TWI391388B - 以黃酮取代吡咯烷之對映選擇合成及其中間體 - Google Patents
以黃酮取代吡咯烷之對映選擇合成及其中間體 Download PDFInfo
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- TWI391388B TWI391388B TW096122651A TW96122651A TWI391388B TW I391388 B TWI391388 B TW I391388B TW 096122651 A TW096122651 A TW 096122651A TW 96122651 A TW96122651 A TW 96122651A TW I391388 B TWI391388 B TW I391388B
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- Prior art keywords
- compound
- trans
- methyl
- trimethoxyphenyl
- group
- Prior art date
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- 239000000543 intermediate Chemical group 0.000 title description 9
- 230000015572 biosynthetic process Effects 0.000 title description 8
- 238000003786 synthesis reaction Methods 0.000 title description 8
- 150000003235 pyrrolidines Chemical group 0.000 title description 2
- 229930003944 flavone Natural products 0.000 title 1
- 150000002213 flavones Chemical group 0.000 title 1
- 235000011949 flavones Nutrition 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 58
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 37
- 239000002904 solvent Substances 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 26
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 239000011541 reaction mixture Substances 0.000 claims description 21
- 239000002585 base Substances 0.000 claims description 17
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- 239000003638 chemical reducing agent Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-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
- 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
- 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
- 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 5
- 229910021626 Tin(II) chloride Inorganic materials 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
- 238000010438 heat treatment Methods 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
- 239000001119 stannous chloride Substances 0.000 claims description 5
- 235000011150 stannous chloride Nutrition 0.000 claims description 5
- 238000004519 manufacturing process Methods 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
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-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
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 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
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 3
- 239000003795 chemical substances by application Substances 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
- 150000004678 hydrides Chemical group 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- BWLBGMIXKSTLSX-UHFFFAOYSA-N 2-hydroxyisobutyric acid Chemical compound CC(C)(O)C(O)=O BWLBGMIXKSTLSX-UHFFFAOYSA-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
- LQIIEHBULBHJKX-UHFFFAOYSA-N 2-methylpropylalumane Chemical compound CC(C)C[AlH2] LQIIEHBULBHJKX-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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 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
- 238000007259 addition reaction Methods 0.000 claims description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 2
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- NYENCOMLZDQKNH-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)bismuthanyl trifluoromethanesulfonate Chemical compound [Bi+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 NYENCOMLZDQKNH-UHFFFAOYSA-K 0.000 claims description 2
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 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
- 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
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 2
- 229910001623 magnesium bromide Inorganic materials 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
- UQPSGBZICXWIAG-UHFFFAOYSA-L nickel(2+);dibromide;trihydrate Chemical compound O.O.O.Br[Ni]Br UQPSGBZICXWIAG-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
- BBPLUGJBEGWJCV-UHFFFAOYSA-N propane-1,1,3-tricarboxylic acid Chemical compound OC(=O)CCC(C(O)=O)C(O)=O BBPLUGJBEGWJCV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012279 sodium borohydride Substances 0.000 claims description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 2
- 230000000707 stereoselective effect Effects 0.000 claims description 2
- 229940102001 zinc bromide Drugs 0.000 claims description 2
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Chemical compound [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
- DVSILEVINNCNTQ-UHFFFAOYSA-L zinc;3-oxobutanoate Chemical compound [Zn+2].CC(=O)CC([O-])=O.CC(=O)CC([O-])=O DVSILEVINNCNTQ-UHFFFAOYSA-L 0.000 claims description 2
- 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 1
- MOHWCOCJGRRUSS-UHFFFAOYSA-N [Cu+2].[CH2-]C(=O)C.[CH2-]C(=O)C Chemical compound [Cu+2].[CH2-]C(=O)C.[CH2-]C(=O)C MOHWCOCJGRRUSS-UHFFFAOYSA-N 0.000 claims 1
- 125000001033 ether group Chemical group 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- FLESAADTDNKLFJ-UHFFFAOYSA-N nickel;pentane-2,4-dione Chemical compound [Ni].CC(=O)CC(C)=O FLESAADTDNKLFJ-UHFFFAOYSA-N 0.000 claims 1
- PDXOPNHXAAQJJO-UHFFFAOYSA-N nickel;trifluoromethanesulfonic acid Chemical compound [Ni].OS(=O)(=O)C(F)(F)F PDXOPNHXAAQJJO-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 49
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 235000019439 ethyl acetate Nutrition 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 14
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 230000022131 cell cycle Effects 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- CRBZVDLXAIFERF-UHFFFAOYSA-N 2,4,6-trimethoxybenzaldehyde Chemical compound COC1=CC(OC)=C(C=O)C(OC)=C1 CRBZVDLXAIFERF-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 229940126062 Compound A Drugs 0.000 description 4
- 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 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 239000012649 demethylating agent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical group 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 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 description 3
- 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 description 2
- QLUYMIVVAYRECT-OCCSQVGLSA-N 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(2r,3s)-2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]chromen-4-one Chemical compound OC[C@@H]1N(C)CC[C@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O QLUYMIVVAYRECT-OCCSQVGLSA-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
- 229910015900 BF3 Inorganic materials 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
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- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WATRIVZUMSBBDY-MEBBXXQBSA-N methyl (2R,3R)-1-methyl-5-oxo-3-(2,4,6-trimethoxyphenyl)pyrrolidine-2-carboxylate Chemical compound CN1[C@H]([C@H](CC1=O)C1=C(C=C(C=C1OC)OC)OC)C(=O)OC WATRIVZUMSBBDY-MEBBXXQBSA-N 0.000 description 1
- LNUMNTDMTRECOT-YMTOWFKASA-N methyl (2R,3R)-5-oxo-3-(2,4,6-trimethoxyphenyl)pyrrolidine-2-carboxylate Chemical compound O=C1C[C@@H]([C@@H](N1)C(=O)OC)C1=C(C=C(C=C1OC)OC)OC LNUMNTDMTRECOT-YMTOWFKASA-N 0.000 description 1
- WATRIVZUMSBBDY-ZUZCIYMTSA-N methyl (2R,3S)-1-methyl-5-oxo-3-(2,4,6-trimethoxyphenyl)pyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1N(C(C[C@H]1C1=C(C=C(C=C1OC)OC)OC)=O)C WATRIVZUMSBBDY-ZUZCIYMTSA-N 0.000 description 1
- LNUMNTDMTRECOT-LKFCYVNXSA-N methyl (2R,3S)-5-oxo-3-(2,4,6-trimethoxyphenyl)pyrrolidine-2-carboxylate Chemical compound O=C1C[C@H]([C@@H](N1)C(=O)OC)C1=C(C=C(C=C1OC)OC)OC LNUMNTDMTRECOT-LKFCYVNXSA-N 0.000 description 1
- 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 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
- 229940050176 methyl chloride Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification 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
- JGJGLMZEXTZURL-UHFFFAOYSA-N neodymium nickel Chemical compound [Ni].[Nd] JGJGLMZEXTZURL-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
- DEPMYWCZAIMWCR-UHFFFAOYSA-N nickel ruthenium Chemical compound [Ni].[Ru] DEPMYWCZAIMWCR-UHFFFAOYSA-N 0.000 description 1
- 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 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
- 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
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229910052700 potassium Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 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
- 238000010187 selection method Methods 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
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 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
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 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
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 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)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
本發明係關於一種以黃酮取代吡咯烷之(+)-反式對映異構物的對映選擇合成,其係由分子式1的化合物或其鹽類所表示,其為細胞週期依賴激酶的抑制劑及可用於增生性失調例如癌症的治療。
細胞週期依賴激酶(CDKs)為細胞週期控制的必需激酶,細胞週期依賴激酶的抑制劑係預期為擁有對廣範圍增生性疾病的特別是癌症的醫療效用。結果,CDKs已標的用於藥物發現及已辨識及研究數個小分子CDKs抑制劑,由下列通式1所表示的CDK/細胞週期複合物之抑制劑;
其中Ar係定義於詳細敘述;已敘述於PCT專利申請案第PCT/IB2006/052002號,其係併入本文做為參考,這些化合物顯現良好選擇性及抗各種增生細胞血源的細胞毒性。在先前所提及專利申請案所揭示的新穎化合物,具兩個對掌中心及於是,可以四種對映異構物存在,亦即(+)-反式
、(-)-反式及
(+)-順式
、(-)-順式
。對掌性在醫藥工業愈加重要,如同由超過80%目前發展的藥物具對掌性質之事實而證明,各種對映異構物於身體可發展完全不同的效用,使得所投藥的二或許多對映異構物形式的僅其中一種為有效的。在分子式1化合物的情況,已發現僅(+)-反式
對映異構物具活性然而(-)-反式
對映異構物為不活性的。由本發明者所進行的分子式1消旋化合物效用及其個別對映異構物的廣泛研究已產生申請者的PCT專利申請案第PCT/IB2006/052002號。由分子式1所表示的任何化合物的(+)-反式
對映異構物,基本上不含其的其他異構物,之投藥實質上產生藥物劑量的降低。因為由分子式1所表示的化合物的活性(+)-反式
對映異構物做為細胞週期依賴激酶的抑制劑之重要性,存在發展一種經濟及有效合成方法以製造它們之需求。
申請者的PCT專利申請案第PCT/IB2006/052002號敘述一種由下列分子式1所表示的以黃酮取代吡咯烷之(+)-反式
對映異構物的製備方法;分子式1其中Ar係定義於詳細敘述;如在PCT專利申請案第PCT/IB2006/052002號所敘述的方法係涉及中間化合物的分解及所分解中間化合物成為由分子式1所表示的化合物之後續轉化反應。例如,(+)-反式
-2-(2-氯苯基)-5,7-二羥基-8-(2-羥甲基-1-甲基-吡咯烷-3-基)-苯並吡喃-4-酮係由中間體,稱之為(±)-反式
-[1-甲基-3-(2,4,6-三甲氧基-苯基)-吡咯烷-2-基]-甲醇,的分解及該中間體的(-)-反式
異構物成為(+)-反式
-2-(2-氯苯基)-5,7-二羥基-8-(2-羥甲基-1-甲基-吡咯烷-3-基)-苯並吡喃-4-酮的後續轉化反應所製備。該中間體的(-)-反式
異構物的製備涉及以掌性輔助劑處理其消旋體的步驟以得到相對應(+)-及(-)-反式對映異構物鹽類接著為藉由結晶分離該所欲對映異構物鹽類及使用鹼處理以產生所欲(-)-反式對映異構物,此分解方法涉及顯著加工及亦涉及分解劑的使用使得該方法為昂貴的,該分解劑的部份回收為可行的但是此種回收為昂貴的因為其需要額外加工及亦伴隨廢棄物生成,不欲的對映異構物無法被回收及被丟棄,於實驗室規模合成所得到關鍵中間體的最大理論產率僅為50%因為損失一半的消旋體,此產率可能因為高對掌純度的需求(>95%對映異構物過量)而進一步減少,於是,存在發展替代不對稱合成的清楚需求,其可以有效及更特定的方式提供所欲(+)-反式對映異構物。
此發明目的為提供一種分子式1所表示化合物的(+)-反式對映異構物的替代製備方法,其為一種對映選擇方法。本發明方法使得藉由克服習知分解技術的缺點而使有效大規模合成可進行。
本發明提供一種由分子式1所表示化合物的(+)-反式對映異構物的對映選擇合成之新穎方法:
其中Ar係如在詳細敘述中所定義。
本發明方法亦涉及下列分子式A化合物的對映選擇合成;其為分子式1化合物的掌性前軀體;
本發明方法提供一種分子式1化合物的(+)-反式對映異構物的對映選擇合成,其避免先前所提及方法的缺點。
本發明方法亦具以成本及時間為觀點的額外優點因為在該方法的所有中間體為結晶及不需進一步純化。
本發明方法係特定相關於一種由分子式1所表示化合物的(+)-反式對映異構物的對映選擇合成方法;
其中Ar係為苯基,其為未經取代的或是由1、2、或3個相同或不同取代基所取代的,這些取代基係選自:鹵素、硝基、氰基、C1
-C4
-烷基、氟甲基、二氟甲基、三氟甲基、羥基、C1
-C4
-烷氧基、羧基、C1
-C4
-烷氧基羰基、C1
-C4
-烯基羥基、CONH2,CONR1R2,SO2NR1R2、環烷基、NR1R2及SR3
;其中R1
及R2
每一個係獨立地選自:氫、C1
-C4
-烷基、C1
-C4
-烷基羰基及芳基、或是R1
及R2
,一起與它們所鍵結的氮原子形成五或六元環,其可選擇性地包含至少一個額外雜原子;及R3
係選自氫、C1
-C4
-烷基、芳基及SR4
,其中R4
係為C1
-C4-
烷基或芳基。
為本揭示目的,下文所列為用於敘述本發明化合物的各種名稱之定義,這些定義應用於這些名稱當這些名稱個別地或是做為較大分子的一部分用於專利說明書全文時(除非它們另外於特定實例受限制)。它們不應以文獻方式解釋,它們不為通用定義及僅相關於此申請案。
名稱"烷基"係表示飽和脂肪基的自由基,其包含直鏈烷基及支鏈烷基。而且,除非另外說明,名稱"烷基"包含未經取代的烷基及以一或更多不同取代基所取代的烷基。包含自1至20碳原子的烷基餘基之實例為:甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十四烷基、十六烷基、十八烷基及二十烷基,所有這些餘基的n-異構物、異丙基、異丁基、1-甲基丁基、異戊基、新戊基、2,2-二甲基丁基、2-甲基戊基、3-甲基戊基、異己基、2,3,4-三甲基己基、異癸基、第二-丁基、或第三-丁基。
名稱"環烷基"係表示約3至7個碳原子的非芳香族單或多環環狀系統,其可為未經取代的或是由一或更多不同取代基所取代的。環烷基的實例包含環丙基、環丁基、環戊基、環己基及其類似物。
名稱"烷氧基"當於此處使用時係表示具氧自由基接附於其上的如上所敘述的烷基。代表性烷氧基包含甲氧基、乙氧基、丙氧基、第三-丁氧基及其類似物。
名稱"鹵素"係表示氯、溴、氟及碘。
名稱"雜原子"係表示一種氮、氧、硫及磷。
名稱”對映異構物過量”係表示存在於產品混合物中一個對映異構物的量與另一個對映異構物的量之間的差。於是例如,對映異構物過量96%係表示一種具98%的一個對映異構物及2%另一個對映異構物的產品混合物。
當立體化學說明於結構中此表示一種相對而非絕對結構。
在本發明一個具體實施例,提供一種化合物,(-)-反式-(1-甲基-3-(2,4,6-三甲氧苯基)-吡咯烷-2-基)甲醇,或是其醫藥可接受鹽類,的對映選擇合成方法,此化合物係由下列分子式A表示;
(後文稱為化合物A),其包含步驟:(a)在觸媒複合物、鹼及分子篩存在下於溶劑中進行丙二酸二甲酯成為(E)-甲基-2-硝基-3-(2,4,6-三甲氧苯基)丙烯酸酯的立體特定性麥可加成反應,其中該觸媒複合物包含掌性雙(噁唑啉)配位基及金屬複合物,以得到由下列分子式B所表示的(+)-三甲基-3-硝基-2-(2,4,6-三甲氧苯基)丙烷-1,1,3-三羧酸酯;
(後文稱為化合物B);(b)以還原劑在適當溶劑中處理在步驟(a)所得到的化合物B以得到由下列分子式C所表示的(+)-二甲基5-氧代-3-(2,4,6-三甲氧基苯基)-吡咯烷-2,4-二碳酸酯;
(後文稱為化合物C);(c)以氯化鈉於溶劑中處理化合物C及加熱所得反應混合物至在120-170℃範圍的溫度以得到由下列分子式D所表示的(+)-甲基5-氧代-3-(2,4,6-三甲氧基苯基)-吡咯烷-2-碳酸酯,其係為順式及反式異構物的混合物;
(後文稱為化合物D);(d)將化合物D與甲基化試劑及選自:鹼金屬氫化物及鹼金屬碳酸鹽的鹼,於溶劑中,反應,接著為將所得順式及反式化合物的混合物與鹼金屬氫氧化物於醇中進行加鹼水解並加熱至在50-100℃範圍的溫度以得到(-)-反式-1-甲基5-氧代-3-(2,4,6-三甲氧基苯基)-吡咯烷-2-羧酸,其係由下列分子式E所表示;
(後文稱為化合物E)為單一順式異構物;(e)將化合物E以還原劑在溶劑中處理以得到所欲(-)-反式-(1-甲基-3-(2,4,6-三甲氧基苯基)吡咯烷-2-基)-甲醇,由分子式A所表示。
在一個具體實施例,本發明提供一種由所敘述新穎方法所得到的化合物A之使用,以製備由分子式1所表示的化合物。
根據本發明另一具體實施例,提供一種由分子式1所表示的化合物的(+)-反式對映異構物的製備方法;
其中Ar為苯基,其為未經取代的或是由1、2、或3相同或不同取代基所取代的,這些取代基係選自:鹵素、硝基、氰基、C1
-C4
-烷基、氟甲基、二氟甲基、三氟甲基、羥基、C1
-C4
-烷氧基、羧基、C1
-C4
-烷氧基羰基、C1
-C4
-烯基羥基、CONH2
,CONR1
R2
、SO2
NR1
R2
、環烷基、NR1
R2
及SR3
;其中R1
及R2
每一個係獨立地選自:氫、C1
-C4
-烷基、C1
-C4
-烷氧基羰基及芳基;或是R1
及R2
一起與它們所鍵結的氮原子形成5-或6-元環,其可選擇性地包含至少一個額外雜原子;及R3
係選自氫、C1
-C4
-烷基、芳基及SR4
,其中R4
係為C1
-C4
-烷基或芳基;或是其醫藥可接受鹽類;此方法包含:(i)將化合物A(上文)在觸媒存在下以醋酸酐處理以得到由下列分子式F所表示的(-)-反式-醋酸3-(3-乙醯基-2-羥基-4,6-二甲氧基-苯基)-1-甲基-吡咯烷-2-基甲酯;
(後文稱為化合物F);(ii)以鹼的水溶液處理化合物F及將反應混合物溫度升高至約50℃以得到由下列分子式G所表示的(-)-反式-1-[2-羥基-3-(2-羥甲基-1-甲基-吡咯烷-3-基)-4,6-二甲氧基-苯基)-乙酮;
(後文稱為化合物G);(iii)於氮氣壓下,在鹼及適當溶劑存在下將化合物G與分子式ArCOOCH3
(其中Ar係定義於分子式1)的酯類反應,接著為藉由酸催化環化反應以得到由下列分子式2所表示的二甲氧基化合物;
(後文稱為化合物2);(iv)藉由在範圍120-180 C的溫度將化合物2與去甲基化劑加熱將化合物2進行脫甲基反應以得到由分子式1所表示化合物的所欲(+)-反式對映異構物。
在最佳具體實施例中,本發明係提供一種由下文分子式1A所表示的(+)-反式-2-(2-氯-苯基)-5,7-二羥基-8-(2-羥甲基-1-甲基-吡咯烷-3-基)-苯並吡喃-4-酮的對映選擇合成方法,於此在通用分子式1的化合物中Ar基表示以氯取代的苯基;
(後文稱為化合物1A),此方法包含:(i)將化合物A在觸媒存在下以醋酸酐處理以得到由下列分子式F所表示的(-)-反式-醋酸3-(3-乙醯基-2-羥基-4,6-二甲氧基-苯基)-1-甲基-吡咯烷-2-基甲酯;
(後文稱為化合物F);(ii)以鹼的水溶液處理化合物F及將反應混合物溫度升高至約50℃以得到由下列分子式G所表示的(-)-反式-1-[2-羥基-3-(2-羥甲基-1-甲基-吡咯烷-3-基)-4,6-二甲氧基-苯基)-乙酮;
(後文稱為化合物G);(iii)於氮氣壓下,在鹼及適當溶劑存在下將化合物G與2-氯苯甲酸甲酯反應,接著為藉由酸催化環化反應以得到由下列分子式2A所表示的(+)-反式-2-(2-氯苯基)-8-(2-羥甲基-1-甲基-吡咯烷-3-基)-5,7-二甲氧基-苯並吡喃-4-酮;
(後文稱為化合物2A);(iv)藉由在範圍120-180 C的溫度將化合物2A與鹽酸吡啶加熱以將化合物2A進行脫甲基反應以得到化合物1A;及(v)選擇性地,藉由習知方法轉化分子式1A為其醫藥可接受鹽類,例如其鹽酸鹽類,(+)-反式-2-(2-氯苯基)-5,7-二羥基-8-(2-羥甲基-1-甲基-吡咯烷-3-基)-苯並吡喃-4-酮鹽酸。
用於步驟(a)的化合物(E)-甲基-2-硝基-3-(2,4,6-三甲氧苯基)丙烯酸酯可在醋酸銨及硫酸鎂的存在下由2,4,6-三甲氧基苯甲醛及硝基乙酸甲酯之間的反應製備。化合物2,4,6-三甲氧基苯甲醛可藉由習知方法自2,4,6-三甲氧基苯與磷醯氯及N,N-二甲替甲醯胺反應而製備。化合物硝基乙酸甲酯可藉由習知方法例如於160oC加熱硝基甲烷與鹼如氫氧化鉀,接著以硫酸及甲醇於15oC處理而由硝基甲烷製備。
用於上文步驟(a)的觸媒複合物包含掌性雙(噁唑啉)配位基及金屬複合物,掌性雙(噁唑啉)配位基於催化性不對稱合成的使用已被廣泛報告(Ghosh,A.K.;Mathivanan,P.;Cappiello,J.Tetrahedron:Asymmetry 1998,9,1-45)。根據本發明,較佳掌性雙(噁唑啉)配位基為(3aS,3a’S,8aR,8a’R)-2,2’(環丙烷-1,1-二基)雙(8,8a-二氫-3aH-茚滿[1,2d]噁唑),其可根據在美國化學協會期刊2002,124(44),13097-13105所報告的方法製備,其係併入本文做為參考,反應可僅使用4至6莫耳%的掌性雙(噁唑啉)配位基進行。
適合用於提供觸媒複合物的金屬複合物包含三氟甲磺酸鎂、高氯酸鎂、三氟甲磺酸銅、三氟甲磺酸鋅、三氟甲磺酸鑭、三氟甲磺酸鎳、溴化鎂、溴化銅、溴化鋅、溴化鎳、碘化鎂、碘化銅、碘化鋅、碘化鎳、乙醯丙酮鎂、乙醯丙酮銅、乙醯丙酮鋅、及乙醯丙酮鎳。根據本發明,較佳金屬複合物為三氟甲磺酸鎂。
用於步驟(a)的鹼可選自:三乙胺、二異丙胺、2,6-二甲基吡啶、N-甲基嗎啉、N-乙基哌啶、咪唑及5,6-二甲基苯駢咪唑,較佳為,N-甲基嗎啉用做鹼。
用於步驟(b)的還原劑可為氯化亞錫或是阮來鎳,當使用氯化亞錫做為還原劑時,化合物C係以單一異構物得到。當使用阮來鎳做為還原劑時,化合物C係以異構物混合物得到,如由1
H NMR所顯示。若小樣品的異構物混合物由柱型色層分析法純化以分離這些異構物,可確認這些異構物的其中一個與使用氯化亞錫做為還原劑所得到的單一異構物相同。在步驟(b)所使用的溶劑較佳為非質子溶劑,例如醋酸乙酯、二噁烷、N,N-二甲替甲醯胺及四氫呋喃。當使用氯化亞錫進行還原反應時,所使用的溶劑較佳為醋酸乙酯,及當使用阮來鎳進行還原反應時,所使用的溶劑較佳為選自:四氫呋喃、二噁烷及N,N-二甲替甲醯胺。
用於脫羧基反應步驟(c)的溶劑較佳為極性非質子溶劑例如N-甲基吡咯烷酮及二甲基亞碸。
用於步驟(d)的甲基化試劑可為甲基碘或二甲基硫酸酯,用於步驟(d)的溶劑較佳為極性非質子溶劑其可選自:N,N-二甲替甲醯胺、四氫呋喃及二噁烷。鹼性金屬碳酸鹽可為碳酸鈉或碳酸鉀,鹼性金屬氫化物可為氫化鈉,鹼性金屬氫氧化物可為氫氧化鈉或氫氧化鉀,所使用醇類較佳為一種無環醇,更佳為,該醇類係選自:乙醇、甲醇及異丙醇。
用於步驟(e)的還原劑較佳為一種氫化物,更佳為選自:氫化鋁鋰、氫化第三異丁基鋁及硼氫化鈉的氫化物。用於還原步驟的溶劑較佳為醚類,更佳為該溶劑係選自:四氫呋喃、二噁烷及乙醚。
在由分子式A的中間化合物製備分子式1化合物的方法中,用於步驟(i)的觸媒係選自路易士酸及多聚磷酸。該路易士酸觸媒可選自氯化鋅、氯化鋁、三氟化硼及三溴化硼,最佳路易士酸觸媒為三氟化硼。
用於步驟(ii)的鹼可為氫氧化鈉或氫氧化鉀。
用於步驟(iii)的鹼可選自:氫化鈉、正-丁基鋰、六甲基二矽氨烷鋰及二異丙氨基鋰,所使用鹼較佳為氫化鈉。用於步驟(iii)的溶劑可選自:四氫呋喃、N,N-二甲替甲醯胺及二噁烷,所使用溶劑較佳為N,N-二甲替甲醯胺。
用於步驟(iv)的脫甲基劑可選自鹽酸吡啶、三溴化硼、三氟化硼乙醚及三氯化鋁,較佳脫甲基劑為鹽酸吡啶。
於是,根據本發明方法,分子式A化合物係以大於97% ee(對映異構物過量)的對掌純度得到產生具大於99% ee的對掌純度的分子式1化合物。
由本發明新穎方法所得到的分子式1化合物可選擇性地轉化為它們的相對應醫藥或是毒性可接受鹽類,特別是它們的醫藥可利用鹽類。
包含一或更多鹼性團,亦即可被質子化的基,的分子式1化合物可根據本發明以其與無毒性的無機或有機酸的加成鹽之形式使用。合適無機酸的實例包含:硼酸、高氯酸、鹽酸、氫溴酸、硫酸、氨基磺酸、磷酸、硝酸及熟知該技藝者所已知的其他無機酸。合適有機酸的實例包含:醋酸、葡萄糖酸、丙酸、丁二酸、乙醇酸、硬脂酸、丙醇酸、羥基丁二酸、酒石酸、檸檬酸、抗壞血酸、哌酸、順式丁烯二酸、羥基順式丁烯二酸、苯醋酸、谷氨酸、苯甲酸、水楊酸、對氨基苯磺酸、2-醋酸基苯酸、反式丁烯二酸、甲苯磺酸、甲磺酸、乙磺酸、草酸、羥乙基磺酸、氧代戊二酸、苯磺酸、甘油磷酸及為熟知該技藝者所已知的其他有機酸。包含酸性團的分子式1化合物可根據本發明使用,例如,做為鹼金屬鹽類如Li、Na、及K鹽類。本發明的醫藥可接受鹽類可由包含鹼性及酸性團的該主題化合物藉由習知化學方法合成,一般言之,這些鹽類可藉由將自由鹼或酸與化學計量或是與過量的所欲鹽形成無機或有機酸或鹼於合適溶劑或分散劑接觸而製備或是藉由與其他鹽類陰離子交換或陽離子交換而製備,合適溶劑為,例如,醋酸乙酯、乙醇、丙酮、四氫呋喃、二噁烷或這些溶劑的混合物。
要了解在不影響各種本發明具體實施例的對掌性的反應條件的修改係包含於此處所揭示本發明內。據此,下列實例意欲用於說明而不在限制本發明。
(E)-甲基-2-硝基-3-(2,4,6-三甲氧苯基)丙烯酸酯將2,4,6-三甲氧苯甲醛(20.75公克,0.105莫耳)溶解於二氯甲烷(300毫升)及將硫酸鎂(15公克,0.124莫耳)、醋酸銨(10公克,0.129莫耳)及硝基乙酸甲酯(12.60公克,0.105莫耳)加至此溶液及於室溫攪拌2小時。在二小時結束時,加入水(300毫升)於該反應質體,分離有機層及以二氯甲烷(2 x 100毫升)萃取水相層,於減壓下合併有機層及濃縮之以得到固體,其係由甲醇(100毫升)結晶。
產率:22公克(66.82%)
1
H NMR(CDCl3
):8.37(s,1H),6.08(s,2H),3.86(s,3H),3.84(s,3H),3.82(s,6H)。
MS(ES+):298(M+1)
(+)-三甲基-3-硝基-2-(2,4,6-三甲氧苯基)丙烷-1,1,3-三羧酸酯於維持在氮氣壓的雙頸500毫升圓底燒瓶中,加入氯仿(10毫升)、三氟甲磺酸鎂(0.161公克,0.5毫莫耳)及水(0.036毫升,2.0毫莫耳),將(3aS,3a’S,8aR,8a’R)-2,2’(環丙烷-1,1-二基)雙(8,8a-二氫-3aH-茚滿[1,2d]噁唑)(雙(噁唑啉))(0.196公克,0.55毫莫耳)加至此經攪拌溶液及將反應混合物攪拌1小時。在1小時結束時,加入氯仿(30毫升)及分子篩(2公克)及將該混合物另外攪拌90分鐘,加入(E)-甲基-2-硝基-3-(2,4,6-三甲氧苯基)丙烯酸酯(3.1公克,0.01莫耳)、丙二酸二甲酯(1.92公克,0.014莫耳)及N-甲基嗎啉(0.06公克,0.6毫莫耳)及將反應混合物攪拌12小時接著於40 oC加熱4小時。將石油醚(15毫升)加至該反應混合物,攪拌10分鐘及過濾該混合物,將分子篩以甲基第三丁基醚洗及該合併有機層以5%磷酸(10毫升)及鹽水(15毫升)洗,於減壓下濃縮該有機層以得到油,將該油溶解於甲醇(10毫升),冷卻及過濾之以得到白色結晶固體。
產率:2.9公克(67.82%)
1
H NMR(CDCl3
):(6.05(br.s,1H),6.03(br.s,1H),6.0(d,1H,12.0 Hz),5.24(dd,1H,9.0 Hz,12.0 Hz),4.26(d,1H,9.0 Hz),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)
(-)-二甲基-5-氧代-3-(2,4,6-三甲氧苯基)吡咯烷-2,4-二羧酸酯方法1將(+)-三甲基-3-硝基-2-(2,4,6-三甲氧苯基)丙烷-1,1,3-三羧酸酯(7.8公克,0.018莫耳)溶解於醋酸乙酯(100毫升),於此溶液,將氯化亞錫二水合物(25公克,0.118莫耳)以數個部份於10分鐘並攪拌下加入。將反應混合物加熱至55oC維持2小時,將該混合物冷卻至10 oC,以10%氫氧化鈉溶液鹼化至pH 9,經由矽澡土過濾及使用醋酸乙酯(50毫升)洗矽澡土。以醋酸乙酯(2 x 100毫升)萃取水相層,合併有機層,於無水硫酸鈉上乾燥及於減壓下濃縮以得到該標題化合物,其為白色固體。
產率:4.5公克(67.44%)
1
H NMR(CDCl3
):6.06(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)
方法2將四氫呋喃(100毫升)及阮來鎳(20公克)加至1公升壓力反應器,接著加入(+)-三甲基-3-硝基-2-(2,4,6-三甲氧苯基)丙烷-1,1,3-三羧酸酯(32公克,0.074莫耳)於四氫呋喃(300毫升)的溶液。在攪拌下,反應器以氮氣接著氫氣吹驅三次,將反應混合物於80磅/平方英吋的氫氣壓下攪拌過夜,在反應結束,濾出阮來鎳及在氮氣壓下以四氫呋喃(150毫升)洗,於減壓下濃縮有機層以得到白色固體。1
H NMR顯示異構物混合物的存在,順式及反式異構物的混合物係以25公克(91.32%)的產率得到。一小部份的反應混合物係藉由使用5%甲醇於氯仿做為洗提劑的柱型色層分析法純化以分離該異構物及發現該經分離異構物的其中一個與由使用氯化亞錫的還原反應所得到的異構物相同,此係由1
H NMR、質譜儀及HPLC確認。
1
H NMR(CDCl3
):6.06(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)
(-)-甲基-5-氧代-3-(2,4,6-三甲氧苯基)吡咯烷-2-羧酸酯將(+)-二甲基-5-氧代-3-(2,4,6-三甲氧苯基)吡咯烷-2,4-二羧酸酯(4.0公克,0.0109莫耳)溶解於N-甲基吡咯烷酮(15毫升),加入氯化鈉(0.631公克,0.0109莫耳)及水(0.196毫升,0.0109莫耳)及加熱反應混合物至170oC維持5小時,將反應混合物倒至冰(50公克)及過濾固體及乾燥。
產率:1.5公克(44.5%)
產物係為順式及反式異構物的混合物如在1
H NMR所見,該異構物的混合物係使用而不需進一步反應的分離,一小部份的混合物係藉由柱型色層分析法(5%甲醇於氯仿)純化以進行該順式及反式異構物的光譜特徵。
(+)-順式-甲基-5-氧代-3-(2,4,6-三甲氧苯基)吡咯烷-2-羧酸酯
1
H NMR(CDCl3
):6.08(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)
(+)-反式-甲基-5-氧代-3-(2,4,6-三甲氧苯基)吡咯烷-2-羧酸酯
1
H NMR(CDCl3
):6.15(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)
(+)-甲基-1-甲基-5-氧代-3-(2,4,6-三甲氧苯基)吡咯烷-2-羧酸酯將(+)-甲基-5-氧代-3-(2,4,6-三甲氧苯基)吡咯烷-2,4-二羧酸酯(1.7公克,0.0055莫耳)溶解於N,N-二甲替甲醯胺(15毫升)及將溶液冷卻至0oC。將氫化鈉(0.134公克,0.0056毫莫耳)以數個部份於10分鐘期間加入並於0oC另外攪拌20分鐘。逐滴加入甲基碘(0.514毫升,0.0082莫耳)及使反應於1小時加溫至室溫。將反應混合物緩慢倒至碎冰(20公克)及1:1鹽酸溶液(5毫升)的混合物上,將混合物以醋酸乙酯(2 x 50毫升)萃取,以鹽水洗,於無水硫酸鈉上乾燥及於減壓下濃縮以得到油狀物,該油狀物以石油醚輾製及過濾所得固體。
產率:1.7公克(96.04%)
產物係為順式及反式異構物的混合物如在1
H NMR所見,該異構物的混合物係使用而不需進一步反應的分離,一小部份的混合物係藉由柱型色層分析法(5%甲醇於氯仿)純化以進行該順式及反式異構物的光譜特徵。
(+)-順式-甲基-1-甲基-5-氧代-3-(2,4,6-三甲氧苯基)吡咯烷-2-羧酸酯
1
H NMR(CDCl3
):6.07(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)
(+)-反式-甲基-1-甲基-5-氧代-3-(2,4,6-三甲氧苯基)吡咯烷-2-羧酸酯
1
H NMR(CDCl3
):6.12(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)。
(-)-反式-1-甲基-5-氧代-3-(2,4,6-三甲氧苯基)吡咯烷-2-羧酸酯將甲基-1-甲基-5-氧代-3-(2,4,6-三甲氧苯基)吡咯烷-2-羧酸酯(1.6公克,0.0049莫耳)的順式及反式異構物的混合物溶解於甲醇(15毫升)。於此溶液,加入氫氧化鉀(0.96公克,0.017莫耳)於水(4毫升)的溶液及於65oC加熱反應混合物3小時。於減壓下移除甲醇,加入15毫升水及使用1:1鹽酸溶液酸化混合物至pH 2,過濾所得固體,以水洗及乾燥。
產率:0.94公克(61.44%)
1
H NMR(CDCl3
):6.13(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]D25:-37.83(c=0.518,甲醇)
(-)-反式-(1-甲基-3-(2,4,6-三甲氧苯基)吡咯烷-2-基)甲醇將氫化鋁鋰(0.304公克,0.008莫耳)於氮氣壓下於四氫呋喃(40毫升)攪拌,將(-)-反式-1-甲基-5-氧代-3-(2,4,6-三甲氧苯基)吡咯烷-2-羧酸(1.0公克,0.0032莫耳)以數個部份加入及於50oC加熱反應混合物並攪拌90分鐘,將反應混合物冷卻至10oC及於攪拌下以水(2.5毫升)及15%氫氧化鈉溶液(0.6毫升)稀釋,過濾固體及以醋酸乙酯(10毫升)洗,於減壓下合併有機層及濃縮之以得到白色固體。
產率:0.91公克(100%)
1
H NMR(CDCl3
):6.16(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]D25:-20(c=0.2,甲醇)
(-)-反式-醋酸3-(3-乙醯基-2-羥基-4,6-二甲氧基-苯基)-1-甲基-吡咯烷-2-基甲酯於氮氣壓下於0oC逐滴加入三氟化硼乙醚(25.2公克,0.178莫耳)至(-)-反式-(1-甲基-3-(2,4,6-三甲氧苯基)吡咯烷-2-基)甲醇(10公克,0.0356莫耳)於醋酸酐(18公克,0.178莫耳)的溶液並攪拌,於室溫攪拌反應混合物2小時,將其倒於碎冰(1公斤)上,使用飽和碳酸鈉水溶液鹼化及使用醋酸乙酯萃取(3 x 200毫升),以鹽水洗有機萃取物,乾燥(無水硫酸鈉)及濃縮以得到標題化合物。
產率:10公克(80%)
1
H NMR(CDCl3
,):δ 14.20(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)。
(-)-反式-1-[2-羥基-3-(2-羥甲基-1-甲基-吡咯烷-3-基)-4,6-二甲氧基-苯基]-乙酮於室溫下,將10%氫氧化鈉溶液(25毫升)攪拌加入(-)-反式-醋酸3-(3-乙醯基-2-羥基-4,6-二甲氧基-苯基)-1-甲基-吡咯烷-2-基甲酯(10公克,0.0284莫耳)於甲醇(25毫升)的溶液,反應混合物的溫度升高至50℃維持45分鐘,冷卻至室溫,使用1:1鹽酸溶液酸化及濃縮以移除甲醇,使用標準碳酸鈉水溶液鹼化,過濾經沉澱化合物,以水洗及乾燥。
產率:7.14公克(81.1%)
IR(KBr):3400,3121,3001,1629,1590公分-1.
1
H 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/z 310(M+1)。
(+)-反式-2-(2-氯苯基)-8-(2-羥甲基-1-甲基-吡咯烷-3-基)-5,7-二甲氧基-苯並吡喃-4-酮在氮氣壓下,於0 oC將氫化鈉(50%,0.54公克,0.01125莫耳)以數個部份加至(-)-反式-醋酸3-(3-乙醯基-2-羥基-4,6-二甲氧基-苯基)-1-甲基-吡咯烷-2-基甲酯(0.7公克,0.0022莫耳)於N,N-二甲替甲醯胺(15毫升)的溶液並攪拌,10分鐘後,加入2-氯苯酸甲酯(1.15公克,0.00675莫耳),將反應混合物於25 oC攪拌2小時,在低於20 oC小心加入甲醇。將反應混合物倒於碎冰(300公克)上,使用1:1鹽酸溶液酸化混合物至pH 2及使用醋酸乙酯(2 x 100毫升)萃取,水層使用飽和碳酸鈉水溶液鹼化至pH 10及使用氯仿(3 x 200毫升)萃取,有機層於無水硫酸鈉上乾燥及濃縮,將濃鹽酸(25毫升)加置餘基及於室溫攪拌2小時。將反應混合物倒於碎冰(300公克)上及使用飽和碳酸鈉水溶液使之成鹼性,混合物使用氯仿(3 x 200毫升)萃取,有機提出物以水洗,於無水硫酸鈉上乾燥及濃縮以得到該標題化合物。
產率:0.67公克(68.88%)熔點:95-97 oCIR(KBr):3400,1660公分-1。
[α]D25=+5.8(c=0.7,甲醇)
1
H NMR(CDCl3
):δ 7.7(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)
(+)-反式-2-(2-氯苯基)-8-(2-羥甲基-1-甲基-吡咯烷-3-基)-5,7-二羥基-苯並吡喃-4-酮將熔融鹽酸吡啶(4.1公克,0.0354莫耳)加至(+)-反式-2-(2-氯苯基)-8-(2-羥甲基-1-甲基-吡咯烷-3-基)-5,7-二甲氧基-苯並吡喃-4-酮(0.4公克,0.0009莫耳)及於180 oC加熱1.5小時。將反應混合物冷卻至25 oC,以甲醇(10毫升)稀釋及使用碳酸鈉鹼化至pH 10,將混合物過濾及濃縮有機層,將餘基懸浮於水(5毫升),攪拌30分鐘,過濾及乾燥以得到該標題化合物。
產率:0.25公克(66.86%)IR(KBr):3422,3135,1664,1623,1559公分-1。
1
H NMR(CDCl3
):δ 7.56(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:C21
H20
ClNO5
C,62.24(62.71);H,5.07(4.97);N,3.60(3.48);Cl,9.01(8.83)。
(+)-反式-2-(2-氯-苯基)-5,7-二羥基-8-(2-羥甲基-1-甲基-吡咯烷-3-基)-苯並吡喃-4-酮鹽酸將(+)-反式-2-(2-氯苯基)-8-(2-羥甲基-1-甲基-吡咯烷-3-基)-5,7-二羥基-苯並吡喃-4-酮(0.2公克,0.48毫莫耳)懸浮於甲醇(2毫升)及加入乙醚HCl(5毫升),攪拌懸浮液以得到清澈溶液,將溶液於減壓下濃縮以得到該標題化合物。
產率:0.21公克(97%)
[α]D25=+21.2°(c=0.2,甲醇)
1
H NMR(CD3
OD,300MHz):δ 7.80(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),自由鹼。
Claims (15)
- 一種製備分子式A所表示的(-)-反式 -(1-甲基-3-(2,4,6-三甲氧苯基)-吡咯烷-2-基)甲醇化合物的方法;
- 如申請專利範圍第1項的方法,其中該還原劑係為一氫化物。
- 如申請專利範圍第2項的方法,其中該氫化物係選自氫化鋁鋰、氫化第三異丁基鋁或硼氫化鈉。
- 如申請專利範圍第1項的方法,其中該溶劑係為一醚類。
- 如申請專利範圍第4項的方法,其中該醚類係選自四 氫呋喃、二噁烷或乙醚。
- 如申請專利範圍第1項的方法,其中該化合物E係由下列步驟製備:(a)在一觸媒複合物、一鹼及多個分子篩存在下於一溶劑中進行丙二酸二甲酯至(E)-甲基-2-硝基-3-(2,4,6-三甲氧苯基)丙烯酸酯的立體特定性麥可加成反應,其中該觸媒複合物係包含一掌性雙(噁唑啉)配位基及一金屬複合物,以得到由下列分子式B所表示的(+)-三甲基-3-硝基-2-(2,4,6-三甲氧苯基)丙烷-1,1,3-三羧酸酯:
- 如申請專利範圍第6項的方法,其中用於步驟(a)的該掌性雙(噁唑啉)配位基係為(3aS,3a’S,8aR,8a’R)-2,2’(環丙烷-1,1-二基)雙(8,8a-二氫-3aH-茚滿[1,2d]噁唑)。
- 如申請專利範圍第6項的方法,其中用於步驟(a)的該金屬複合物係選自三氟甲磺酸鎂、高氯酸鎂、三氟甲磺酸銅、三氟甲磺酸鋅、三氟甲磺酸鑭、三氟甲磺酸 鎳、溴化鎂、溴化銅、溴化鋅、溴化鎳、碘化鎂、碘化銅、碘化鋅、碘化鎳、乙醯丙酮鎂、乙醯丙酮銅、乙醯丙酮鋅、或乙醯丙酮鎳。
- 如申請專利範圍第8項的方法,其中該金屬複合物係為三氟甲磺酸鎂。
- 如申請專利範圍第6項的方法,其中用於步驟(a)的該鹼係選自三乙胺、二異丙胺、2,6-二甲基吡啶、N-甲基嗎啉、N-乙基哌啶、咪唑或5,6-二甲基苯駢咪唑。
- 如申請專利範圍第10項的方法,其中該鹼係為N-甲基嗎啉。
- 如申請專利範圍第6項的方法,其中在步驟(b)的該還原劑係為氯化亞錫。
- 如申請專利範圍第6項的方法,其中用於步驟(b)的該溶劑係為醋酸乙酯。
- 如申請專利範圍第6項的方法,其中在步驟(b)的該還原劑係為阮來鎳。
- 如申請專利範圍第6項的方法,其中用於步驟(b)的該溶劑係選自四氫呋喃、二噁烷或N,N-二甲替甲醯胺。
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CN1433410A (zh) * | 2000-05-03 | 2003-07-30 | 株式会社Lg生命科学 | 具有3-羟基色烯-4-酮结构的cdk抑制剂 |
EP1326829A2 (en) * | 2000-09-29 | 2003-07-16 | Bayer Pharmaceuticals Corporation | 17-beta-hydroxysteroid dehydrogenase-ii inhibitors |
ES2491140T3 (es) | 2006-06-21 | 2014-09-05 | Piramal Enterprises Limited | Derivados de flavona enantioméricamente puros para el tratamiento de trastornos proliferativos y procesos para su preparación |
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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TW200406202A (en) * | 2002-07-08 | 2004-05-01 | Nicholas Piramal India Ltd | Inhibitors of cyclin-dependent kinases and their use |
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CA2658215A1 (en) | 2008-01-17 |
AU2006346193C1 (en) | 2014-02-20 |
ATE517892T1 (de) | 2011-08-15 |
AU2006346193A2 (en) | 2009-02-12 |
MX2009000109A (es) | 2009-03-16 |
KR101285957B1 (ko) | 2013-07-12 |
AU2006346193A1 (en) | 2008-01-17 |
BRPI0621851A2 (pt) | 2013-01-29 |
DK2041121T3 (da) | 2011-11-14 |
IL196298A0 (en) | 2009-09-22 |
HK1126762A1 (en) | 2009-09-11 |
CN101484445A (zh) | 2009-07-15 |
TW200815413A (en) | 2008-04-01 |
NZ573841A (en) | 2011-11-25 |
EP2041121B1 (en) | 2011-07-27 |
CA2658215C (en) | 2013-08-27 |
AU2006346193B2 (en) | 2012-11-15 |
US20100113803A1 (en) | 2010-05-06 |
WO2008007169A1 (en) | 2008-01-17 |
JP2009542796A (ja) | 2009-12-03 |
JP5006396B2 (ja) | 2012-08-22 |
KR20090033465A (ko) | 2009-04-03 |
CN101484445B (zh) | 2012-09-05 |
EP2041121A1 (en) | 2009-04-01 |
US7951961B2 (en) | 2011-05-31 |
AR061964A1 (es) | 2008-08-10 |
PT2041121E (pt) | 2011-09-12 |
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