CN101172989B - Method for producing 5-O-acetyl-3-deoxidization-1,2-isopropylidene-alpha-D-tetrol xylose and intermediate - Google Patents
Method for producing 5-O-acetyl-3-deoxidization-1,2-isopropylidene-alpha-D-tetrol xylose and intermediate Download PDFInfo
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- CN101172989B CN101172989B CN2006101179921A CN200610117992A CN101172989B CN 101172989 B CN101172989 B CN 101172989B CN 2006101179921 A CN2006101179921 A CN 2006101179921A CN 200610117992 A CN200610117992 A CN 200610117992A CN 101172989 B CN101172989 B CN 101172989B
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- ethanoyl
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- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 title claims abstract description 55
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 title claims abstract description 51
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 96
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 238000000034 method Methods 0.000 claims abstract description 58
- 239000003153 chemical reaction reagent Substances 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 30
- -1 p-toluenesulfonyl Chemical group 0.000 claims description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 19
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 238000006192 iodination reaction Methods 0.000 claims description 15
- 230000002829 reductive effect Effects 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 13
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 12
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 12
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 12
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 11
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 235000015320 potassium carbonate Nutrition 0.000 claims description 10
- ODLMAHJVESYWTB-UHFFFAOYSA-N propylbenzene Chemical compound CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 claims description 10
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000003999 initiator Substances 0.000 claims description 9
- 230000026045 iodination Effects 0.000 claims description 9
- 235000017550 sodium carbonate Nutrition 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 9
- 239000012346 acetyl chloride Substances 0.000 claims description 8
- 239000012434 nucleophilic reagent Substances 0.000 claims description 8
- 230000006103 sulfonylation Effects 0.000 claims description 8
- 238000005694 sulfonylation reaction Methods 0.000 claims description 8
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- 150000002460 imidazoles Chemical class 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 150000003254 radicals Chemical class 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 6
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 150000008065 acid anhydrides Chemical class 0.000 claims description 6
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- 239000012442 inert solvent Substances 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 6
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 claims description 5
- YTZKOQUCBOVLHL-UHFFFAOYSA-N tert-butylbenzene Chemical compound CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 claims description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 4
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 150000003053 piperidines Chemical class 0.000 claims description 4
- KUGQQSKAOJYCDL-UHFFFAOYSA-N C1(=CC=C(C=C1)[P])C Chemical compound C1(=CC=C(C=C1)[P])C KUGQQSKAOJYCDL-UHFFFAOYSA-N 0.000 claims description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 3
- 230000001143 conditioned effect Effects 0.000 claims description 3
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical group CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 claims description 2
- CTFNJPHOILFHEL-UHFFFAOYSA-N CC1=C(C=CC=C1)[P] Chemical compound CC1=C(C=CC=C1)[P] CTFNJPHOILFHEL-UHFFFAOYSA-N 0.000 claims description 2
- YTNSNFSZEOAYRF-UHFFFAOYSA-N CN(C)C.P Chemical compound CN(C)C.P YTNSNFSZEOAYRF-UHFFFAOYSA-N 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 2
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 claims description 2
- 229910052728 basic metal Inorganic materials 0.000 claims 2
- 239000007806 chemical reaction intermediate Substances 0.000 claims 1
- 125000001033 ether group Chemical group 0.000 claims 1
- 230000000977 initiatory effect Effects 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 2
- 229940125782 compound 2 Drugs 0.000 abstract 1
- 229940126214 compound 3 Drugs 0.000 abstract 1
- 238000005831 deiodination reaction Methods 0.000 abstract 1
- 229960003487 xylose Drugs 0.000 description 52
- 238000003756 stirring Methods 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 19
- 239000000243 solution Substances 0.000 description 12
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 10
- SRBFZHDQGSBBOR-LECHCGJUSA-N alpha-D-xylose Chemical compound O[C@@H]1CO[C@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-LECHCGJUSA-N 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 125000002346 iodo group Chemical group I* 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000003513 alkali Substances 0.000 description 5
- 230000009286 beneficial effect Effects 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 5
- 238000006277 sulfonation reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 230000021736 acetylation Effects 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000003843 furanosyl group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 230000003068 static effect Effects 0.000 description 2
- NQIBQILAMKZKFE-UHFFFAOYSA-N 2-(5-bromo-2-fluorophenyl)-3-fluoropyridine Chemical compound FC1=CC=C(Br)C=C1C1=NC=CC=C1F NQIBQILAMKZKFE-UHFFFAOYSA-N 0.000 description 1
- PFCMYFUJKFYZED-UHFFFAOYSA-N 2-methylphenol phosphane Chemical compound P.C1(=CC=CC=C1O)C.C1(=CC=CC=C1O)C.C1(=CC=CC=C1O)C PFCMYFUJKFYZED-UHFFFAOYSA-N 0.000 description 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- YEFDVPCECOPVDQ-UHFFFAOYSA-N C(C)P(CC)CC.C1(=CC=CC=C1)C Chemical compound C(C)P(CC)CC.C1(=CC=CC=C1)C YEFDVPCECOPVDQ-UHFFFAOYSA-N 0.000 description 1
- AUYDCDFGKWMOKV-LJSVPSOQSA-N CC(C)(OC12)OC1O[C@H](COC(C)=O)C2O Chemical compound CC(C)(OC12)OC1O[C@H](COC(C)=O)C2O AUYDCDFGKWMOKV-LJSVPSOQSA-N 0.000 description 1
- YGIFXGKXESSIBK-UHFFFAOYSA-N CC(C)(OC1C2C3CO)OC1OC23O Chemical compound CC(C)(OC1C2C3CO)OC1OC23O YGIFXGKXESSIBK-UHFFFAOYSA-N 0.000 description 1
- GYBQSKBVWQTIDV-UHFFFAOYSA-N CC1(C)OCC1C1OC2OC(C)(C)OC2C1O Chemical compound CC1(C)OCC1C1OC2OC(C)(C)OC2C1O GYBQSKBVWQTIDV-UHFFFAOYSA-N 0.000 description 1
- UOATVWFHMCPDHP-UHFFFAOYSA-N CCCCP(CCCC)CCCC.C1=CC=CC=C1 Chemical compound CCCCP(CCCC)CCCC.C1=CC=CC=C1 UOATVWFHMCPDHP-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical group C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DAMMJZIZXXMWKM-UHFFFAOYSA-M [Na+].OC([O-])=O.CC1=CC=CC=C1 Chemical compound [Na+].OC([O-])=O.CC1=CC=CC=C1 DAMMJZIZXXMWKM-UHFFFAOYSA-M 0.000 description 1
- LOQLIGWYJNUOKL-UHFFFAOYSA-N acetyl chloride 1,2-dichloroethane Chemical compound C(C)(=O)Cl.C(CCl)Cl LOQLIGWYJNUOKL-UHFFFAOYSA-N 0.000 description 1
- QTKQJGIIAYHPMC-UHFFFAOYSA-N acetyl chloride chloroform Chemical compound C(Cl)(Cl)Cl.C(C)(=O)Cl QTKQJGIIAYHPMC-UHFFFAOYSA-N 0.000 description 1
- SCBVAXOHPRNUKB-UHFFFAOYSA-N acetyl chloride propan-2-one Chemical compound CC(=O)C.C(C)(=O)Cl SCBVAXOHPRNUKB-UHFFFAOYSA-N 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- WINYCIXPFGVTOS-UHFFFAOYSA-M sodium;dichloromethane;hydroxide Chemical compound [OH-].[Na+].ClCCl WINYCIXPFGVTOS-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Abstract
The invention relates to a novel method of preparing 5-O-acetyl-3-deoxygenation-1 and 2-isopropylidene group-Alpha-D-furan xylose 1, and the specific steps are as follow: firstly, a compound 3 can get a compound 2 through iodo-reaction; secondly, deiodination reaction is reacted with deoxidizer to get the 5-O-acetyl-3-deoxygenation-1 and the 2-isopropylidene group-Alpha-D-furan xylose 1, wherein,Ac is acetyl. The method is simple and practical with low cost, high getting rate and easy operation, thereby being not only applicable for the small device in a lab, but also is applicable for the mass production in the industry. The invention also provides a new compound intermediate compound of 5-O-acetyl-3Alpha- iodonium-1 and 2-O-isopropylidene group-Alpha-D-furan xylose, wherein, Ac is the acetyl.
Description
Technical field
The present invention relates to a kind of 5-O-ethanoyl-3-deoxidation-1 of novelty, the compound method of 2-isopropylidene-α-D-furyl xylose; The invention still further relates to a kind of midbody 5-O-ethanoyl-3 alpha-iodine-1 in its preparation process, 2-O-isopropylidene-α-D-furyl xylose.
Background technology
5-O-ethanoyl-3-deoxidation-1,2-isopropylidene-α-D-furyl xylose (I) has following structural formula:
Wherein, Ac is an ethanoyl.
This compound is the synthetic field of a medicine midbody commonly used, and particularly at the microbiotic of preparation treatment infectation of bacteria, the diagnostic medicine of anti-AIDS medicine, cancer etc. has a wide range of applications.
Compound I main compound method at present is described below, but up to the present can't obtain gratifying result.
PCT/US93/14494 discloses a kind of preparation 5-O-ethanoyl-3-deoxidation-1, the method for 2-isopropylidene-α-D-furyl xylose I, and this method obtains through the reactions step:
This method reactions step is long, complicated operation, and total recovery is low to be merely 10.5%.Not only be not suitable for the laboratory and prepare on a small scale, nor be fit to large-scale industrial production.
Summary of the invention
The objective of the invention is provides a kind of simple possible in order to overcome the defective of prior art, and cost is lower; Yield can reach 30%; And be suitable for the 5-O-ethanoyl-3-deoxidation-1 of suitability for industrialized production, the compound method of 2-isopropylidene-α-D-furyl xylose I, this method comprises following steps:
(1) compound III makes compound I I through iodide reaction;
(2) make 5-O-ethanoyl-3-deoxidation-1 through taking off Iod R, 2-isopropylidene-α-D-furyl xylose I with reductive agent again;
Wherein, Ac is an ethanoyl.
Among the present invention, described step (1) can adopt dual mode to carry out:
Mode one, compound III and iodination reagent make compound I I through iodide reaction under the effect of nucleophilic reagent.
In the mode one, that described iodination reagent is preferable is I
2Or NaI; The consumption of described iodination reagent is preferable is and the mol ratio of compound III 1: 1.1～1: 10.0, and better mol ratio is 1: 1.1～1: 2.0.
In the mode one, that described nucleophilic reagent is preferable is triphenyl phosphorus (Ph
3P), tributyl phosphorus, tri-tert phosphorus, three p-methylphenyl phosphorus, three o-methyl-phenyl-phosphorus, trimethylammonium phosphorus or triethyl phosphine.
In the mode one, the preferable mol ratio for compound III of described nucleophilic reagent consumption is 1: 3.
The preferred solvents that the reaction of mode one is adopted be any inert solvent, for example benzene, toluene, ethylbenzene, propyl benzene, isopropyl benzene, trimethylphenylmethane, YLENE, chlorobenzene, bromobenzene, methyl-phenoxide, 1, one or more in the 4-dioxane.
What the temperature of the iodination reaction of mode one was preferable is 80-130 ℃, and better is 90-120 ℃.
In order to be beneficial to the carrying out of reaction, in reaction system, can add alkaline reagents, the alkaline reagents that can add is exemplified below: inorganic base (salt of wormwood, yellow soda ash, sodium hydrogencarbonate, sodium hydroxide); Organic bases (piperidines, imidazoles, pyridine, quinoline, triethylamine, diisopropyl ethyl amine).
The peroxosulphuric hydrogen potassium agent treated that can add capacity after reaction is accomplished is fallen the excessive nucleophilic reagent of reaction system, for example triphenyl phosphorus.
Method two, compound III and sulfonated reagent react under the alkaline reagents condition and make compound IV, obtain compound I I with iodination reagent through iodide reaction again, and its reactions step is following:
Wherein Ac is an ethanoyl, and R is the positive fourth alkylsulfonyl of p-toluenesulfonyl, methylsulfonyl, benzenesulfonyl, three fluorosulfonyls or perfluor; Be preferably p-toluenesulfonyl, methylsulfonyl or benzenesulfonyl.
In the mode two, what described sulfonated reagent was preferable is toluene sulfonyl chloride, tolylsulfonyl acid anhydride, methylsulfonyl chloride, methylsulfonyl acid anhydride, benzene sulfonyl chloride, benzene sulfonyl acid anhydride, trifluoro SULPHURYL CHLORIDE, trifluoro sulphonyl acid anhydride, the positive fourth SULPHURYL CHLORIDE of perfluor or the positive fourth sulphonyl of perfluor acid anhydride.The usage quantity of said sulphonyl reagent is the amount that the conventional sulfonylation in this area is adopted, and for example embodiment 40.
Described alkaline reagents is identical with the alkaline reagents described in the mode one.
In the mode two, what described sulfonylation temperature was preferable is-20 ℃～60 ℃.
In the mode two, compound IV behind the sulfonylation and iodo reagent react change compound I I into.That said iodo reagent is preferable is I
2Or NaI.The consumption of described iodination reagent can be identical with the consumption described in the mode one.
In the mode two, the temperature of described iodination reaction is 80 ℃～130 ℃.
In the mode two, described iodination reaction can add alkaline reagents, is beneficial to reaction and carries out.Described alkaline reagents can be identical with the alkaline reagents described in the mode one.
The solvent that sulfonation reaction and iodination reaction adopted of mode two can be same with the solvent phase described in the mode one.
Among the present invention, that the described reductive agent of step (2) is preferable is H
3PO
2Or Bu
3SnH.The consumption of said reductive agent is preferable is 1.0～50.0 times of compound I I weight, and better is 1.0～10 times, and best is 1.0～2.5 times.
Among the present invention, step (2) is described takes off preferable under following three kinds of conditions, the carrying out of Iod R:
Condition one is under the radical initiator condition.Described radical initiator can be this area radical initiator commonly used, for example 2,2 '-two azo isobutyronitriles (AIBN) or Benzoyl Peroxide (BPO).The consumption of said initiator is the conventional amount of initiator in this area, for example catalytic amount.
The reaction solvent that condition reaction is once adopted can be selected from benzene, toluene, ethylbenzene, propyl benzene, isopropyl benzene, trimethylphenylmethane, YLENE, chlorobenzene, bromobenzene, methyl-phenoxide or 1, one or several in the 4-dioxane.
What the temperature of condition reaction once was preferable is 20 ℃～100 ℃, and better is 80～100 ℃.
Condition two is under hydrogenation conditions.For example, at H
2-Pd, H
2Reduce under-Ni the condition.The usage quantity that said catalyst consumption this area hydro-reduction is conventional for example is the 1-5% of compound I I weight.
Condition two times, that the absolute pressure that described hydrogenation reaction adopted is preferable is 0.1-20Mpa, that better is 1-10Mpa.
Condition three is carried out under the n-Butyl Lithium condition.The consumption of described n-Butyl Lithium is preferable is 1.0～1.2 times of compound I I mole number.
What the reaction solvent that the reaction under the condition three is adopted was preferable is hexanaphthene, THF or ether.
Among the present invention, described compound III can adopt following method to make:
(1) compound VI I (wood sugar) is at H
2SO
4Change compound VI under/acetone the system; Adopt alkaline substance solution conditioned reaction liquid pH value between the 7-8;
(2) in the solvent, under sour condition, obtain compound V;
(3) in the solvent, make compound III with the acylating reagent reaction again.
In the step (1), compound VI I (wood sugar) is at H
2SO
4Change compound VI under/acetone the system.What the mole number of described acetone was preferable is 20～100 times of compound VI I (wood sugar) mole numbers, and better is 20-60 times.In order to reduce byproduct of reaction, described H
2SO
4That volume is preferable is the 1-4% of acetone volume.
What the temperature of the reaction of step (1) was preferable is 15-35 ℃, and better is 15-25 ℃.
The described alkaline matter of step (1) is preferable is selected from Pottasium Hydroxide, sodium hydroxide, salt of wormwood, yellow soda ash, sodium hydrogencarbonate or saleratus etc.
The reaction of step (1) also can be adopted in the conventional reaction system and carry out, for example H
2SO
4/ CuSO
4/ acetone, concrete reaction conditions can be with reference to embodiment 7.
Step (2), compound VI are under sour condition, and selectivity is sloughed hydroxyl protection and obtained compound V.What described acid was preferable is hydrochloric acid or sulfuric acid.Carry out being principle in order optionally to slough the protection base on 4,5 and to be beneficial to reaction, said sour volume is controlled at the 0.1-20% of solvent volume, and that better is the 0.5-5% of solvent volume; Selected solvent can be selected from methyl alcohol, ethanol, THF.
The preferred solvents that step (2) reaction is adopted be selected from methyl alcohol, ethanol, THF or 1,4-dioxane.
What the temperature of the reaction of step (2) was preferable is 10-35 ℃.
Step (3), compound V optionally introduces ethanoyl on the furanose ring.What the acylating reagent that is adopted was preferable is Acetyl Chloride 98Min. or diacetyl oxide.Optionally introduce acyl group on the furanose ring in order to control to be reflected at, what the mol ratio of the consumption of employed acylating reagent and compound V was preferable in the acylation reaction is 1: 1.0～1: 1.5, and better is 1: 1.0～1: 1.2.
In the step (3), in order to be beneficial to the carrying out of reaction, can in reaction system, add alkaline reagents, with the acid that is produced in the neutralization reaction, the alkaline matter that can add is exemplified below: inorganic base (like yellow soda ash, salt of wormwood, sodium amide, sodium hydride); Alkali metal alcohol compounds (like sodium methylate, sodium ethylate, potassium tert.-butoxide); Organic bases (like triethylamine, pyridine, quinoline, diisopropyl ethyl amine).Reaction solvent adopts any inert solvent such as ether (like THF, ether, glycol dimethyl ether, dioxan); Arene (like benzene,toluene,xylene); Halohydrocarbon (like methylene dichloride, trichloromethane, ethylene dichloride); N, N,N-DIMETHYLACETAMIDE or acetone etc.
The temperature of the acetylization reaction of step (3) is that being beneficial on compound V, optionally introduce acyl group is principle in the interior popular response temperature of this area scope, and concrete reaction conditions can be referring to embodiment 17.
The compound I that method of the present invention prepares can be at AcOH/Ac
2In the system of O 1,2,5-O-ethanoyl-3-deoxidation-1,2-isopropylidene-α-D-furyl xylose.
The present invention also provides a kind of new compound intermediate 5-O-ethanoyl-3 alpha-iodine-1,2-O-isopropylidene-α-D-furyl xylose, and structural formula is following:
Positive progressive effect of the present invention is: the present invention has overcome the defective of prior art; A kind of simple possible is provided, and cost is lower, and yield can reach 30%; And be suitable for the 5-O-ethanoyl-3-deoxidation-1 of suitability for industrialized production, the compound method of 2-isopropylidene-α-D-furyl xylose I.
Embodiment
Further illustrate content of the present invention below in conjunction with embodiment, these embodiment are not to be the restriction to the scope of the invention or spirit.
Embodiment 1 preparation 1,2,3,5-diisopropylidene-α-D-furyl xylose
(15.9g 0.106mol) is dissolved in 156mL (2.17mol) acetone, and the mol ratio of wood sugar and acetone is 1: 20 with wood sugar.Bathe adding vitriol oil 1.6mL under the cooling, H at cryosel
2SO
4Volume is 1.0% of an acetone volume.After slowly being raised to room temperature (20-25 ℃); It is complete up to TLC tracking raw material reaction to stir the 4-5h reaction, under the icy salt solution cooling, in reaction solution, adds yellow soda ash solid conditioned reaction liquid pH to 7.8, fully stirs after-filtration; Obtain white slurry like material after the filtrating body concentrates, promptly get target compound.
Embodiment 2-6 preparation 1,2,3,5-diisopropylidene-α-D-furyl xylose
Reactions step is with reference to embodiment 1, and wood sugar is 15.9g (0.106mol), and other concrete reaction parameters are seen table 1.
Table 1 embodiment 2～6 reaction parameters
| Embodiment | Acetone (mL) | The mol ratio of wood sugar/acetone | The vitriol oil (mL) | H 2SO 4/ acetone v% | Temperature of reaction (℃) | Alkaline matter | pH |
| 2 | 156 | 1∶20 | 3.0 | 1.92 | 15-25 | Pottasium Hydroxide | 7.5 |
| 3 | 312 | 1∶40 | 12.48 | 4.0 | 25-30 | Sodium hydroxide | 7.0 |
| 4 | 770 | 1∶100 | 8.0 | 1.0 | 15-20 | Salt of wormwood | 7.5 |
| 5 | 468 | 1∶60 | 9.4 | 2.0 | 30-35 | Sodium hydrogencarbonate | 8.0 |
| 6 | 156 | 1∶20 | 6.42 | 4.0 | 25-35 | Saleratus | 7.0 |
Embodiment 7 preparations 1,2,3,5-diisopropylidene-α-D-furyl xylose
With wood sugar (100g 0.666mol) is dissolved in the 1800mL acetone, bathe cooling at cryosel and add vitriol oil 10mL down, copper sulfate (190g, 1.19mol), slowly be raised to room temperature (20-25 ℃) after, stirring reaction is complete up to TLC tracking raw material reaction.Reacting liquid filtering, filtrating drip 25% oxyammonia solution adjusting pH value to 7-8, fully stir after-filtration, and filtrate decompression concentrates the material that obtains white pulpous state, promptly gets target compound.。
Embodiment 8 preparations 1,2-O-isopropylidene-α-D-furyl xylose
With embodiment 1 obtained 1,2,3; 5-diisopropylidene-α-D-furyl xylose (10g; 0.042mol) be dissolved in the 150mL methyl alcohol, adding volume ratio is the hydrochloric acid of methyl alcohol 0.5%, the back that stirs is in reaction is complete up to TLC tracking raw material reaction down in room temperature (20-25 ℃).Cooling adds NaHCO down
3Neutralization reaction liquid is 7-8 to pH, filters, and the material that filtrate decompression concentrates, obtain after the drying obtains 7.6g 1 through recrystallizing methanol, 2-O-isopropylidene-α-D-furyl xylose.
Embodiment 9～16 preparations 1,2-O-isopropylidene-α-D-furyl xylose
Reactions step is with reference to embodiment 8,1,2,3, and 5-diisopropylidene-α-D-furyl xylose is 10g (0.042mol), and other reaction parameters are seen table 2.
Table 2 embodiment 9～16 reaction parameters
| Embodiment | Acid | Acid/solvent volume compares % | Solvent | Temperature of reaction/℃ |
| 9 | Hydrochloric acid | 1.0 | Methyl alcohol | 20-25 |
| 10 | Hydrochloric acid | 2.5 | Ethanol | 10-20 |
| 11 | Hydrochloric acid | 5.0 | Methyl alcohol | 25-30 |
| 12 | Hydrochloric acid | 0.5 | THF | 20-25 |
| 13 | Hydrochloric acid | 0.1 | Methyl alcohol | 30-40 |
| 14 | Hydrochloric acid | 10 | THF | 20-25 |
| 15 | Hydrochloric acid | 20 | Ethanol | 30-35 |
| 16 | Sulfuric acid | 15 | 1, the 4-dioxane | 20-25 |
Embodiment 17 preparation 5-O-ethanoyl-1,2-O-isopropylidene-α-D-furyl xylose
Embodiment 8 is obtained 1, and (30g 0.158mol) is dissolved in 200mL CH to 2-O-isopropylidene-α-D-furyl xylose
2Cl
2In, abundant stirring adds 25mL triethylamine (0.18mol) down, and adding Acetyl Chloride 98Min. under the frozen water cooling (10.86g, 0.174mol), Acetyl Chloride 98Min./1, the mol ratio of 2-O-isopropylidene-α-D-furyl xylose is 1: 1.1.0-5 ℃ of following stirring reaction, it is complete that TLC follows the tracks of raw material reaction, after the back adding 150mL frozen water that reacts completely fully stirs; Standing demix obtains organic layer; (3 * 50mL) extract water layer, and the organic layer after the merging is used anhydrous sodium sulfate drying, filtration, concentrating under reduced pressure, methylene dichloride recrystallization with ETHYLE ACETATE; Obtain target compound 31g, yield is 85%.
Embodiment 18-29 prepares 5-O-ethanoyl-1,2-O-isopropylidene-α-D-furyl xylose
Reactions step is with reference to embodiment 17,1, and 2-O-isopropylidene-α-D-furyl xylose is 30g (0.158mol), and other reaction parameters are seen table 3.
Table 3 embodiment 18～29 reaction parameters
| Embodiment | The mol ratio of alkali/acetylation reagent | Alkali | Solvent | Acetylation reagent | The mol ratio of acetylation reagent/compound V | Temperature of reaction/℃ |
| 18 | 1∶1.02 | Salt of wormwood | Glycol dimethyl ether | Acetyl Chloride 98Min. | 1∶1.0 | -5～0 |
| 19 | 1∶1.05 | Pyridine | N | Diacetyl oxide | 1∶1.5 | -10～-5 |
| 20 | 1∶1.1 | Diisopropyl ethyl amine | Dioxan | Acetyl Chloride 98Min. | 1∶1.2 | -20～-10 |
| 21 | 1∶1.05 | Sodium methylate | Benzene | Acetyl Chloride 98Min. | 1∶1.2 | -10～-5 |
| 22 | 1∶1.0 | Sodium amide | Toluene | Diacetyl oxide | 1∶1.2 | -5～0 |
| 23 | 1∶1.0 | Yellow soda ash | THF | Diacetyl oxide | 1∶1.2 | -20～-10 |
| 24 | 1∶1.05 | Sodium hydride | N,N-DIMETHYLACETAMIDE | Acetyl Chloride 98Min. | 1∶1.2 | -5～0 |
| 25 | 1∶1.2 | Sodium ethylate | Acetone | Acetyl Chloride 98Min. | 1∶1.2 | -5～0 |
| 26 | 1∶1.15 | Potassium tert.-butoxide | Ether | Acetyl Chloride 98Min. | 1∶1.2 | -5～0 |
| 27 | 1∶1.05 | Quinoline | YLENE | Acetyl Chloride 98Min. | 1∶1.2 | -5～0 |
| 28 | 1∶1.0 | \ | Trichloromethane | Acetyl Chloride 98Min. | 1∶1.2 | -5～0 |
| 29 | 1∶1.1 | \ | Ethylene dichloride | Acetyl Chloride 98Min. | 1∶1.2 | -5～0 |
Embodiment 30 preparation 5-O-ethanoyl-3 alpha-iodines-1,2-O-isopropylidene-α-D-furyl xylose
With embodiment 17 prepared 5-O-ethanoyl-1,2-O-isopropylidene-α-D-furyl xylose (30g, 0.129mol) be dissolved in 200mL toluene, 26.3g imidazoles, triphenyl phosphorus (101g, 0.387mol) in, after stirring, add I
2(36.1g 0.14mol), slowly is heated to 100-110 ℃ after fully stirring, and follows the tracks of reacting completely up to TLC, after reacting completely, behind the reaction solution cool to room temperature, adds the saturated Na of 200mL
2CO
3Solution fully stirs static layering, the organic layer concentrating under reduced pressure; Filter, add peroxosulphuric hydrogen potassium (0.31mmol) and 200mL methylene dichloride in the resulting filtrating, fully stir back (5h) after-filtration; Filtrate decompression concentrates, and drying obtains target compound 26.5g, and yield is 60%.
Embodiment 31-39 prepares 5-O-ethanoyl-3 alpha-iodine-1,2-O-isopropylidene-α-D-furyl xylose
Reactions step is with reference to embodiment 30,5-O-ethanoyl-1, and 2-O-isopropylidene-α-D-furyl xylose is 30g (0.129mol), and other reaction parameters are seen table 4.
Table 4 embodiment 31～39 reaction parameters
| Embodiment | The mol ratio of nucleophilic reagent/compound III | Nucleophilic reagent | Solvent | The mol ratio of iodo agents/compounds III | Iodo reagent | Temperature of reaction/℃ | The mol ratio of alkali/compound III | Alkali |
| 31 | 1.3 | Triphenyl phosphorus | Ethylbenzene | 1.1 | I 2 | 100-120 | 1.5 | Quinoline |
| 32 | 2.5 | Tributyl phosphorus | Benzene | 1.5 | NaI | 80-90 | 3.0 | Triethylamine |
| 33 | 3.0 | Tri-tert phosphorus | Methyl-phenoxide | 2.0 | I 2 | 120-130 | 3.0 | Piperidines |
| 34 | 1.5 | Three p-methylphenyl phosphorus | YLENE | 8.0 | I 2 | 100-110 | 2.0 | Sodium hydrogencarbonate |
| 35 | 2.0 | Trimethylammonium phosphorus | Chlorobenzene | 2.0 | I 2 | 100-110 | 2.5 | Diisopropyl ethyl amine |
| 36 | 3.0 | Three o-methyl-phenyl-phosphorus | Propyl benzene | 10.0 | NaI | 80-90 | 3.0 | Salt of wormwood |
| 37 | 1.5 | Triethyl phosphine | Toluene | 5.0 | I 2 | 90-100 | 2.5 | Sodium hydroxide |
| 38 | 3.0 | Triphenyl phosphorus | 1, the 4-dioxane | 1.5 | I 2 | 90-100 | 3.0 | Pyridine |
| 39 | 2.5 | Triphenyl phosphorus | Ethylbenzene | 1.2 | I 2 | 100-120 | 3.0 | Imidazoles |
Embodiment 40 preparation 5-O-ethanoyl-3 alpha-iodines-1,2-O-isopropylidene-α-D-furyl xylose
Sulfonation reaction: with embodiment 17 prepared 5-O-ethanoyl-1, (30g 0.129mol) is dissolved in 200mL CH to 2-O-isopropylidene-α-D-furyl xylose
2Cl
2In, under the abundant stirring, adding 25mL triethylamine, adding Tosyl chloride under the frozen water cooling (25.82g, 0.135mol), 0-5 ℃ of stirring reaction, TLC tracking raw material reaction is complete, and filtration, concentrating under reduced pressure directly are used for next step reaction.
Iodide reaction: the resulting material of above-mentioned sulfonylation is dissolved in 250mL toluene, 11.5mL pyridine, after stirring, adds I
2(36.1g 0.14mol), slowly is heated to 100-110 ℃ after fully stirring, and follows the tracks of reacting completely up to TLC, after reacting completely, behind the reaction solution cool to room temperature, adds the saturated Na of 200mL
2CO
3Solution fully stirs static layering, and the organic layer concentrating under reduced pressure filters, and filtrate decompression concentrates, and drying obtains 35.0g 5-O-ethanoyl-1, and 2-O-isopropylidene-α-D-furyl xylose, yield are 80%
Embodiment 41～49 preparation 5-O-ethanoyl-3 alpha-iodines-1,2-O-isopropylidene-α-D-furyl xylose
Sulfonation reaction: step is with reference to embodiment 40,5-O-ethanoyl-1, and 2-O-isopropylidene-α-D-furyl xylose is 30g (0.129mol), and other concrete reaction parameters are seen table 5.
Table 5 embodiment 41～49 sulfonation reaction parameters
| Embodiment | Alkali (mL) | Solvent | Sulfonylation agent consumption (mol) | Sulfonylation agent | Temperature of reaction/℃ |
| 41 | Sodium hydroxide | Methylene dichloride | 0.129 | The positive fourth SULPHURYL CHLORIDE of perfluor | -5～0 |
| 42 | Pyridine | Trimethylphenylmethane | 0.130 | Methylsulfonyl chloride | -10～-5 |
| 43 | Diisopropyl ethyl amine | Methylene dichloride | 0.140 | Benzene sulfonyl chloride | -20～-10 |
| 44 | Yellow soda ash | THF | 0.130 | The tolylsulfonyl acid anhydride | -10～-5 |
| 45 | Imidazoles | Isopropyl benzene | 0.145 | The trifluoro SULPHURYL CHLORIDE | -5～0 |
| 46 | Piperidines | Bromobenzene | 0.150 | Trifluoro sulphonyl acid anhydride | -20～10 |
| 47 | Salt of wormwood | THF | 0.130 | The methylsulfonyl acid anhydride | -10～-5 |
| 48 | Sodium hydrogencarbonate | Toluene | 0.135 | The benzene sulfonyl acid anhydride | -5～0 |
| 49 | Quinoline | YLENE | 0.140 | The positive fourth sulphonyl of perfluor acid anhydride | 20～60 |
Iodide reaction: the compound with sulfonation reaction makes, with reference to the step of embodiment 40, carry out iodide reaction by the concrete reaction parameter of table 6.
Table 6 embodiment 41～49 iodide reaction parameters
| Embodiment | Solvent | The mol ratio of iodo agents/compounds IV | Iodo reagent | Temperature of reaction/℃ | The mol ratio of alkali/compound IV | Alkali |
| 41 | Ethylbenzene | 1.2 | I 2 | 100-120 | 1.0 | Quinoline |
| 42 | Benzene | 1.5 | NaI | 80-90 | 1.1 | Triethylamine |
| 43 | Chlorobenzene | 2.0 | I 2 | 100-110 | 1.05 | Diisopropyl ethyl amine |
| 44 | Propyl benzene | 10 | NaI | 80-90 | 1.02 | Imidazoles |
| 45 | Toluene | 5.0 | I 2 | 90-100 | 1.0 | Sodium hydroxide |
| 46 | 1, the 4-dioxane | 1.5 | I 2 | 90-100 | 1.5 | Pyridine |
| 47 | Ethylbenzene | 1.2 | I 2 | 100-120 | 1.3 | \ |
| 48 | Toluene | 2.5 | NaI | 100-110 | 1.2 | Imidazoles |
| 49 | 1, the 4-dioxane | 3.0 | I 2 | 90-95 | 1.2 | Triethylamine |
Embodiment 50 preparation 5-O-ethanoyl-3-deoxidations-1,2-isopropylidene-α-D-furyl xylose
With 5-O-ethanoyl-3 alpha-iodine-1 that embodiment 30 makes, (30g 0.088mol) joins 50% ortho phosphorous acid (30g), 200mL triethylamine, 200mL 1 to 2-O-isopropylidene-α-D-furyl xylose; In the 4-dioxane, slowly be heated to 80-85 ℃ after fully stirring, slowly add (0.73g; 4.4mmol) Diisopropyl azodicarboxylate (AIBN) is in reaction solution, the post-heating that stirs is to 80-90 ℃ of reaction, and it is complete to follow the tracks of raw material reaction up to HPLC; After reacting completely, reaction solution cool to room temperature (30-35 ℃) adds 200mL water in the reaction solution; (2 * 150mL) extract organic layer with ETHYLE ACETATE; Organic layer concentrating under reduced pressure after the merging, the dry target compound 17.08g that gets, yield is 90%.
HNMR(CDCI
3)：5.85(d，1H)，4.64(d，1H)，4.50(m，1H)，4.25(m，1H)，1.78(m，1H)，2.08(s，1H)，1.56，1.36(2s，1H)。
Embodiment 51～58 preparation 5-O-ethanoyl-3-deoxidations-1,2-isopropylidene-α-D-furyl xylose
Reactions step is with reference to embodiment 50,5-O-ethanoyl-3 alpha-iodine-1, and 2-O-isopropylidene-α-D-furyl xylose (compound I I) is 30g (0.088mol), and other reaction parameters are seen table 7.
Table 7 embodiment 51～58 reduction reaction parameters
| Embodiment | Solvent | The weight ratio of reductive agent/compound I I | Reductive agent | Temperature of reaction/℃ | The mol ratio of radical initiator/compound I I (%) | Radical initiator | Yield |
| 51 | Benzene | 1.33 | 50％H 3PO 2 | 80-90 | 1.0 | Azo isobutyl cyanogen | 85％ |
| 52 | Toluene | 9 | 50％H 3PO 2 | 85-90 | 1.5 | Azo isobutyl cyanogen | 88％ |
| 53 | YLENE | 2.5 | 50％H 3PO 2 | 90-100 | 5.0 | Azo isobutyl cyanogen | 88％ |
| 54 | 1, the 4-dioxane | 10 | 50％H 3PO 2 | 20-40 | 2.5 | Azo isobutyl cyanogen | 90％ |
| 55 | Trimethylphenylmethane | 5.0 | Bu 3SnH | 80-100 | 1.5 | Benzoyl Peroxide | 82％ |
| 56 | Bromobenzene | 50 | Bu 3SnH | 45-55 | 3.0 | Benzoyl Peroxide | 75％ |
| 57 | Chlorobenzene | 2.0 | Bu 3SnH | 70-80 | 3.5 | Benzoyl Peroxide | 85％ |
| 58 | Methyl-phenoxide | 1.5 | 50％H 3PO 2 | 90-100 | 4.0 | Azo isobutyl cyanogen | 78％ |
Embodiment 59 preparation 5-O-ethanoyl-3-deoxidations-1,2-isopropylidene-α-D-furyl xylose
With 5-O-ethanoyl-3 alpha-iodine-1 that embodiment 30 makes, 2-O-isopropylidene-α-D-furyl xylose (30g, 0.088mol) and Pd-C (0.75g) join in the 150mL methyl alcohol; In absolute pressure is in 20-30 ℃ of reaction under the 0.1Mpa; Complete up to raw material reaction, after reacting completely, filtration, filtrate decompression concentrate; The dry target compound 17.0g that gets, yield is 90%.
Embodiment 60～67 preparation 5-O-ethanoyl-3-deoxidations-1,2-isopropylidene-α-D-furyl xylose
Reactions step is with reference to embodiment 57,5-O-ethanoyl-3 alpha-iodine-1, and 2-O-isopropylidene-α-D-furyl xylose (compound I I) is 30g (0.088mol), and other reaction parameters are seen table 8.
Table 8 embodiment 60～67 reduction reaction parameters
| Embodiment | Solvent | The weight ratio of catalyzer/compound I I (%) | Temperature of reaction/℃ | Reaction pressure (Mpa) | Yield |
| 60 | Methyl alcohol | 1.0 | 30-35 | 20 | 88％ |
| 61 | Virahol | 2.0 | 20-25 | 7.5 | 84％ |
| 62 | Ethanol | 2.5 | 25-30 | 10 | 83％ |
| 63 | Methyl alcohol | 3.5 | 20-25 | 5.0 | 90％ |
| 64 | Virahol | 5.0 | 25-30 | 1.5 | 86％ |
| 65 | Ethanol | 3.0 | 30-35 | 3.5 | 92％ |
| 66 | Methyl alcohol | 4.0 | 40-45 | 5.0 | 94％ |
| 67 | Virahol | 2.5 | 40-45 | 15 | 90％ |
Embodiment 68 preparation 5-O-ethanoyl-3-deoxidations-1,2-isopropylidene-α-D-furyl xylose
5-O-ethanoyl-3 alpha-iodine-1 that embodiment 30 is made; (30g 0.088mol) joins in the 200mL THF 2-O-isopropylidene-α-D-furyl xylose, is cooled to-30--20 ℃ adding n-Butyl Lithium (0.75g; Mmol) reaction; It is complete to follow the tracks of raw material reaction up to HPLC, after reacting completely, adds saturated NH
4Cl solution after abundant the stirring, adds dichloromethane solution and extracts, drying, and filtrate decompression concentrates, the dry target compound 17.10g that gets, yield is 90%.
Embodiment 69～73 preparation 5-O-ethanoyl-3-deoxidations-1,2-isopropylidene-α-D-furyl xylose
Reactions step is with reference to embodiment 66,5-O-ethanoyl-3 alpha-iodine-1, and 2-O-isopropylidene-α-D-furyl xylose (compound I I) is 30g (0.088mol), and other reaction parameters are seen table 9.
Table 9 embodiment 69～73 reduction reaction parameters
| Embodiment | Solvent | The mol ratio of n-Butyl Lithium/compound I I | Temperature of reaction/℃ | Yield |
| 69 | Ether | 1.0 | -30--25℃ | 88％ |
| 70 | THF | 1.05 | -35--30℃ | 90％ |
| 71 | Normal hexane | 1.2 | -40--35℃ | 83％ |
| 72 | Ether | 1.1 | -20--30℃ | 90％ |
| 73 | Ether | 1.05 | -25--20℃ | 86％ |
Claims (46)
1. one kind prepares 5-O-ethanoyl-3-deoxidation-1, the method for 2-isopropylidene-α-D-furyl xylose I, and concrete steps are:
(1) compound III makes compound I I through iodide reaction;
(2) make 5-O-ethanoyl-3-deoxidation-1 through taking off Iod R, 2-isopropylidene-α-D-furyl xylose I with reductive agent again;
Wherein, Ac is an ethanoyl.
2. the method for claim 1; It is characterized in that: described step (1) is: in solvent; Compound III and iodination reagent make compound I I through iodide reaction under the effect of nucleophilic reagent, wherein said nucleophilic reagent is selected from one or more in following: triphenyl phosphorus, tributyl phosphorus, tri-tert phosphorus, three p-methylphenyl phosphorus, three o-methyl-phenyl-phosphorus, trimethylammonium phosphorus or triethyl phosphine.
3. the method for claim 1, it is characterized in that: described step (1) is: in solvent, compound III and sulfonated reagent make compound IV through sulfonylation under the alkaline reagents effect, obtain compound I I with iodination reagent through iodide reaction again,
Wherein, Ac is an ethanoyl; R is the positive fourth alkylsulfonyl of p-toluenesulfonyl, methylsulfonyl, benzenesulfonyl, three fluorosulfonyls or perfluor, and described sulfonated reagent is toluene sulfonyl chloride, tolylsulfonyl acid anhydride, methylsulfonyl chloride, methylsulfonyl acid anhydride, benzene sulfonyl chloride, benzene sulfonyl acid anhydride, trifluoro SULPHURYL CHLORIDE, trifluoro sulphonyl acid anhydride, the positive fourth SULPHURYL CHLORIDE of perfluor or the positive fourth sulphonyl of perfluor acid anhydride.
4. like the method for claim 2 or 3, it is characterized in that: described iodination reagent is I
2Or NaI.
5. method as claimed in claim 4 is characterized in that: the amount of described iodination reagent and the mol ratio of compound III are 1: 1.1～1: 10.0.
6. method as claimed in claim 5 is characterized in that: described mol ratio is 1: 1.1～1: 2.0.
7. like claim 2 or 3 described methods; It is characterized in that: described iodide reaction carries out under the alkaline reagents effect, and described alkaline reagents is one or more in salt of wormwood, yellow soda ash, sodium hydrogencarbonate, sodium hydroxide, piperidines, imidazoles, pyridine, quinoline, triethylamine and the diisopropyl ethyl amine.
8. like claim 2 or 3 described methods, it is characterized in that: described solvent is an inert solvent.
9. method as claimed in claim 8 is characterized in that: described inert solvent is selected from one or more in following: benzene, toluene, ethylbenzene, propyl benzene, isopropyl benzene, trimethylphenylmethane, YLENE, chlorobenzene, bromobenzene, methyl-phenoxide or 1,4-dioxane.
10. like claim 2 or 3 described methods, it is characterized in that: described iodination reaction temperature is between 80～130 ℃.
11. method as claimed in claim 10 is characterized in that: described iodination reaction temperature is between 90～120 ℃.
12. method as claimed in claim 3 is characterized in that: described sulfonylation temperature is between-20 ℃～60 ℃.
13. the method for claim 1 is characterized in that: the described reductive agent of step (2) is H
3PO
2Or Bu
3SnH.
14. the method for claim 1 is characterized in that: the described reductive agent consumption of step (2) is 1.0～50.0 times of compound I I weight.
15. method as claimed in claim 14 is characterized in that: the consumption of described reductive agent is 1.0～10 times of compound I I weight.
16. method as claimed in claim 15 is characterized in that: the consumption of described reductive agent is 1.0～2.5 times of compound I I weight.
17. the method for claim 1 is characterized in that: the described Iod R temperature of taking off of step (2) is between 20～100 ℃.
18. method as claimed in claim 17 is characterized in that: described temperature of reaction is between 80～100 ℃.
19. the method for claim 1 is characterized in that: the described Iod R that takes off of step (2) is undertaken by the radical initiator initiation in solvent, and wherein said radical initiator is azo isobutyronitrile or Benzoyl Peroxide.
20. method as claimed in claim 19 is characterized in that: described solvent is selected from one or more in following: benzene, toluene, ethylbenzene, propyl benzene, isopropyl benzene, trimethylphenylmethane, YLENE, chlorobenzene, bromobenzene, methyl-phenoxide and 1,4-dioxane.
21. the method for claim 1 is characterized in that: the described Iod R that takes off of step (2) carries out under hydrogenation conditions.
22. method as claimed in claim 21 is characterized in that: described hydrogenation conditions H
2-Pd or H
2-Ni condition.
23. method as claimed in claim 22 is characterized in that: described catalyst consumption is 1～5% of a compound I I weight.
24. method as claimed in claim 21 is characterized in that: the absolute pressure of described hydrogenation conditions is 0.1～20Mpa.
25. method as claimed in claim 24 is characterized in that: the absolute pressure of described hydrogenation conditions is 1-10Mpa.
26. the method for claim 1 is characterized in that: the described Iod R that takes off of step (2) carries out under the condition of adding n-Butyl Lithium in solvent.
27. method as claimed in claim 26 is characterized in that: the mole dosage of described n-Butyl Lithium is 1.0～1.2 times of compound I I.
28. the method for claim 1, wherein compound (III) obtains through following steps:
(1) compound VI I is at H
2SO
4Change compound VI under/acetone the system, adopt alkaline substance solution conditioned reaction liquid pH value between the 7-8;
(2) in the solvent, under sour condition, obtain compound V;
(3) in the solvent, make compound III with the acylating reagent reaction again.
29. method as claimed in claim 28 is characterized in that: the mole number of the described acetone of step (1) is 20～100 times of compound VI I mole number.
30. method as claimed in claim 29 is characterized in that: the mole number of described acetone is 20-60 a times of compound VI I mole number.
31. method as claimed in claim 30 is characterized in that: the described H of step (1)
2SO
4Volume is the 1-4% of acetone volume.
32. method as claimed in claim 31 is characterized in that: the temperature of reaction of described step (1) is 15-35 ℃.
33. method as claimed in claim 32 is characterized in that: described temperature of reaction is 15-25 ℃.
34. method as claimed in claim 33 is characterized in that: the described alkaline matter of step (1) is selected from Pottasium Hydroxide, sodium hydroxide, salt of wormwood, yellow soda ash, sodium hydrogencarbonate or saleratus.
35. method as claimed in claim 28 is characterized in that: described step (1) is at H
2SO
4/ CuSO
4Carry out under/acetone the system.
36. method as claimed in claim 28 is characterized in that: the described acid of step (2) is hydrochloric acid or sulfuric acid.
37. method as claimed in claim 36 is characterized in that: the 0.1-20% that the described sour volume of step (2) is a solvent volume.
38. method as claimed in claim 37 is characterized in that: the volume of described acid is the 0.5-5% of solvent volume.
39. method as claimed in claim 28 is characterized in that: the described solvent of step (2) is methyl alcohol, ethanol, THF or 1, the 4-dioxane.
40. method as claimed in claim 28 is characterized in that: the temperature of the reaction of described step (2) is 10-35 ℃.
41. method as claimed in claim 28 is characterized in that: the described acylating reagent of step (3) is Acetyl Chloride 98Min. or diacetyl oxide.
42. method as claimed in claim 41 is characterized in that: the consumption of the described acylating reagent of step (3) and the mol ratio of compound V 1: 1.0～1: 1.5.
43. method as claimed in claim 42 is characterized in that: the mol ratio of the consumption of described acylating reagent and compound V is 1: 1.0～1: 1.2.
44. method as claimed in claim 28 is characterized in that: in described step (3), add alkaline reagents, described alkaline reagents is inorganic base, basic metal alcohols or organic bases compounds; Described inorganic base is yellow soda ash, salt of wormwood, sodium amide or sodium hydride; Described basic metal alcohols is sodium methylate, sodium ethylate or potassium tert.-butoxide; Described organic bases is triethylamine, pyridine, quinoline or diisopropyl ethyl amine.
45. method as claimed in claim 28 is characterized in that: the described solvent of step (3) is an inert solvent, and described inert solvent is ether, arene, halohydrocarbon, N, N,N-DIMETHYLACETAMIDE or acetone; Described ether is THF, ether, glycol dimethyl ether or dioxan; Described arene is benzene, toluene or YLENE; Described halohydrocarbon is methylene dichloride, trichloromethane or ethylene dichloride.
46. reaction intermediate 5-O-ethanoyl-3 alpha-iodine-1 shown in compound I I in the reaction stream formula in the claim 1,2-O-isopropylidene-α-D-furyl xylose,
Wherein, Ac is an ethanoyl.
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Non-Patent Citations (3)
| Title |
|---|
| Silvano De Bernardo，et al.Clavalanine (Ro 22-5417), a New Clavam Antibiotic from Streptomyces clavuligerus . 4. A Stereorational Synthesis.《Journal of Organic Chemistry》.1985,第50卷(第19期),3457-3462. |
| Silvano De Bernardo,et al.Clavalanine (Ro 22-5417), a New Clavam Antibiotic from Streptomyces clavuligerus . 4. A Stereorational Synthesis.《Journal of Organic Chemistry》.1985,第50卷(第19期),3457-3462. * |
| 王晓晨.STN检索.《STN》.2010, * |
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