CN101058557A - Method of preparing polyhydroxy annular nitrone - Google Patents
Method of preparing polyhydroxy annular nitrone Download PDFInfo
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- CN101058557A CN101058557A CN 200610066638 CN200610066638A CN101058557A CN 101058557 A CN101058557 A CN 101058557A CN 200610066638 CN200610066638 CN 200610066638 CN 200610066638 A CN200610066638 A CN 200610066638A CN 101058557 A CN101058557 A CN 101058557A
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- nitrone
- methyl
- sugar
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- 238000000034 method Methods 0.000 title claims abstract description 20
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 title claims description 25
- 150000002373 hemiacetals Chemical class 0.000 claims abstract description 11
- -1 methyl oxime ether Chemical compound 0.000 claims abstract description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims abstract description 6
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims abstract description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000003342 alkenyl group Chemical group 0.000 claims abstract 2
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 150000001299 aldehydes Chemical class 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 229960003487 xylose Drugs 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- SRBFZHDQGSBBOR-LECHCGJUSA-N alpha-D-xylose Chemical group O[C@@H]1CO[C@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-LECHCGJUSA-N 0.000 claims description 4
- SRBFZHDQGSBBOR-QMKXCQHVSA-N alpha-L-arabinopyranose Chemical compound O[C@H]1CO[C@@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-QMKXCQHVSA-N 0.000 claims description 4
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 235000010755 mineral Nutrition 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 3
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 3
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 3
- SRBFZHDQGSBBOR-STGXQOJASA-N alpha-D-lyxopyranose Chemical compound O[C@@H]1CO[C@H](O)[C@@H](O)[C@H]1O SRBFZHDQGSBBOR-STGXQOJASA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- VBKNTGMWIPUCRF-UHFFFAOYSA-M potassium;fluoride;hydrofluoride Chemical compound F.[F-].[K+] VBKNTGMWIPUCRF-UHFFFAOYSA-M 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 abstract description 3
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 abstract 1
- 239000002253 acid Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 12
- 239000012141 concentrate Substances 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 239000002994 raw material Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000004252 FT/ICR mass spectrometry Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 229930182478 glucoside Natural products 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910001623 magnesium bromide Inorganic materials 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000000725 suspension Substances 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
- VXZYWQYETUQRMH-NAKRPEOUSA-N (2s,3s,4s,5s)-2-(hydroxymethyl)-5-phenylpyrrolidine-3,4-diol Chemical compound O[C@@H]1[C@@H](O)[C@H](CO)N[C@H]1C1=CC=CC=C1 VXZYWQYETUQRMH-NAKRPEOUSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- VXGOBKMZBNJSTA-UHFFFAOYSA-N 1-hydroxy-2-phenylpyrrolidine Chemical compound ON1CCCC1C1=CC=CC=C1 VXGOBKMZBNJSTA-UHFFFAOYSA-N 0.000 description 1
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 1
- VXZYWQYETUQRMH-UHFFFAOYSA-N 2-(hydroxymethyl)-5-phenylpyrrolidine-3,4-diol Chemical compound OC1C(O)C(CO)NC1C1=CC=CC=C1 VXZYWQYETUQRMH-UHFFFAOYSA-N 0.000 description 1
- XGKRSXPTDNCEFJ-SITLLQIKSA-N Cl.C(O)[C@@H]1N[C@H]([C@@H]([C@H]1O)O)CCCCCCCCCCCC Chemical compound Cl.C(O)[C@@H]1N[C@H]([C@@H]([C@H]1O)O)CCCCCCCCCCCC XGKRSXPTDNCEFJ-SITLLQIKSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 1
- BGMYHTUCJVZIRP-UHFFFAOYSA-N Nojirimycin Natural products OCC1NC(O)C(O)C(O)C1O BGMYHTUCJVZIRP-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-IOVATXLUSA-N Xylose Natural products O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 239000003316 glycosidase inhibitor Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- BGMYHTUCJVZIRP-GASJEMHNSA-N nojirimycin Chemical compound OC[C@H]1NC(O)[C@H](O)[C@@H](O)[C@@H]1O BGMYHTUCJVZIRP-GASJEMHNSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical group OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Images
Abstract
The invention discloses a preparing method of annular polyhydroxy nitriketone with structure as formula I, which comprises the following steps: 1) reacting hemiacetal as formula II and O-methyl hydroxylamine hydrochlorate under alkaline condition; obtaining methyl oxime ether with structure as formula III; 2) reacting the methyl oxime ether with structure as formula III and methane sulfonyl chlo-ride to produce methanesulfonates with structure as formula IV; 3) releasing aldehydo of methanesulfonates as formula IV under acid condition; obtaining the aldehydo as formula V; 4) acting the aldehydo as formula V and hydroxylamine hydrochlorate under alkaline condition; obtaining the product (R1, R2 and R3 is alkyl, alkenyl, aromatic radical or substituted aryl).
Description
Technical field
The present invention relates to a kind of simple and practical preparation method of polyhydroxy annular nitrone.
Background technology
Glycosylase is being played the part of important role in life entity, they have participated in a series of important bioprocesses relevant with glycoconjugates, as metabolism of the glycoconjugates of the synthetic and decomposition of the digestion in the intestines, glycoprotein, lysosome (lysosomal) or the like, therefore, they and numerous disease are closely related.Iminosugar be proved to be Glycosylase effective inhibitor and the treatment numerous disease potential drug [referring to (a) St ü tz, A.E.Iminosugars as GlycosidaseInhibitors:Nojirimycin and Beyond; Wiley-VCH:Weinheim, 1999. (b) Asano, N.; Nash, R.J.; Molyneux, R.J.; Fleet, G.W.J.Tetrahedron:Asymmetry 2000,11,1645-1680. (c) Watson, A.A.; Fleet, G.W.J.; Asano, N.; Molyneux, R.J.; Nash, R.J.Phytochemistry2001,56,265-295.].Many iminosugar have been arranged, and (as: NBDNJ Miglitol) has been developed to medicine and listing.
Polyhydroxy annular nitrone is that one of effective intermediate of preparation iminosugar is [referring to (a) Cicchi, S.; Marradi, M.; Vogel, P.; Goti, A.J.Org.Chem.2006,71,1614-1619. (b) Carmona, A.T.; Wightman, R.H.; Robina, I.; Vogel, P.Helv.Chim.Acta 2003,86,3066-3073. (c) Desvergnes, S.; Py, S.; Vall é e, Y.J.Org.Chem.2005,70,1459-1462. (d) Holzapfel, C.W.; Crous, R.Heterocycles 1998,48,1337-1346. (b) Duff, F.J.; Vivien, V.; Wightman, R.H.Chem.Commun.2000,2127-2128. (c) Toyao, A.; Tamura, O.; Takagi, H.; Ishibashi, H.Synlett 2003,35-38. (d) Chevrier, C.; LeNouen, D.; Neuburger, M.; Defoin, A.; Tarnus, C.Tetrahedron Lett.2004,45,5363-5366.], but preparation method's productive rate of the polyhydroxy annular nitrone of having reported is not high, inefficiency, can not prepare in a large number, these have all seriously limited the research in this field and the process of new drug development.A kind of common polyhydroxy annular nitrone structure is suc as formula I, wherein R
1, R
2And R
3For methyl, ethyl, propyl group, butyl, allyl group, benzyl or to methoxy-benzyl etc.
Summary of the invention
The purpose of this invention is to provide a kind of easy, practical preparation polyhydroxy annular nitrone method.
The method of the polyhydroxy annular nitrone of preparation formula I structure provided by the present invention comprises the steps:
1) hemiacetal and the O-methyl hydroxylamine hydrochloride with formula II structure reacts under alkaline condition, obtains the methyloxime ether of formula III structure;
2), obtain the methanesulfonates of formula IV structure with the methyloxime ether and the methane sulfonyl chloride reaction of formula III structure;
3) methanesulfonates with formula IV structure discharges aldehyde radical under acidic conditions, obtains the aldehyde of formula V structure;
4) aldehyde of formula V structure with the hydroxylamine hydrochloride effect, obtains described polyhydroxy annular nitrone under alkaline condition;
(formula II) (formula III) (formula IV) (formula V)
Wherein, R
1, R
2And R
3For methyl, ethyl, propyl group, butyl, allyl group, benzyl or to methoxy-benzyl etc.
In above-mentioned reaction process, alkali can be organic bases or mineral alkali, and organic bases commonly used is diethylamine, triethylamine, diisopropylamine, diisopropyl ethyl amine, pyridine, 2 or tetrabutyl ammonium fluoride; Mineral alkali commonly used is yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, sodium hydroxide, potassium hydroxide or potassium bifluoride.
The hemiacetal of the described formula II structure of step 1) can be prepared by sugar, and described sugar is wood sugar, pectinose, ribose and lyxose etc.But preparation method's reference carries out [(a) Barker, R.; Fletcher, H.G.J.Org.Chem.1961,26,4605-4609. (b) Tejima, S.; Fletcher, H.G.J.Org.Chem.1963,28,2999-3004.]
The solvent of step 4) reaction is methanol-water, alcohol-water, tetrahydrofuran (THF), toluene or acetone.The temperature of reaction is 0-100 ℃, and the reaction times is 5 minutes-2 weeks.
The sugar that the present invention can nature extensively exists be raw material, through the polyhydroxy annular nitrone that a few step prepared in reaction have the height reactive behavior, has realized succinct, efficient and a large amount of preparations of this compounds.The present invention is raw materials used to be cheap various sugar such as wood sugar, pectinose, ribose and lyxose, and raw material is easy to get, and the preparation method is simple, the productive rate height, and preparation condition is less demanding, and the purifying of intermediate is easy easily.Present method is easy to realize a large amount of synthetic, thereby synthetic at short notice a large amount of iminosugar compounds provide solid basis for screening has the compound of biological activity and pharmaceutical use.
Description of drawings
Fig. 1, Fig. 2 be (2R, 3R, 4R)-4-mesyloxy-2,3, the proton nmr spectra of 5-three benzyloxies-1-valeral and carbon-13 nmr spectra figure;
Fig. 3, Fig. 4 be polyhydroxy annular nitrone (2S, 3S, 4S)-2-benzyloxymethyl-3,4-benzyloxy-3,4-dihydro-1-oxygen pyrroles's proton nmr spectra and carbon-13 nmr spectra figure;
Fig. 5, Fig. 6 be (2S, 3S, 4R)-4-mesyloxy-2,3, the proton nmr spectra of 5-three benzyloxies-1-valeral and carbon-13 nmr spectra figure;
Fig. 7, Fig. 8 be polyhydroxy annular nitrone (2R, 3R, 4S)-2-benzyloxymethyl-3,4-benzyloxy-3,4-dihydro-1-oxygen pyrroles's proton nmr spectra and carbon-13 nmr spectra figure;
Fig. 9, Figure 10 be (2S, 3S, 4S, 5S)-2-benzyloxymethyl-3, the 4-benzyloxy-proton nmr spectra of 5-phenyl-1-hydroxyl pyrrolidine, carbon-13 nmr spectra figure;
Figure 11, Figure 12, Figure 13 be respectively (2S, 3S, 4S, 5S)-2-methylol-3, the proton nmr spectra of 4-dihydroxyl-5-Phenylpyrrolidine, carbon-13 nmr spectra figure and two-dimentional nuclear-magnetism NOESY spectrogram.
Embodiment
The present invention at first makes glucosides with various sugar; free hydroxyl on the sugar ring is protected with alkyl; resulting alkoxyl group glucosides carries out deprotection and becomes hemiacetal II; this hemiacetal II protects (III) with the form of methyloxime ether; the free hydroxyl is converted into methanesulfonate ester IV; then methyloxime ether is hydrolyzed to aldehyde V, under alkaline condition, but this intermediate aldehydes V high yield change into the polyhydroxy annular nitrone derivative.The purifying of intermediate is through extraction and dry, and the crude product after concentrating directly drops into next step reaction, and this nitrone just can separate out with solid form from solution at last, perhaps passes through column chromatography (silica gel) separation and obtains oily matter.Reaction formula is as follows:
This nitrone derivative Yu Geshi reagent react, can set up a new chiral centre efficiently, and the azanol that generates can effectively be reduced by zinc powder acetic acid or catalytic hydrogenation condition is converted into iminosugar, thereby realized the succinct of iminosugar, efficiently, economical and practical and general is synthetic.For example, with the metal reagent addition, generate azanol VI, and compound V promptly can synthesize iminosugar VII through a step or the conversion of a few step, reaction formula is as follows:
According to literature method [(a) Barker, R.; Fletcher, H.G.J.Org.Chem.1961,26,4605-4609. (b) Tejima, S.; Fletcher, H.G.J.Org.Chem.1963,28,2999-3003.] prepare hemiacetal 2,3 by the D-wood sugar, 5-O-tribenzyl-D-furyl xylose II.With pyridine (30mL, 0.37mol) add in methylene dichloride (100mL) solution of this hemiacetal crude product (calculating according to 0.2mol), toward wherein adding O-methyl hydroxylamine hydrochloride (20.88g, 0.25mol), stirring at room is after 12 hours, with the solvent evaporate to dryness, in concentrated solution, add ethyl acetate and hydrochloric acid (1N then, 30mL), through extracting and demixing, merge organic phase, dry, concentrate, get yellow oil (2S, 3S, 4R)-2,3,5-three benzyloxies-4-hydroxyl-1-valeral methyloxime ether III are directly thrown in next step reaction.
This yellow oil (calculating according to 0.2mol) is dissolved in methylene dichloride (100mL), add pyridine (30mL, 0.37mol) and methane sulfonyl chloride (15.6mL, 0.20mol), stirring at room is after 8 hours, adding hydrochloric acid (1N) cancellation should react.Through extracting and demixing, merge organic phase, drying concentrates, and (4R)-2,3,5-three benzyloxies-4-sulfonyloxy methyl oxygen-1-valeral methyloxime ether IV are directly used in next step reaction for 2S, 3S to get yellow oil.
In tetrahydrofuran (THF) (300mL) solution of this yellow oil (calculating), add p-methyl benzenesulfonic acid (38.00g according to 0.2mol, 0.2mol) and 37% formalin (50mL), stirring at room is up to raw material completely dissolve (TLC monitoring), in mixed solution, add ethyl acetate and water then, through extracting and demixing, merge organic phase, dry, concentrate gained yellow oil (2R, 3R, 4R)-4-mesyloxy-2,3,5-three benzyloxies-1-valeral V, its proton nmr spectra and carbon spectrum are respectively as depicted in figs. 1 and 2.
(37.80g, (31.05g in water 0.45mol) (50mL) solution, can observe a large amount of bubbles in the reinforced process and produce 0.45mol) to add oxammonium hydrochloride with sodium bicarbonate earlier.Toward ethanol (200mL) solution that wherein adds above-mentioned yellow oil (calculating) according to 0.2mol, stirring at room 15 hours, post-heating stirred 48 hours.Add ethyl acetate and water then in mixed solution, through extracting and demixing, merge organic phase, drying concentrates, and gets yellow oil.This oily matter is dissolved in the ethyl acetate and sherwood oil of suitable proportion, room temperature is placed and is spent the night, separate out white solid 10.40g, mother liquor continues crystallization, and 9.95g white solid (2S gets back, 3S, 4S)-and 2-benzyloxymethyl-3,4-benzyloxy-3,4-dihydro-1-oxygen pyrroles I, mother liquor amounts to the 22.00g product through the white solid 1.35g that gets back behind the column chromatography purifying.With the wood sugar is that raw material calculates, and seven steps reaction overall yield is 26%.The proton nmr spectra of nitrone I and carbon-13 nmr spectra figure are respectively as shown in Figure 3 and Figure 4.
m.p.：90-91℃.
[α]
D＝+45°(c＝0.4，CHCl
3)
IR(cm
-1)：3049(w)，2945，2923，2901，2884，2868，2851(w)，1593(s)，1551(s)，1496(s)，1452(s)，1361(s)，1247(vs)，1131(vs)，1247(vs)，1028(vs).
1H-NMR(CDCl
3)：δ(ppm)7.38-7.26(m，15H)，6.91(d，J＝1.9Hz，1H)，4.69-4.67(m，1H)，4.644.46(m，6H)，4.39(dd，J＝3.2，2.2Hz，1H)，4.10-4.04(m，2H)，3.78(d，J＝7.3Hz，1H)；)
13C-NMR(CDCl
3，75M)：δ(ppm)66.03(CH
2O)，71.67，71.91，73.47，80.30(CHO)，82.74(CHO)，127.70，127.75，127.92，128.14，128.17，128.38，128.55，128.61，133.02(N＝CH)，137.06(C)，137.16(C)，137.63(C).
ESI-MS：m/z?440.3[M+Na]
+，calcd?for?C
26H
27NO
4
FT-ICRMS：m/z?418.2007[M+H]
+(C
26H
28NO
4requires?418.2013).
Embodiment 2, preparation polyhydroxy annular nitrone (2R, 3R, 4S)-2-benzyloxymethyl-3,4-benzyloxy-3,4-dihydro-1-oxygen pyrroles I
According to literature method [(a) Barker, R.; Fletcher, H.G.J.Org.Chem.1961,26,4605-4609. (b) Tejima, S.; Fletcher, H.G.J.Org.Chem.1963,28,2999-3003.], prepare hemiacetal 2,3 by the D-pectinose, 5-O-tribenzyl-D-furans pectinose II.With pyridine (2.7mL, 34.2mmol) add this hemiacetal (8.40g, 11.4mmol) methylene dichloride (20mL) solution in, toward wherein add O-methyl hydroxylamine hydrochloride (1.91g, 22.8mmol), after the stirring at room 24 hours, with the solvent evaporate to dryness, add in the concentrated solution then ethyl acetate and hydrochloric acid (1N, 30mL), through extracting and demixing, merge organic phase, drying concentrates, obtain faint yellow oily thing (2R behind the gained crude product process column chromatography purifying, 3R, 4R)-2,3,5-three benzyloxies-4-hydroxyl-1-valeral methyloxime ether III (8.20g, productive rate 91%).
With secondary alcohol (7.34g 16.3mmol) is dissolved in methylene dichloride (30mL), add pyridine (5mL, 62mmol) and methane sulfonyl chloride (1.9mL, 24mmol), stirring at room is after 8 hours, adding hydrochloric acid (1N) cancellation should react.Through extracting and demixing, merge organic phase, drying concentrates, and (4R)-2,3,5-three benzyloxies-4-sulfonyloxy methyl Oxy-1-valeral methyloxime ether IV (9.35g) are directly used in next step reaction for 2R, 3S to get yellow oil.
Past yellow oil (6.94g, (4.95g is 26mmol) with 37% formalin (5mL) to add p-methyl benzenesulfonic acid in tetrahydrofuran (THF) 13mmol) (50mL) solution, stirring at room adds ethyl acetate and water, through extracting and demixing then up to raw material completely dissolve (TLC monitoring) in mixed solution, merge organic phase, drying concentrates, gained yellow oil (2S, 3S, 4R)-4-mesyloxy-2,3,5-three benzyloxies-1-valeral V (6.83g) are directly thrown in next step reaction.Its proton nmr spectra and carbon-13 nmr spectra figure are respectively as shown in Figure 5 and Figure 6.
(3.36g, (2.08g in water 30mol) (10mL) solution, can observe a large amount of bubbles in the reinforced process and produce 40mmol) to add oxammonium hydrochloride with sodium bicarbonate earlier.Toward methyl alcohol (30mL) solution that wherein adds above-mentioned yellow oil, stirring at room 1 hour, post-heating stirred 32 hours.Add ethyl acetate and water then in mixed solution, through extracting and demixing, merge organic phase, drying concentrates, and gets yellow oil.This oily matter is obtained faint yellow oily thing after by the column chromatography purifying, (2R, 3R, 4S)-and 2-benzyloxymethyl-3,4-benzyloxy-3,4-dihydro-1-oxygen pyrroles I (1.62g, three step productive rates 30%).Its proton nmr spectra and carbon-13 nmr spectra figure are respectively as shown in Figure 7 and Figure 8.(the another kind of synthesis method of this nitrone is seen: Cicchi, S.; Marradi, M.; Vogel, P.; Goti, A.J.Org.Chem.2006,71,1614-1619.)
1H-NMR(CDCl
3，300MHz)：δ(ppm)7.57-7.31(m，15H)，6.85(s，1H)，4.80-4.78(m，1H)，4.72-4.52(m，6H)，4.40(dd，1H，J＝4.6and?7.6Hz)，4.19(br?s，1H)，4.01(dd，1H，J＝4.3and?10.1Hz)，3.86(d，J＝9.9Hz).
13C-NMR(CDCl
3，75MHz)：δ(ppm)137.92，137.33，137.25，133.45，128.66，128.58，128.35，128.24，128.12，127.99，127.86，127.61，83.22，80.64，74.18，73.60，73.19，72.51，64.48.
DEPT?135(CDCl
3，75MHz)：δ(ppm)positive?133.44，128.65，128.58，128.35，128.23，128.11，127.98，127.86，127.61，83.21，80.64，74.19；negative?73.60，73.19，72.50，64.49.
Embodiment 3: the addition reaction of nitrone and phenyl-magnesium-bromide obtain (2S, 3S, 4S, 5S)-2-(benzyloxymethyl)-3,4-benzyloxy-5-phenyl-N-hydroxyl pyrrolidine VI
Under the nitrogen protection condition, with bromobenzene (0.26mL, 2.5mmol) add magnesium rod (60mg, 2.5mmol) and in the new suspension that steams tetrahydrofuran (THF) (5mL), the tetrahydrofuran solution of reflux preparation in 3 hours phenyl-magnesium-bromide.Under condition of ice bath, toward filling the nitrone (2R that vigorous stirring, 3R, 4R)-2-benzyloxymethyl-3,4-benzyloxy-3, (200mg dropwise adds the as above prepared Grignard reagent of method to 4-dihydro-1-oxygen pyrroles in the flask of tetrahydrofuran solution 0.5mmol), the reinforced back that finishes continues to stir half an hour.Add this reaction of saturated aqueous ammonium chloride cancellation then, add ethyl acetate extraction, merge organic phase.Solvent is spin-dried under vacuum condition, and the thick product of gained gets colorless oil through column chromatography purification, becomes white solid (216mg, productive rate 91%) after room temperature is placed, and its proton nmr spectra and carbon spectrum are respectively as Fig. 9 and shown in Figure 10.
m.p.81-82℃.
[α]
D＝+16.8(c＝2.5，CHCl
3)
IR(cm-1)：3343(w)，3107(w)，3087(w)，3063(w)，3031(w)，2971(w)，2870(w)，1604(w)，1595(w)，1496(w)，1472(w)，1454(m)，1365(w)，1098(s)，1076(vs).
1H-NMR(CDCl
3)：δ(ppm)：3.69-3.75(m，1H)，3.78(t，1H，J＝7.2Hz)，3.89(dd，1H，J＝3.7and?8.7Hz)，4.06(dd，1H，J＝3.4and?7.2Hz)，4.11(dd，1H，J＝2.7and?3.2Hz)，4.23(d，1H，J＝7.2Hz)，4.33(ABQ，2H，J＝11.8Hz)，4.55(ABQ，2H，J＝12.0Hz)，4.56(ABQ，2H，J＝12.1Hz)，4.94(s，1H，OH)，7.07-7.44(m，20H).
1H-NMR(CDCl
3+D
2O)：δ(ppm)：3.73-3.77(m，1H)，3.80(t，1H，J＝7.2Hz)，3.93(dd，1H，J＝3.9and?8.9Hz)，4.09(dd，1H，J＝3.4and?7.2Hz)，4.14(dd，1H，J＝2.8and?3.2Hz)，4.26(d，1H，J＝7.2Hz)，4.37(ABQ，2H，J＝11.9Hz)，4.60(s，2H)，4.58(ABQ，2H，J＝12.0Hz)，7.12-7.47(m，20H).
DEPT-135(CDCl
3，75M)：δ(ppm)positive：128.50，128.38，128.34，128.23，128.05，127.78，127.69，127.67，127.62，127.56，87.49，83.68，74.06，68.93.negative：73.44，72.01，71.66，66.86.
13C-NMR(CDCl
3，75M)：δ(ppm)139.36，138.25，138.11，137.89，128.49，128.38，128.34，128.23，128.05，127.77，127.69，127.67，127.61，127.55，87.50，83.69，74.07，73.44，72.01，71.66，68.93，66.87.
ESI-MS：m/z?496.5[M+H]
+；
FT-ICRMS：m/z?496.2485[M+H]
+，(C
32H
33NO
4requires?496.2482).
Embodiment 4: nitrone with to the addition of 10-alkene-undecyl magnesium bromide (2S, 3S, 4S, 5S)-2-benzyloxymethyl-3,4-benzyloxy-5-(10-alkene-undecyl)-N-hydroxyl pyrrolidine VI
Under the nitrogen protection condition, with 11-bromo-1-alkene (0.4mL, 2.4mmol) add magnesium rod (40mg, 2.4mmol) and in the new suspension that steams ether (5mL), the diethyl ether solution of reflux preparation in 30 minutes 10-alkene-undecyl magnesium bromide.Under condition of ice bath, (100mg dropwise adds the as above prepared Grignard reagent of method in the flask of tetrahydrofuran solution 0.2mmol), the reinforced back that finishes continues to stir half an hour toward filling the nitrone that vigorous stirring.Add this reaction of saturated aqueous ammonium chloride cancellation then, add ethyl acetate extraction, merge organic phase.Solvent is spin-dried under vacuum condition, and the thick product of gained gets colorless oil (120mg, productive rate 86%) through column chromatography purification.
Embodiment 5: through the catalytic hydrogenation deprotection obtain iminosugar (2S, 3S, 4S, 5S)-2-methylol-3,4-dihydroxyl-5-Phenylpyrrolidine VII
Toward (2S, 3S, 4S, 5S)-2-(benzyloxymethyl)-3,4-benzyloxy-5-phenyl-N-hydroxyl pyrrolidine (200mg, add in dichloromethane solution 0.4mmol) methyl alcohol (10mL) and hydrochloric acid (6N, 1mL) with 10% palladium/carbon (10%, 60mg).Utilize rush oxygen in the reaction system of nitrogen, be full of this reaction system with hydrogen then.After the stirring at room 20 hours, TLC (EA/MeOH:5/1) shows raw material completely dissolve, has generated the species of high polarity.With rush hydrogen in the reaction system of nitrogen, catalyzer is filtered, filtrate concentrates under vacuum condition.Crude product is dissolved in methyl alcohol again, and with strong aqua neutralization, goes out behind the unnecessary ammonia through vacuum condition, and residuum is with a small amount of dissolved in distilled water and transfer on the ion exchange resin of anticipating.Obtain target compound (2S, 3S, 4S after treatment, 5S)-and 2-methylol-3,4-dihydroxyl-5-Phenylpyrrolidine (72mg, productive rate 85%), its proton nmr spectra and carbon spectrum are respectively as Figure 11 and shown in Figure 12, and its two-dimentional nuclear-magnetism NOESY spectrogram as shown in figure 13.
[α]
D＝-52°(c＝0.65，H
2O)
1H-NMR(D
2O，300M)：δ(ppm)：7.41(m，5H)，4.09(dd，1H，J＝7.4?and?8.3Hz)，3.93(broad?t，2H)，3.72(dd，1H，J＝4.7and?11.6Hz)，3.65(dd，1H，J＝6.3?and?11.6Hz)，3.22(dd，1H，J＝6.3?and?11.5Hz).
1H-NMR(D
2O，600M)：δ(ppm)：7.36(broad?d，4H，H-2’，H-3’，H-5’，H-6’)，7.32-7.27(m，1H，H-4’)，4.04(dd，1H，J＝7.5and?9.0Hz，H-4)，3.88(d，1H，J＝5.6Hz，H-3or?H-5)，3.87(d，1H，J＝7.4Hz，H-5or?H-3)，3.67(dd，1H，J＝4.5and?11.6Hz，H-1a)，3.61(dd，1H，J＝6.5and?11.6Hz，H-1b)，3.17(dd，1H，J＝2.1and?6.8Hz，H-2).
DEPT-135(D
2O，75M)：δ(ppm)positive：128.95，128.23，127.35，82.26，77.51，64.00，61.79.negative：62.46.
13C-NMR(D
2O，75M)：δ(ppm)139.73，128.96，128.23，127.36，82.27，77.53，64.01，62.47，61.81.
ESI-MS：m/z?210.2[M+H]
+，232.2[M+Na]
+.
FT-ICRMS：m/z?210.1126[M+H]
+，(C
11H
16NO
3requires?210.1125).
Implement 6: through the catalytic hydrogenation deprotection obtain iminosugar (2S, 3S, 4S, 5S)-2-methylol-3,4-dihydroxyl-5-dodecyl pyrrolidine hydrochloride VII
Toward (2S, 3S, 4S, 5S)-2-benzyloxymethyl-3, (100mg adds methyl alcohol (10mL) and concentrated hydrochloric acid and 10% palladium/carbon (20mg) to 4-benzyloxy-5-(10-alkene-undecyl)-N-hydroxyl pyrrolidine in methylene dichloride 1.7mmol) (10mL) solution.Utilize rush oxygen in the reaction system of nitrogen, be full of this reaction system with hydrogen then.Stirring at room shows raw material completely dissolve up to TLC (EA/MeOH:5/1), has generated the species of high polarity.With rush hydrogen in the reaction system of nitrogen, catalyzer is filtered, filtrate concentrates under vacuum condition.Crude product is dissolved in methyl alcohol and the ethyl acetate again, obtains white solid (5mg) after leaving standstill, and mother liquor obtains brown solid thing (37mg) after concentrating, obtain 42mg target compound (2S, 3S, 4S altogether, 5S)-and 2-methylol-3,4-dihydroxyl-5-undecyl-tetramethyleneimine, productive rate 88%.
1H-NMR(D
2O，600M)：δ(ppm)：3.90(t，1H，J＝7.1and?7.4Hz)，3.80(t，1H，J＝7.6and?7.1Hz)，3.77(dd，1H，J＝3.7，3.6and?12.7，12.6Hz)，3.70(dd，1H，J＝6.1and?12.7Hz)，3.41-3.38(m，1H)，3.26(dd，1H，J＝8.3and?14.4Hz)，1.77-1.71(m，1H)，1.63-1.56(m，1H)，1.29-1.12(m，18H)，0.70(t，3H，J＝6.7and?7.1Hz)
13C-NMR(D
2O)：δ(ppm)：78.1(OCH)，74.2(OCH)，62.1(OCH
2)，61.5(NCH)，57.9(NCH)，31.2，30.1，28.7，28.6，28.5，28.3，28.2，25.1，22.0，13.4.
Claims (6)
1, a kind of method of polyhydroxy annular nitrone of preparation formula I structure comprises the steps:
1) hemiacetal and the O-methyl hydroxylamine hydrochloride with formula II structure reacts under alkaline condition, obtains the methyloxime ether of formula III structure;
2), obtain the methanesulfonates of formula IV structure with the methyloxime ether and the methane sulfonyl chloride reaction of formula III structure;
3) methanesulfonates with formula IV structure discharges aldehyde radical under acidic conditions, obtains the aldehyde of formula V structure;
4) aldehyde of formula V structure with the hydroxylamine hydrochloride effect, obtains described polyhydroxy annular nitrone under alkaline condition;
(formula II) (formula III) (formula IV) (formula V)
Wherein, R
1, R
2And R
3Be alkyl, alkenyl, aromatic base or substituted aryl.
2, method according to claim 1 is characterized in that: R
1, R
2And R
3For methyl, ethyl, propyl group, butyl, allyl group, benzyl or to methoxy-benzyl.
3, method according to claim 1 and 2 is characterized in that: described alkali is organic bases or mineral alkali, and described organic bases is diethylamine, triethylamine, diisopropylamine, diisopropyl ethyl amine, pyridine, 2 or tetrabutyl ammonium fluoride; Described mineral alkali is yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus, sodium hydroxide, potassium hydroxide or potassium bifluoride.
4, method according to claim 1 and 2 is characterized in that: the hemiacetal of the described formula II structure of step 1) is prepared by sugar, and described sugar is wood sugar, pectinose, ribose, lyxose.
5, method according to claim 1 and 2 is characterized in that: the solvent of step 4) reaction is methanol-water, alcohol-water, tetrahydrofuran (THF), toluene or acetone.
6, method according to claim 1 and 2 is characterized in that: the temperature of step 4) reaction is 0-100 ℃, and the reaction times is 5 minutes-2 weeks.
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|---|---|---|---|---|
| IL123345A (en) * | 1995-09-11 | 2003-07-31 | Aventis Pharma Inc | Cyclic nitrones and pharmaceutical compositions containing them |
| CN100567298C (en) * | 2006-09-25 | 2009-12-09 | 中国科学院化学研究所 | A kind of method of synthesizing polyhydroxy pyrroline acridine alkaloid |
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