZFQMGDH-FDGPNNRMSA-L nickel(2+);(z)-4-oxopent-2-en-2-olate Chemical compound [Ni+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O BMGNSKKZFQMGDH-FDGPNNRMSA-L 0.000 claims description 2
- UQPSGBZICXWIAG-UHFFFAOYSA-L nickel(2+);dibromide;trihydrate Chemical compound O.O.O.Br[Ni]Br UQPSGBZICXWIAG-UHFFFAOYSA-L 0.000 claims description 2
- KVRSDIJOUNNFMZ-UHFFFAOYSA-L nickel(2+);trifluoromethanesulfonate Chemical compound [Ni+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F KVRSDIJOUNNFMZ-UHFFFAOYSA-L 0.000 claims description 2
- BFSQJYRFLQUZKX-UHFFFAOYSA-L nickel(ii) iodide Chemical compound I[Ni]I BFSQJYRFLQUZKX-UHFFFAOYSA-L 0.000 claims description 2
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 2
- 229940102001 zinc bromide Drugs 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Substances [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 claims description 2
- ZMLPZCGHASSGEA-UHFFFAOYSA-M zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F ZMLPZCGHASSGEA-UHFFFAOYSA-M 0.000 claims description 2
- NHXVNEDMKGDNPR-UHFFFAOYSA-N zinc;pentane-2,4-dione Chemical compound [Zn+2].CC(=O)[CH-]C(C)=O.CC(=O)[CH-]C(C)=O NHXVNEDMKGDNPR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 229910001623 magnesium bromide Inorganic materials 0.000 claims 1
- 108091007914 CDKs Proteins 0.000 abstract description 7
- 239000003112 inhibitor Substances 0.000 abstract description 6
- 102000003903 Cyclin-dependent kinases Human genes 0.000 abstract description 5
- 108090000266 Cyclin-dependent kinases Proteins 0.000 abstract description 5
- 230000002062 proliferating effect Effects 0.000 abstract description 4
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 201000011510 cancer Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 150000003235 pyrrolidines Chemical group 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 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 7
- 238000003756 stirring Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
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- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WATRIVZUMSBBDY-UHFFFAOYSA-N methyl 1-methyl-5-oxo-3-(2,4,6-trimethoxyphenyl)pyrrolidine-2-carboxylate Chemical compound C1C(=O)N(C)C(C(=O)OC)C1C1=C(OC)C=C(OC)C=C1OC WATRIVZUMSBBDY-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
本発明は、具体的には式1;
ここで、R1およびR2は各々、水素、C1−C4−アルキル、C1−C4−アルキルカルボニルおよびアリールから独立して選択されるか、またはR1およびR2は、それらが結合される窒素原子と共に、任意で少なくとも1つの追加ヘテロ原子を含んでもよい5員環または6員環を形成し;
R3は、水素、C1−C4−アルキル、アリールおよびSR4から選択され、ここでR4は、C1−C4−アルキルまたはアリールである)によって表わされる化合物の(+)−トランスエナンチオマーのエナンチオ選択的合成方法に関する。
(a)錯体触媒、塩基およびモレキュラーシーブの存在下の溶媒中で、(E)−メチル−2−ニトロ−3−(2,4,6−トリメトキシフェニル)アクリレートへのマロン酸ジメチルの立体選択的マイケル付加を行って(ここで、錯体触媒はキラルビス(オキサゾリン)配位子および金属錯体を含む)、以下の式B;
(b)適切な溶媒中にて、工程(a)において得られるような化合物Bを還元剤で処理し、以下の式C;
(c)溶媒中にて化合物Cを塩化ナトリウムで処理し、結果として生じる反応混合物を120〜170℃の範囲内の温度まで熱して、以下の式D;
(d)溶媒中でメチル化剤ならびにアルカリ金属水素化物およびアルカリ金属炭酸塩から選択される塩基と化合物Dとを反応させ、続いて結果として生じるシスおよびトランスの化合物の混合物を、50〜100℃の範囲内の温度まで加熱しながら、アルコール中のアルカリ金属水酸化物によりアルカリ加水分解し、単一トランス異性体として以下の式E;
(e)溶媒中にて、還元剤で化合物Eを処理し、式Aによって表わされる所望の(−)−トランス−(1−メチル−3−(2,4,6−トリメトキシフェニル)ピロリジン−2−イル)−メタノールを得る工程とを含む。
ここで、R1およびR2は各々、水素、C1−C4−アルキル、C1−C4−アルキルカルボニルおよびアリールから独立して選択されるか、またはR1およびR2は、それらが結合される窒素原子と共に、任意で少なくとも1つの追加ヘテロ原子を含んでもよい5員環または6員環を形成し;
R3は、水素、C1−C4−アルキル、アリールおよびSR4から選択され、ここでR4は、C1−C4−アルキルまたはアリールである)
によって表わされる化合物の(+)−トランスエナンチオマー;またはその薬学的に許容される塩の調製方法が提供され;この方法は、
(i)触媒の存在下において無水酢酸を化合物A(上記)で処理し、以下の式F;
(ii)アルカリ水溶液で化合物Fを処理し、反応混合物の温度を約50℃まで上昇させて、以下の式G;
(iii)化合物Gを、窒素雰囲気下で塩基および適切な溶媒の存在下において、式ArCOOCH3(式中、Arは式1において定義されるようなものである)のエステルと反応させ、続いて酸触媒環化を行って、以下の式2;
(iv)120〜180℃の範囲内の温度で脱メチル化剤と共に熱することによって、化合物2を脱メチル化し、式1によって表わされる化合物の所望の(+)−トランスエナンチオマーを得ることとを含む。
(i)化合物Aを触媒の存在下において無水酢酸で処理し、以下の式F;
(ii)アルカリ水溶液により化合物Fを処理し、反応混合物の温度を約50℃まで上昇させて、以下の式G;
(iii)化合物Gを、窒素雰囲気下で塩基および適切な溶媒の存在下において、メチル2−クロロベンゾエートと反応させ、続いて酸触媒環化を行い、以下の式2A;
(iv)120〜180℃の範囲内の温度でピリジン塩酸塩と共に熱することによって化合物2Aを脱メチル化し、化合物1Aを得ることと;
(v)任意で、化合物1Aを、従来の手段によって、その塩酸塩((+)−トランス−2−(2−クロロフェニル)−5,7−ジヒドロキシ−8−(2−ヒドロキシメチル−1−メチル−ピロリジン−3−イル)−クロメン−4−オン塩酸塩)のような、その薬学的に許容される塩に変換することとを含む。
2,4,6−トリメトキシベンズアルデヒド(20.75g、0.105mol)をジクロロメタン(300mL)中で溶解し、この溶液に、硫酸マグネシウム(15g、0.124mol)および酢酸アンモニウム(10g、0.129mol)およびニトロ酢酸メチル(12.60g、0.105mol)を加えて2時間室温で撹拌した。2時間の終了時に、水(300mL)を反応生成量まで加え、有機層を分離し、水層をジクロロメタン(2×100mL)により抽出した。有機層を組み合わせ、減圧下で濃縮して固体を得て、この固体をメタノール(100mL)から結晶化した。
1H NMR(CDCl3):δ8.37(s,1H),6.08(s,2H),3.86(s,3H),3.84(s,3H),3.82(s,6H).
MS(ES+):298(M+1)
窒素下で維持された二首の500mL丸底フラスコ中で、クロロホルム(10mL)、マグネシウムトリフラート(0.161g、0.5mmol)および水(0.036mL、2.0 mmol)を加えた。この撹拌された溶液に、(3aS,3a’S,8aR,8a’R)−2,2’(シクロプロパン−1,1−ジイル)ビス(8,8a−ジヒドロ−3aH−インデノ[1,2d]オキサゾール)(ビス(オキサゾリン))(0.196g,0.55mmol)を加え、反応混合物を1時間撹拌した。1時間の終了時に、クロロホルム(30mL)およびモレキュラーシーブ(2g)を加え、その混合物をさらに90分間撹拌した。(E)−メチル−2−ニトロ−3−(2,4,6−トリメトキシフェニル)アクリレート(3.1g、0.01mol)、マロン酸ジメチル(1.92g、0.014mol)およびN−メチルモルホリン(0.06g、0.6 mmol)を加え、反応混合物を12時間撹拌し、続いて40℃で4時間加熱した。石油エーテル(15mL)を反応混合物へ加え、10分間撹拌し、その混合物をろ過した。モレキュラーシーブをメチル−t−ブチルエーテルにより洗浄し、組み合わせた有機層を、5%リン酸(10mL)およびブライン(15mL)により洗浄した。有機層を減圧下で濃縮し、油脂を生じさせた。油脂をメタノール(10mL)中に溶解させ、白色冷却し、濾過して、結晶性固体を生じさせた。
1H NMR(CDCl3):δ6.05(br.s,1H),6.03(br.s,1H),6.0(d,1H,12.0Hz), 5.24 (dd,1H,9.0Hz,12.0Hz),4.26 (d,1H,9.0Hz),3.83(s,6H),3.77(s,3H),3.76(s,3H),3.72(s,3H),3.4(s,3H).
MS(ES+):430(M+1)
方法1:
(+)−トリメチル3−ニトロ−2−(2,4,6−トリメトキシフェニル)プロパン−1,1,3−トリカルボキシラート(7.8g、0.018mol)を酢酸エチル(100mL)中に溶解させた。この溶液に、塩化第一スズ二水和物(25g、0.118mol)を、撹拌下で10分間にわたって小分けにして加えた。反応混合物を55℃まで2時間加熱した。その混合物を10℃まで冷却し、10%水酸化ナトリウム溶液によりpH9まで塩基性化し、セライトパッドを介して濾過し、パッドを酢酸エチル(50mL)により洗浄した。水層を酢酸エチル(2×100mL)により抽出した。有機層を組み合わせ、無水硫酸ナトリウムの上で乾燥させ、減圧下で濃縮して、白色固形物として表題化合物を生じさせた。
1H NMR(CDCl3):δ6.06(br.s,2H),6.00(br.s,1H),4.98(dd,1H),4.59(d,1H),3.96(d,1H),3.79(s,3H),3.76(s,9H),3.35(s,3H).
MS(ES+):368(M+1)
1L圧力反応装置へ、テトラヒドロフラン(100mL)およびラネーニッケル(20g)を加え、続いてテトラヒドロフラン(300mL)中の(+)−トリメチル3−ニトロ−2−(2,4,6−トリメトキシフェニル)プロパン−1,1,3−トリカルボキシラート(32g、0.074mol)溶液を加えた。撹拌下で、反応装置を窒素により3回、続いて水素によりパージした。反応混合物を80psiの水素圧力下で一晩撹拌した。反応の終了時に、ラネーニッケルをろ過して除去し、窒素下でテトラヒドロフラン(150mL)により洗浄した。有機層を減圧下で濃縮して、白色固形物を産出させた。1H NMRにより、異性体の混合物の存在が示された。シスおよびトランスの異性体の混合物が、25g(91.32%)の収率で得られた。クロロホルム中の5%のメタノールを溶出剤として用いたカラムクロマトグラフイーによって、反応混合物の一部を精製して異性体を分離させ、分離された異性体のうちの1つを、1H NMR、質量スペクトルおよびHPLCによって確認すると、塩化第一スズを用いた還元によって得られた異性体と同一であることが分かった。
MS(ES+):368(M+1)
(+)−ジメチル5−オキソ−3−(2,4,6−トリメトキシフェニル)ピロリジン−2,4−ジカルボキシラート(4.0g、0.0109mol)を、N−メチルピロリドン(15mL)中に溶解させた。塩化ナトリウム(0.631g、0.0109mol)および水(0.196mL、0.0109mol)を加え、反応混合物を5時間170℃まで加熱した。反応混合物を氷(50g)上に注ぎ、固体を濾過し、乾燥させた。
1H NMR(CDCl3):δ6.08(s,2H),5.89(br.s,1H),4.62(m,1H),4.48(d,1H,9.6Hz),3.79(s,3H),3.76(s,6H),3.34(s,3H),2.74(dd,1H),2.60(dd,1H).
MS(ES+):310(M+1)
1H NMR(CDCl3):δ6.15(s,2H),5.87(br.s,1H),4.42(d,1H,7.5Hz),4.26(m,1H),3.82(s,3H),3.81(s,6H),3.68(s,3H),2.76(dd,1H),2.53(dd,1H).
MS(ES+):310(M+1)
(+)−メチル−5−オキソ−3−(2,4,6−トリメトキシフェニル)ピロリジン−2−カルボキシラート(1.7g、0.0055mol)を、N,N−ジメチルホルムアミド(15mL)中に溶解させ、溶液を0℃まで冷却した。水素化ナトリウム(0.134g、0.0056mmol)を、10分間にわたって小分けにして加え、0℃でさらに20分間撹拌した。ヨウ化メチル(0.514mL、0.0082mol)を一滴づつ加え、反応を1時間で室温まで温めた。反応混合物を、砕いた氷(20g)と1:1塩酸溶液(5mL)の混合物上にゆっくり注いだ。混合物を酢酸エチル(2×50mL)により抽出し、ブラインにより洗浄し、無水硫酸ナトリウムの上で乾燥させ、減圧下で濃縮して油脂を産出させた。石油エーテルで油脂をこね、結果として生じる固体を濾過した。
1H NMR(CDCl3):δ6.07(s,2H),4.44(dd,1H),4.27(d,1H,9.6Hz),3.79(s,3H),3.74(s,6H),3.38(s,3H),3.20(dd,1H),2.90(s,3H),2.45(dd,1H)
MS(ES+):324(M+1)
1H NMR(CDCl3):δ6.12(s,2H),4.13(d,1H,6.3Hz),4.05(dd,1H),3.80(s,3H),3.76(s,6H),3.70(s,3H),2.88(s,3H),2.64(m,2H).
MS(ES+):324(M+1)
メチル−1−メチル−5−オキソ−3−(2,4,6−トリメトキシフェニル)ピロリジン−2−カルボキシラート(1.6g、0.0049mol)のシスおよびトランスの異性体の混合物を、メタノール(15mL)中に溶解させた。これに水(4mL)中の水酸化カリウム(0.96g、0.017mol)溶液を加え、反応混合物を65℃で3時間加熱した。メタノールを減圧下で除去し、15mLの水を加え、混合物を1:1塩酸溶液によりpH2まで酸性化した。結果として生じる固体を濾過し、水により洗浄し、乾燥させた。
1H NMR(CDCl3):δ6.13(s,2H),4.16(m,2H),3.80(S,3H),3.77(S,6H),2.93(S,3H),2.74(m,1H),2.62(m,1H).
MS(ES+);310(M+1)
[α]D 25:−37.83°(c=0.518,MeOH)
水素化アルミニウムリチウム(0.304g、0.008mol)を、窒素雰囲気下でテトラヒドロフラン(40mL)中で撹拌した。(−)−トランス−1−メチル−5−オキソ−3−(2,4,6−トリメトキシフェニル)ピロリジン−2−カルボン酸(1.0g、0.032mol)を小分けにして加え、反応混合物を50℃で加熱して90分間撹拌した。反応混合物を10℃まで冷却し、撹拌下で水(2.5mL)および15%水酸化ナトリウム溶液(0.6mL)により希釈した。固体を濾過し、酢酸エチル(10mL)により洗浄した。有機層を組み合わせ、減圧下で濃縮して、白色固形物を生じさせた。
1H NMR(CDCl3):δ6.16(s,2H),3.98(m,1H),3.64(s,9H),3.62(dd,1H),3.43(d,1H),3.21(m,1H),2.78(m,1H),2.63(m,1H),2.44(s,3H),2.04(m,2H)
MS(ES+):282(M+1)
[α]D 25:−20°(c=0.2,MeOH)
三フッ化ホウ素ジエチルエーテル(25.2g、0.178mol)を、窒素雰囲気下の0℃で、無水酢酸(18g、0.178mol)中の(−)−トランス−(1−メチル−3−(2,4,6−トリメトキシフェニル)ピロリジン−2−イル)メタノール(10g、0.0356mol)の溶液へ撹拌しながら一滴づつ加えた。反応混合物を2時間室温で撹拌した。それを砕いた氷(1kg)の上に注ぎ、飽和炭酸ナトリウム水溶液を用いて塩基性化し、酢酸エチル(3×200mL)を用いて抽出した。有機抽出物をブラインにより洗浄し、乾燥させ(無水硫酸ナトリウム)、濃縮して、表題化合物を得た。
1H NMR(CDCl3,):δ14.20(s,1H),5.96(s,1H),4.10(d,2H),3.90(s,3H),3.89(s,3H),3.85(m,1H),3.26(m,1H),2.82(m,1H),2.74(m,1H),2.66(s,3H),2.52(s,3H),2.21(m,2H),2.10(s,3H).
メタノール(25mL)中の(−)−トランス−酢酸−3−(3−アセチル−2−ヒドロキシ−4,6−ジメトキシ−フェニル)−1−メチル−ピロリジン−2−イルメチルエステル)(10g、0.0284mol)の溶液に、10%水酸化ナトリウム水溶液(25mL)溶液を撹拌しながら室温で加えた。反応混合物の温度を45分間50℃まで上昇させ、室温まで冷却し、1:1塩酸溶液を用いて酸性化し、濃縮してメタノールを除去した。これを飽和水溶性の炭酸ナトリウム溶液を用いて塩基性化した。沈殿した化合物を濾過し、水により洗浄し、乾燥した。
IR(KBr):3400,3121,3001,1629,1590cm−1.
1H NMR(CDCl3):δ5.96(s,1H),3.93(m,1H),3.90(s,3H),3.88(s,3H),3.59(dd,1H),3.37(d,1H),3.13(m,1H),2.75(m,1H),2.61(s,3H),2.59(m,1H),2.37(s,3H),2.00(m,2H).
MS(ES+):m/z310(M+1)
水素化ナトリウム(50%、0.54g、0.01125mol)を、窒素雰囲気下の0℃で撹拌しながら、N,N−ジメチルホルムアミド(15mL)中の(−)−トランス−酢酸3−(3−アセチル−2−ヒドロキシ−4,6−ジメトキシ−フェニル)−1−メチル−ピロリジン−2−イルメチルエステル(0.7g、0.0022mol)の溶液へ、小分けにして加えた。10分後に、メチル2−クロロベンゾエート(1.15g、0.00675mol)を加えた。反応混合物を25℃で2時間撹拌した。メタノールを20℃以下の温度で注意深く加えた。反応混合物を砕いた氷(300g)の上に注ぎ、pH2まで1:1塩酸溶液により酸性化し、酢酸エチル(2×100mL)を用いて抽出した。水層を、飽和炭酸ナトリウム溶液を用いてpH10へ塩基性化し、クロロホルム(3×200mL)を用いて抽出した。有機層を無水硫酸ナトリウムの上で乾燥させ、濃縮した。この残留物に濃塩酸(25mL)を加え、2時間室温で撹拌した。反応混合物を砕いた氷(300g)の上に注ぎ、飽和炭酸ナトリウム溶液を用いて、塩基性にした。混合物をクロロホルム(3×200mL)を用いて抽出した。有機抽出物を水により洗浄し、無水硫酸ナトリウムの上で乾燥および濃縮し、表題化合物を得た。
mp:95―97℃
IR(KBr):3400,1660cm−1.
[α]D 25=+5.8°(c=0.7,メタノール)
1H NMR(CDCl3):δ7.7(dd,1H),7.41(m,1H),7.45(m,2H),6.55(s,1H),6.45(s,1H),4,17(m,1H),4.05(s,3H),3.95(s,3H),3.65(dd,1H),3.37(dd,1H),3.15(m,1H),2.77(d,1H),2.5(m,1H),2.3(s,3H),2.05(m,2H).
MS:m/e 430(M+),398(M−31)
融解されたピリジン塩酸塩(4.1g、0.0354mol)を、(+)−トランス−2−(2−クロロフェニル)−8−(2−ヒドロキシメチル−1−メチル−ピロリジン−3−イル)−5,7−ジメトキシ−クロメン−4−オン(0.4g、0.0009mol)へ加え、180℃で1.5時間加熱した。反応混合物を25℃まで冷却し、メタノール(10mL)により希釈し、炭酸ナトリウムを用いてpH10まで塩基性化した。混合物を濾過し、有機層を濃縮した。残留物を水(5mL)中に懸濁し、30分間撹拌し、濾過および乾燥させて、表題化合物を得た。
IR(KBr):3422,3135,1664,1623,1559cm−1
1H NMR(CDCl3):δ7.56(d,1H),7.36(m,3H),6.36(s,1H),6.20(s,1H),4.02(m,1H),3.70(m,2H),3.15(m,2H),2.88(m,1H),2.58(s,3H),2.35(m,1H),1.88(m,1H).
MS(ES+):m/z 402(M+1)
分析:C21H20ClNO5C,62.24(62.71);H,5.07(4.97);N,3.60(3.48);Cl,9.01(8.83).
(+)−トランス−2−(2−クロロフェニル)−8−(2−ヒドロキシメチル−1−メチル−ピロリジン−3−イル)−5,7−ジメトキシ−クロメン−4−オン(0.2g、0.48mmol)を、メタノール(2mL)中に懸濁させ、エーテルHCl(5mL)を加えた。懸濁物を撹拌して、清澄溶液を得た。この溶液を減圧下で濃縮し、表題化合物を得た。
[α]D 25=+21.2°(c=0.2,メタノール)
1H NMR(CD3OD,300MHz):δ7.80(d,1H),7.60(m,3H),6.53(s,1H),6.37(s,1H),4.23(m,1H),3.89(m,2H),3.63(m,1H),3.59(dd,1H),3.38(m,1H),2.90(s,3H),2.45(m,1H),2.35(m,1H).
MS(ES+):m/z 402(M+1)、遊離塩基。
Claims (13)
- 式1;
(a)、以下の式A;
(b)水酸化ナトリウムおよび水酸化カリウムから選択されるアルカリ水溶液により化合物Fを処理し、約50℃まで反応混合物の温度を上昇させて、以下の式G;
(c)窒素雰囲気下で、水素化ナトリウム、n−ブチルリチウム、リチウムヘキサメチルジシラジドおよびリチウムジイソプロピルアミドから選択される塩基、ならびにテトラヒドロフラン、N,N−ジメチルホルムアミドおよびジオキサンから選択される溶媒の存在下において、式ArCOOCH3(式中、Arは式1において定義されるようなものである)のエステルと化合物Gを反応させ、続いて酸触媒環化を行ない、以下の式2;
(d)ピリジン塩酸塩、三臭化ホウ素、三フッ化ホウ素エーテラートおよび三塩化アルミニウムから選択される脱メチル化剤と共に、化合物2を、120℃〜180℃の範囲内の温度で加熱することによって、化合物2を脱メチル化する工程と;
(e)任意で、式1の結果として生じる化合物を薬学的に許容される塩に変換する工程と、
を含む方法。 - Arが塩素で置換されたフェニルである、請求項1に記載の方法。
- 化合物Eが、
(a)錯体触媒、塩基およびモレキュラーシーブの存在下の溶媒中で(E)−メチル−2−ニトロ−3−(2,4,6−トリメトキシフェニル)アクリレートへのマロン酸ジメチルの立体選択的マイケル付加を行ない(ここで、錯体触媒はキラルビス(オキサゾリン)配位子および金属錯体を含む)、以下の式B;
(b)溶媒中の還元剤により工程(a)中で得られるような化合物Bを処理し、以下の式C;
(c)溶媒中の塩化ナトリウムにより化合物Cを処理し、結果として生じる反応混合物を120℃〜170℃の範囲内の温度まで加熱し、シスおよびトランスの異性体の混合物として以下の式D;
(d)溶媒中のメチル化剤、ならびにアルカリ金属水素化物およびアルカリ金属炭酸塩から選択される塩基と化合物Dを反応させ、続いて結果として生じるシスおよびトランスの化合物の混合物をアルコール中のアルカリ金属水酸化物によりアルカリ加水分解し、結果として生じる反応混合物を50℃〜100℃の範囲内の温度まで加熱し、単一トランス異性体として化合物Eを得ること、
によって調製される、請求項3に記載の方法。 - 工程(a)において用いられる前記キラルビス(オキサゾリン)配位子が、(3aS,3a’S,8aR,8a’R)−2,2’(シクロプロパン−1,1−ジイル)ビス(8,8a−ジヒドロ−3aH−インデノ[1,2d]オキサゾール)である、請求項4に記載の方法。
- 工程(a)において用いられる前記金属錯体が、トリフルオロメタンスルホン酸マグネシウム、過塩素酸マグネシウム、トリフルオロメタンスルホン酸銅、トリフルオロメタンスルホン酸亜鉛、トリフルオロメタンスルホン酸ランタン、トリフルオロメタンスルホン酸ニッケル、臭化マグネシウム、臭化銅、臭化亜鉛、臭化ニッケル、ヨウ化マグネシウム、ヨウ化銅、ヨウ化亜鉛、ヨウ化ニッケル、マグネシウムアセチルアセトネート、銅アセチルアセトネート、亜鉛アセチルアセトネートおよびニッケルアセチルアセトネートから選択される、請求項4に記載の方法。
- 前記金属錯体がトリフルオロメタンスルホン酸マグネシウムである、請求項6に記載の方法。
- 請求項4の工程(a)において用いられる前記塩基が、トリエチルアミン、ジイソプロピルアミン、2,6−ルチジン、N−メチルモルホリン、N−エチルピペリジン、イミダゾールおよび5,6−ジメチルベンズイミダゾールから選択される、請求項4〜7のいずれか一項に記載の方法。
- 前記塩基が、N−メチルモルホリンである、請求項8に記載の方法。
- 請求項4の工程(b)における前記還元剤が、塩化第一スズである、請求項4〜9のいずれか一項に記載の方法。
- 前記溶媒が酢酸エチルである、請求項10に記載の方法。
- 請求項4の工程(b)における前記還元剤が、ラネーニッケルである、請求項4〜9のいずれか一項に記載の方法。
- 前記溶媒が、テトラヒドロフラン、ジオキサンおよびN,N−ジメチルホルムアミドから選択される、請求項12に記載の方法。
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AR061964A1 (es) | 2008-08-10 |
CN101484445A (zh) | 2009-07-15 |
WO2008007169A1 (en) | 2008-01-17 |
TWI391388B (zh) | 2013-04-01 |
KR101285957B1 (ko) | 2013-07-12 |
AU2006346193B2 (en) | 2012-11-15 |
US7951961B2 (en) | 2011-05-31 |
US20100113803A1 (en) | 2010-05-06 |
BRPI0621851A2 (pt) | 2013-01-29 |
JP5006396B2 (ja) | 2012-08-22 |
IL196298A0 (en) | 2009-09-22 |
EP2041121A1 (en) | 2009-04-01 |
EP2041121B1 (en) | 2011-07-27 |
DK2041121T3 (da) | 2011-11-14 |
CN101484445B (zh) | 2012-09-05 |
TW200815413A (en) | 2008-04-01 |
MX2009000109A (es) | 2009-03-16 |
PT2041121E (pt) | 2011-09-12 |
ATE517892T1 (de) | 2011-08-15 |
AU2006346193A2 (en) | 2009-02-12 |
NZ573841A (en) | 2011-11-25 |
AU2006346193A1 (en) | 2008-01-17 |
CA2658215A1 (en) | 2008-01-17 |
KR20090033465A (ko) | 2009-04-03 |
HK1126762A1 (en) | 2009-09-11 |
CA2658215C (en) | 2013-08-27 |
AU2006346193C1 (en) | 2014-02-20 |
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