CN106967113A - Platelet activating factor derivative and its synthetic method - Google Patents
Platelet activating factor derivative and its synthetic method Download PDFInfo
- Publication number
- CN106967113A CN106967113A CN201710218907.9A CN201710218907A CN106967113A CN 106967113 A CN106967113 A CN 106967113A CN 201710218907 A CN201710218907 A CN 201710218907A CN 106967113 A CN106967113 A CN 106967113A
- Authority
- CN
- China
- Prior art keywords
- compound
- platelet activating
- activating factor
- acid
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical class CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 title claims abstract description 26
- 238000010189 synthetic method Methods 0.000 title claims description 12
- 125000002252 acyl group Chemical group 0.000 claims abstract description 16
- 125000001424 substituent group Chemical group 0.000 claims abstract description 11
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 52
- 238000006243 chemical reaction Methods 0.000 claims description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 239000003153 chemical reaction reagent Substances 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 17
- -1 cetyl sulphonic acid ester Chemical class 0.000 claims description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 10
- 229940125782 compound 2 Drugs 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 5
- 229940125904 compound 1 Drugs 0.000 claims description 5
- 229940125898 compound 5 Drugs 0.000 claims description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DCAYPVUWAIABOU-NJFSPNSNSA-N hexadecane Chemical class CCCCCCCCCCCCCCC[14CH3] DCAYPVUWAIABOU-NJFSPNSNSA-N 0.000 claims description 4
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 229910015900 BF3 Inorganic materials 0.000 claims description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 3
- 150000008065 acid anhydrides Chemical group 0.000 claims description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- HNTGIJLWHDPAFN-UHFFFAOYSA-N 1-bromohexadecane Chemical class CCCCCCCCCCCCCCCCBr HNTGIJLWHDPAFN-UHFFFAOYSA-N 0.000 claims description 2
- KMWHQYDMBYABKL-UHFFFAOYSA-N 1-iodohexadecane Chemical class CCCCCCCCCCCCCCCCI KMWHQYDMBYABKL-UHFFFAOYSA-N 0.000 claims description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 2
- SFYVDGRMYKXCOD-UHFFFAOYSA-N C1=CC=CC=C1.ClC1=C(C=C(C=C1)[N+](=O)[O-])[N+](=O)[O-] Chemical compound C1=CC=CC=C1.ClC1=C(C=C(C=C1)[N+](=O)[O-])[N+](=O)[O-] SFYVDGRMYKXCOD-UHFFFAOYSA-N 0.000 claims description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 2
- SSVFMICWXDVRQN-UHFFFAOYSA-N ethanol;sodium Chemical compound [Na].CCO SSVFMICWXDVRQN-UHFFFAOYSA-N 0.000 claims description 2
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940071536 silver acetate Drugs 0.000 claims description 2
- KZJPVUDYAMEDRM-UHFFFAOYSA-M silver;2,2,2-trifluoroacetate Chemical compound [Ag+].[O-]C(=O)C(F)(F)F KZJPVUDYAMEDRM-UHFFFAOYSA-M 0.000 claims description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 2
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical group C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical class ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 claims 1
- WPHUUIODWRNJLO-UHFFFAOYSA-N 2-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1S(Cl)(=O)=O WPHUUIODWRNJLO-UHFFFAOYSA-N 0.000 claims 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims 1
- 150000001263 acyl chlorides Chemical class 0.000 claims 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims 1
- 229910017604 nitric acid Inorganic materials 0.000 claims 1
- JLKDVMWYMMLWTI-UHFFFAOYSA-M potassium iodate Chemical group [K+].[O-]I(=O)=O JLKDVMWYMMLWTI-UHFFFAOYSA-M 0.000 claims 1
- 229910052709 silver Inorganic materials 0.000 claims 1
- 239000004332 silver Substances 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 18
- 238000003786 synthesis reaction Methods 0.000 abstract description 16
- 230000000694 effects Effects 0.000 abstract description 8
- 238000011160 research Methods 0.000 abstract description 4
- 230000003213 activating effect Effects 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 239000000376 reactant Substances 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- RNVYQYLELCKWAN-UHFFFAOYSA-N solketal Chemical compound CC1(C)OCC(CO)O1 RNVYQYLELCKWAN-UHFFFAOYSA-N 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- DCAYPVUWAIABOU-UHFFFAOYSA-N hexadecane Chemical compound CCCCCCCCCCCCCCCC DCAYPVUWAIABOU-UHFFFAOYSA-N 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 229930195733 hydrocarbon Natural products 0.000 description 7
- 150000002430 hydrocarbons Chemical class 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 108010003541 Platelet Activating Factor Proteins 0.000 description 5
- 210000001772 blood platelet Anatomy 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000001294 propane Substances 0.000 description 5
- 235000002639 sodium chloride Nutrition 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 2
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 2
- 238000007445 Chromatographic isolation Methods 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 108700023400 Platelet-activating factor receptors Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- NZHXEWZGTQSYJM-UHFFFAOYSA-N [bromo(diphenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Br)C1=CC=CC=C1 NZHXEWZGTQSYJM-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 230000003727 cerebral blood flow Effects 0.000 description 2
- 238000011097 chromatography purification Methods 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 102000030769 platelet activating factor receptor Human genes 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- ZXCIEWBDUAPBJF-MUUNZHRXSA-N 2-O-acetyl-1-O-octadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C ZXCIEWBDUAPBJF-MUUNZHRXSA-N 0.000 description 1
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 1
- 101800000734 Angiotensin-1 Proteins 0.000 description 1
- 102400000344 Angiotensin-1 Human genes 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical class ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- RNVYQYLELCKWAN-RXMQYKEDSA-N [(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol Chemical compound CC1(C)OC[C@@H](CO)O1 RNVYQYLELCKWAN-RXMQYKEDSA-N 0.000 description 1
- RNVYQYLELCKWAN-YFKPBYRVSA-N [(4s)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol Chemical compound CC1(C)OC[C@H](CO)O1 RNVYQYLELCKWAN-YFKPBYRVSA-N 0.000 description 1
- DHNSDOWVMJCDBI-UHFFFAOYSA-N [Li].C(C)(=S)O Chemical compound [Li].C(C)(=S)O DHNSDOWVMJCDBI-UHFFFAOYSA-N 0.000 description 1
- WRLRISOTNFYPMU-UHFFFAOYSA-N [S].CC1=CC=CC=C1 Chemical compound [S].CC1=CC=CC=C1 WRLRISOTNFYPMU-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 231100000439 acute liver injury Toxicity 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 150000001334 alicyclic compounds Chemical class 0.000 description 1
- 150000007824 aliphatic compounds Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- OKMQKGODLHNLGC-UHFFFAOYSA-N benzene;methanethiol Chemical compound SC.C1=CC=CC=C1 OKMQKGODLHNLGC-UHFFFAOYSA-N 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- SDJHDRMYZQFJJO-UHFFFAOYSA-N ethanethioic s-acid;potassium Chemical group [K].CC(S)=O SDJHDRMYZQFJJO-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000004429 kidney medulla cell Anatomy 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 108010021666 lipase II Proteins 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- HFNWWJNJKHHGPW-UHFFFAOYSA-N n,n-diethylethanamine;ethanethioic s-acid Chemical compound CC([O-])=S.CC[NH+](CC)CC HFNWWJNJKHHGPW-UHFFFAOYSA-N 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 125000002525 phosphocholine group Chemical class OP(=O)(OCC[N+](C)(C)C)O* 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000012207 quantitative assay Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- GNBVPFITFYNRCN-UHFFFAOYSA-M sodium thioglycolate Chemical compound [Na+].[O-]C(=O)CS GNBVPFITFYNRCN-UHFFFAOYSA-M 0.000 description 1
- 229940046307 sodium thioglycolate Drugs 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/10—Phosphatides, e.g. lecithin
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to chemosynthesis technical field, the platelet activating factor derivative with formula (I) structure is disclosed, substituent R represents acyl group.Its synthetic route is reacted using the solketal of chiral source S configurations as initial reactant by 9 steps, and the present invention synthesizes 2 thio platelet activating factors and its derivative using this method first, has the advantages that yield is high, easily separated.The present invention realizes the low-cost, high-volume synthesis of 2 S PAF and its derivative, significant to the activity research of 2 S PAF and its derivative, Bioexperiment, clinical practice and disease treatment.
Description
Technical field
The invention belongs to chemosynthesis technical field, it is related to a class platelet activating factor derivative, and in particular to 2- sulphur
The preparation method of fat subsitutes chain carboxylic acid platelet activating factor and its derivative.
Background technology
The structure of platelet activating factor (Platelet Activity Factor, PAF) is ehter bond phosphatide -1-O- alkane
Base -2- acetyl group-sn- glycerine -3- phosphatidyl cholines, as shown in Figure 1.PAF molecular weight 1100, its structure has the solid of height
Specificity, and it is closely related with its biological effect, internal various kinds of cell can be synthesized.At present mostly scholar it is believed that in
Property granulocyte, basophilic granulocyte, eosinophil, blood platelet, vascular endothelial cell, kidney medulla cell, epithelial cell exist
Equal energy in the presence of activator (fibrin ferment, slow sharp skin, histamine, TNF, leukotriene, ATP and angiotensin I etc.)
Produce PAF.PAF can act on Various Tissues and cell as a kind of cell factor of specific type, participate in reproduction, asthma, mistake
A variety of physiology such as quick, inflammation, tumour, shock and pathologic effect, play the biological activity for being similar to hormone in vivo.
Platelet activating factor found in 1972 by Bemreniste etc., was most strongly active lipid a kind of so far
Medium.Research initial stage, PAF be considered as with it is hematoblastic aggregation and secrete relevant, its induce platelet aggregation disobey
Rely the metabolite TXA in adenosine diphosphate (ADP) or arachidonic acid (AA)2, it is considered to be the of induced platelet aggregation
Three approach.But further investigations have shown that, acceptor special PAF is coupled with G-protein has an effect, paf receptor also with cell
Interior signal transduction path is relevant, plays diversified biological function.At present, PAF is in acute liver injury, liver fibrosis and liver
Effect in the mechanism of causing a disease of hardening is increasingly taken seriously, and is risen in the inflammatory cytokine of numerous participation liver diseases morbidities
" center amplification " effect, and passes through the infringement of all too many levels exacerbation liver.In addition, PAF can be dropped by promoting thrombosis
Low cerebral blood flow (CBF), increases brain oxygen demand, aggravates encephaledema, influences nerve cell function and participates in cerebrovascular disease and developed
Journey.
Chemical entitled 1- oxygen-alkyl -2- ethanethioyls-sn- of the thio platelet activating factors of 2- (2-S-PAF) is sweet
Oil -3- phosphocholines, are platelet activating factor PAF derivatives, as shown in Figure 1.2-S-PAF can be used as paf receptor excitement
Agent, the guinea-pig macrophage that it is acted on PAF C-18 rabbits platelet aggregations and PAF C-16 are activated is suitable.2-S-PAF is molten
Serium inorganic phosphorus lipase II and PAF-AH substrate, while it also serves as the substrate of PAF-AH detection kits.In recent years, U.S. Cayman
Chemical companies and Azwell companies of Japan, which have released one after another, detects blood plasma type PAF-AH kit, due to its operation letter
It is single and non-toxic, traditional isotope quantitative assay has progressively been instead of.
Synthesis of the 2-S-PAF to PAF plays the role of important, and 2-S-PAF is the class compound using glycerine as parent,
Its 1 is alkyl ether, and 2 are ethanethioyls, and 3 are phosphocholines.The chemical constitution of this kind of compound is similar to phosphatidyl
Choline (lecithin), but have difference, i.e., C1 connections is saturated fatty acid, C2 companies in the glycerol molecule of lecithin
What is connect is unrighted acid, and in 2-S-PAF glycerol molecule C1 connection be ether chain fatty alcohol, C2 connect be sulphur
For acetyl group.
Masahiro Fuji et al. with 1,2-O- isopropylidene-sn- glycerine be raw material, and provide a chiral centre, warp
The deprotection of 1 alkylation and acetonylidene obtains glycol, and glycol is through the trityl as protecting group of 3,2 and 4-Nitrobenzenesulfonyl chloride
Generation configuration reversal, then through deprotection generation key intermediate PAF-7, finally obtain final product with phosphocholine reaction.But
In this building-up process, yield is low, and rearrangement reaction is more.Abul B.Kazi et al. think that rearrangement is that leaving group activity is inadequate, take
It is higher than 4-Nitrobenzenesulfonyl chloride activity to occur configuration reversal to mesyl chloride, above-mentioned route is optimized, to overcome sulphur to oxygen
Migration problem.On the basis of PAF-5, it thinks it is crucial that occur the migration of trityl, 2 are protected, then
Reacted with phosphocholine, finally in the presence of catalyst, 2 substitutions obtain final product, still, phosphoryl chloride phosphorus oxychloride ring are opened in docking
When, yield is unstable, and poisonous gas hydrogen sulfide, and intermediate product easily oxidation deterioration have been used in simultaneously synthesizing route.
Masakazu Murata et al. are using (S) -1-O- acetyl group -2-O- benzyl group glycerols as raw material, by lipase-catalyzed esterification, use
Make chiral source, and the formation and S → O acyl that select THP trtrahydropyranyl to protect primary hydroxyl to prevent epoxides are migrated, 2 with it is right
Configuration reversal occurs for nitrobenzene sulfonyl chloride, then is deprotected the unstable key intermediate of generation through PPTS weak acid and mild base salts, finally
Final product is obtained with phosphocholine reaction, but the synthetic route needs to protect deprotection, and comprehensive yield is low.
Although a little perspective exploration sex works have been done in existing research to 2-S-PAF, existing synthetic route is only applicable
In small-scale preparation, obtained 2-S-PAF amounts are few, and the simultaneously synthesizing route cycle is long, it is impossible to which high-volume is synthesized, and causes 2-S-PAF
It is difficult to commercialization, limits 2-S-PAF marketization application.Currently, 2-S-PAF market quotes is 3.5 ten thousand yuan/100mg, this
It is due to its complicated synthetic route, is difficult to what volume production was caused.Therefore, exploitation is a kind of can be with batch production volume production 2-S-PAF conjunction
Into route, the application for extending 2-S-PAF will have important practical significance, and with very big market potential.
The content of the invention
The present invention is directed to the existing synthetic route cycle length of 2-S-PAF, is difficult to the technological deficiency of high-volume synthesis, seeks one kind
Efficiently, low-cost, high-volume synthesis high-purity 2-S-PAF preparation method.Simple synthetic method of the present invention is easy to implement,
Synthetic route dilatancy is strong, while a variety of derivatives of 2- sulfofatty chain carboxylic acid's platelet activating factors can be obtained quickly.
Platelet activating factor derivative of the present invention, the chemical constitution with formula (I)：
In formula (I), substituent R represents acyl group.
Further, in the formula (I), substituent R represents aliphatic acyl radical.
As the further preferred of substituent R, the substituent R represents chain fatty race acyl group, R=CnH2n+1CO-, n are
Positive integer and the length for representing carbochain.
For the structure of full and accurate description formula (I) platelet activating factor derivative, the present invention is to the term in context
It is explained, but the explanation does not represent and the scope of the present invention is particularly limited to.
Term " acyl group " is interpreted as removing after hydroxyl in the oxygen-containing acid molecule of organic or inorganic, remaining monovalent radical
It is referred to as, or being interpreted as carboxylic acid sloughs the remainder after hydroxyl.Common acyl group chemical formula is R '-C=O-.Acyl group have compared with
Strong chemical reactivity, can be combined with halogen atom, alkoxy, amino or substituted-amino and acyloxy, respectively obtain carboxylic acid halides,
Ester, acid amides and acid anhydrides.Acetyl group is a kind of common acyl group, and chemical formula is CH3- C=O- is designated as Ac-, is one by methyl
The acyl function constituted with carbonyl.
Term " aliphatic acyl radical " is interpreted as acyl group R ' for aliphatic substitution.Aliphatic substitution is by aliphatic
The substituent of compound formation.Aliphatic compound is chain hydro carbons (open chain hydro carbons) and the cyclic hydrocarbon in addition to aromatic compound
The general name of class and its derivative.Wherein, aliphatic carbocyclic compound also known as alicyclic compound is belonged to.
Term " chain fatty race acyl group " is interpreted as acyl group R ' for chain fatty race substituent.Chain fatty compounds of group
It can be understood as the general name of chain hydro carbons (open chain hydro carbons) and its derivative.Chain fatty compounds of group includes the chain hydrocarbon of saturation
Class, such as alkane derivative, in addition to the chain hydro carbons containing unsaturated bond.Unsaturated bond described here has broad sense
Concept, such as can be carbon-carbon double bond, C=O bond, carbon-carbon triple bond etc..Substituent R=CnH2n+1CO-, n are positive integer and expression
The length of carbochain, illustrates that chain fatty race acyl group refers to the acyl group of the chain hydro carbons formation of saturation, than acetyl group described above, just
It is a kind of simple chain fatty race acyl group, its n=1.
On the other hand, the present invention gives the preparation method of the platelet activating factor derivative.Formula (I) compound
Route it is as shown in Figure 2.In order to describe conveniently, intermediate product of the invention is according to compound 1,2,3 ... is numbered.
In said synthesis route, step 1, using compound 1 (S)-solketal as reaction initial compounds, to dissolved with change
In the solvent of compound 1, hexadecane derivative is added, is reacted in the presence of base reagent, obtains compound 2.In this step,
The reaction dissolvent of compound 1 can be selected a variety of, it is preferable that can be dissolved in dimethylformamide.Hexadecane derivative is main
Refer to halo hexadecane, preferably 1- bromohexadecanes or 1- iodohexadecanes, or the mixture of the two；It can also select
Cetyl sulphonic acid ester.This step reaction carries out in the basic conditions, the base reagent that can be selected be NaH, KH, KOH, NaOH,
One kind or its mixed base in NaOt-Bu, preferably NaH.
In said synthesis route, step 2, the acidic hydrolysis of compound 2 obtains compound 3.Compound 2 it is chemical entitled
(R)-solketal hexadecane ether.Compound 2 carry out acidic hydrolysis needed for acid for hydrochloric acid, acetic acid, sulfuric acid, to toluene sulphur
Acid, one kind in camphorsulfonic acid or its mixed acid.Preferably, the acid needed for the progress of compound 2 acidic hydrolysis is from concentration
0.5M hydrochloric acid.
In said synthesis route, step 3, the terminal hydroxyl of selective protection compound 3 obtains compound 4.Compound
3 chemical entitled (R) -3- (hexadecane epoxide) propane -1,2- glycol.This step needs specific reaction reagent and catalyst.
The reaction dissolvent of step 3 be MeCN/ tetrahydrofurans (v/v=1/5), used catalyst be triethylamine, pyridine, 4- dimethylamino-
Pyridine, one kind in 2,6- lutidines or its mixture, used terminal hydroxyl protection reagent is triphenyl chloromethane
One kind or its mixture in alkane, triphenylbromomethane.
In said synthesis route, step 4, compound 4 is generated into leaving group in a solvent, thio examination is added into intermediate
Agent, obtains compound 5.Chemical entitled (S) -1- (the hexadecane epoxide) -3- trityloxy propane -2- alcohol of compound 4.This step
Rapid catalyst be triethylamine, solvent is dichloromethane, generation leaving group reagent for methane sulfonyl chloride, paratoluensulfonyl chloride,
4-Nitrobenzenesulfonyl chloride, ortho-nitrophenyl sulfonic acid chloride, one kind in 2,4- dinitrophenyl chloride benzene or its mixture；In described
The reaction dissolvent of mesosome is dimethylformamide, and used thio reagents are thiacetate.Here thiacetate is
Thioacetic acid potassium, sodium thioglycolate, thioacetic acid lithium, one kind in thioacetic acid triethylamine salt or its mixture.
In said synthesis route, step 5, the deacetylate in the presence of a base of compound 5 obtains compound 6.Compound 5
Chemical entitled (R)-S- (1- (hexadecane epoxide) -3- (trityloxy) thiolacetic acid esters of propane -2.The reaction of this step is molten
Agent be methanol/tetrahydrofuran (v/v=2/1), base reagent used be 28% sodium methoxide methanol solution, or solid sodium methylate,
Solid sodium ethanol, or quantitative lithium hydroxide/hydrogen peroxide system.
In said synthesis route, step 6, compound 6 adds reaction reagent BF in dichloromethane solution3Et2O, is carried out
Trityl transport reaction, obtains compound 7.Chemical entitled (R)-S- (1- (hexadecane epoxide) -3- (triphen first of compound 6
Epoxide) mercaptan of propane -2.This step solvent for use is benzene,toluene,xylene, hexamethylene, dichloromethane, dichloroethanes, 1,1,
One kind or its mixture in 2,2- tetrachloroethanes, used catalyst are alchlor, boron trifluoride, boron trifluoride second
One kind or its mixture in ether, zinc dichloride.
In said synthesis route, step 7, in the solvent dissolved with compound 7, catalyst is added, reaction is complete, is changed
Compound 8.Chemical entitled (S)-S- (3- (hexadecane epoxide) -2- (trityloxy) alcohol of propane -1 of compound 7.This step institute
It is one kind or its mixture in benzene,toluene,xylene, hexamethylene with reaction dissolvent, the catalyst is triethylamine.
In said synthesis route, step 8, into the reaction dissolvent of compound 8, add protection group catalyst, changed
Compound 9.Chemical entitled (R) -3- (1- (hexadecane epoxide) -2- (three benzene methyl sulfonium) propyl group -2- (trimethylamine groups second of compound 8
Base) phosphonate ester.Reaction dissolvent used in this step is one kind or its mixture in tetrahydrofuran, acetonitrile, pyridine, described to fall to protect
Shield base catalyst is one kind or its mixture in silver nitrate, silver acetate, silver trifluoroacetate.
In said synthesis route, step 9, compound 9 is reacted with acylating reagent, obtains target product I.The change of compound 9
Scientific name is (R)-(1- (hexadecane epoxide) -3- (oxo (2- (trimethylamine groups ethyoxyl) phosphonic acids epoxides propyl group) -1- silver sulfides.This
Reaction dissolvent used in step is one kind or its mixture in dichloromethane, tetrahydrofuran, acetonitrile, pyridine, used catalyst
It is KI, one kind in 4- dimethylamino-pyridine (DMAP) or its mixture, the acylating reagent is acid anhydrides or acyl
Chlorine.In this step, the structure of target product I depends on the acylating reagent selected, by selecting different acylating reagents, you can
Obtain 2-S-PAF derivative.
The synthetic route of above-mentioned platelet activating factor derivative is also to be applied successfully first in such compound is synthesized,
The synthetic route is novel, yield is high and product is easily isolated, it may be said that be the optimal route for preparing such compound.Formula (I)
The specific synthetic method of the platelet activating factor derivative of structure, is described later in detail in embodiment.
Compared with prior art, platelet activating factor derivative of the present invention and its synthetic method have and following had
Beneficial effect or advantage：
(1) solketal of the invention for taking cheap chiral source S configurations is as initial reactant, by 9 steps
Reaction, has synthesized 2-S-PAF with 8.11% total recovery, has efficiently solved its original synthetic route length, low yield, raw material valency
The expensive technological deficiency of lattice.
(2), can be with the other a variety of blood platelets of Fast back-projection algorithm from different acylating reagents using the synthetic route of the present invention
Activation factor derivative.
(3) 2-S-PAF and its derivative have the stereospecificity of height, may act on Various Tissues and cell, participate in
A variety of physiology such as reproduction, asthma, allergy, inflammation, tumour, shock and pathologic effect, play the life for being similar to hormone in vivo
Thing activity.But it synthesizes the factors such as difficult, source shortage and limits its activity research and clinical practice.Present invention optimizes
Its synthetic schemes, realizes low-cost, high-volume synthesis 2-S-PAF and its derivative.This is for 2-S-PAF and its derivative
Activity research, Bioexperiment, clinical practice and disease treatment are significant.
Brief description of the drawings
Fig. 1 is the molecular structure of platelet activating factor of the present invention.
Fig. 2 is the syntheti c route figure of platelet activating factor derivative of the present invention.
Fig. 3 is the synthetic route chart of 2-S-PAF derivatives of the present invention.
The present invention is further described in the examples below, without being intended to limit as indicated in claim in any form
Protection scope of the present invention.
Embodiment
Embodiment 1,2-S-PAF synthesis
The present embodiment provides 2-S-PAF synthetic route chart, is specifically shown in Fig. 3.Final product 2-S-PAF is represented with TM.
The present embodiment is given in synthetic route, and the concrete operations of step 1 are to be added in round-bottomed flask and be dissolved with NaH
Dimethylformamide (DMF) the solution 300mL of (7.26g, 0.182mol), adds compound 1 (20.0g, 0.151mol), stirs
Mix 30min；Cetyl sulphonic acid ester (58.21g, 0.182mol) is added into reaction solution again, is reacted at room temperature 12 hours；Processing is anti-
Liquid is answered, organic phase is obtained by extraction, silicagel column purifying (eluant, eluent is n-hexane/ethyl acetate, v/v=95/5) obtains 39.0gization
Compound 2, yield 85%.
1H NMR(CDCl3) (m, the 5H) of δ 0.88 (t, J=6.4Hz, 6H), 1.30 (m, 28H), 1.56 (m, 5H), 3.63
The concrete operations of step 2 are that compound 2 (52.37g, 0.147mol) is dissolved in 370mL acetone, are added
150mL hydrochloric acid (0.5M)；Mixed-liquor return stirs 2h, after question response is complete, is changed to distilling apparatus, distills out most of third
Ketone, then separates out a large amount of solids；This solid is received solution, water, ether with water, unsaturated carbonate hydrogen and cleaned, and is dried to obtain 44.37g white
Color solid chemical compound 3, yield 95%.
1H NMR(CDCl3) δ 0.93 (t, J=6.4Hz, 3H), 1.29 (m, 26H), 1.62 (m, 2H), 1.80-2.43
(2H),3.50-3.92(m,7H).
The concrete operations of step 3 are that 21.5g compounds 3 (67.9mmol) are dissolved in 250mL THF and 50mL MeCN,
Add 22.5g triphenylbromomethanes, 20mL Et3N, back flow reaction 15h；After reaction completely, reaction solution is concentrated, crosses and filters out
Fall the hydrochloride of triethylamine, and precipitation is washed with ethyl acetate dry on a small quantity；Filtrate uses H respectively2O, 1%HCl, saturation
NaHCO3Solution, saturated common salt water washing；Anhydrous magnesium sulfate is dried, and is spin-dried for, and crosses post (PE/EA=10/1~5/1), adds oil
Ether, is positioned over refrigerator overnight, there is white solid precipitation, is filtrated to get 43.6g compounds 4, yield 78%.
1H NMR(CDCl3) δ 0.94 (t, J=6.8Hz, 3H), 1.23-1.44 (m, 26H), 1.40-1.65 (m, 2H),
2.43 (d, J=4.8Hz, 1H), 3.10-3.25 (m, 2H), 3.35-3.60 (m, 4H), 3.88-4.03 (m, 1H), 7.17-
7.55(m,15H).
The concrete operations of step 4 are, at -5 DEG C, and 26.2g (46.8mmol) compound 4 is dissolved in 270mL DCM, and
9.8mL Et are added dropwise simultaneously3N and 3.6mL mesyl chlorides, carefully control is added simultaneously, then in this thermotonus 2h；Instead
Answer mixture to be introduced into frozen water, separate organic phase, inorganic phase is extracted with dichloromethane, merge organic phase；0.1M is used respectively
HCl, saturation NaHCO3Solution, the washing of saturation NaCl solution；Anhydrous MgSO4Dry, be concentrated to give intermediate product.In the middle of 28.7g
Product is dissolved in 240mL DMF, adds 7.6g HSAc and 3mL Et3N is reacted.Bath temperature is set in 90 DEG C, after 12h,
3.8g HSAc and 1.5mLEt are added again3N continues to react after 4h, and reaction is complete.Cooling, and reaction solution is poured into frozen water, and
It is extracted with ethyl acetate, organic phase is washed with water and saturation NaCl solution respectively, anhydrous MgSO4Dry, be spin-dried for, cross post (PE/EA
=100/1~20/1), obtain 17.1g compounds 5, yield 57%.
1H NMR(CDCl3) δ 0.88 (t, J=6.4Hz, 3H), 1.10-1.40 (m, 26H), 1.40-1.60 (m, 2H),
2.31 (s, 3H), 3.22 (dd, J=9.2,5.6Hz, 1H), 3.37 (t, J=6.6Hz, 2H), 3.39 (dd, J=9.2,3.8Hz,
1H), 3.65 (d, J=6.0Hz, 2H), 3.80-3.97 (m, 1H), 7.15-7.50 (m, 15H)
The concrete operations of step 5 are that 13.4g compounds 5 (21mmol) are dissolved in 78mLMeOH and 39mLTHF, and in 0
The MeONa solution that 4.6mL mass fractions are 28% is added dropwise at DEG C.After 30min, reaction is complete, concentration, and dilute with AcOEt
Concentrate is released, solution uses H respectively2O, 0.1M HCl, saturation NaHCO3Solution, the washing of saturation NaCl solution.Anhydrous MgSO4Dry,
It is spin-dried for, crosses post (PE/DCM=50/1~20/1), obtain 9.6g compounds 6, yield 77%.
1H NMR(CDCl3) δ 0.88 (t, J=6.4Hz, 3H), 1.10-1.40 (m, 26H), 1.40-1.65 (m, 2H),
1.89 (d, J=8.2Hz, SH), 2.95-3.15 (m, 1H), 3.26 (dd, J=9.2,5.8Hz, 1H), 3.32 (dd, J=9.2,
5.4Hz, 1H), 3.40 (t, J=6.6Hz, 2H), 3.55-3.70 (m, 2H), 7.15-7.50 (m, 15H)
13C NMR(CDCl3)δ14.12,22.70,26.16,29.38,29.54,29.62,29.65,29.68,29.72,
31.95,39.88,64.86,71.34,72.57,86.63,127.07,127.84,128.77,144.06.
The concrete operations of step 6 are that 9.6g compounds 6 (16.7mmol) are dissolved in 180mLDCM, at -10 DEG C, to
2.4mL BF are added dropwise in reaction system3.OEt2.After 45min, reactant mixture pours into ice saturation NaHCO3In solution, DCM
Extraction, organic phase is washed with saturation NaCl, anhydrous MgSO4Dry, be spin-dried for, cross post (PE/EA=8/1~4/1), obtain 7.1gization
Compound 7, yield 74%.
1H NMR(CDCl3) δ 0.88 (t, J=6.4Hz, 3H), 1.10-1.35 (m, 26H), 1.35-1.55 (m, 2H),
2.54-2.72(m,2H),3.00-3.58(m,6H),7.15-7.35(m,9H),7.40-7.50(m,6H).
13C NMR(CDCl3)δ14.13,22.71,26.05,29.39,29.44,29.52,29.59,29.64,29.69,
29.72,31.95,45.42,64.92,67.46,71.47,72.94,126.80,128.00,129.58,144.88.
The concrete operations of step 7 are, by compound 7 (9.98g, 17.33mmol) and triethylamine (5.5mL, 39.45mmol)
It is dissolved in benzene, then by the chloro- 2- oxygen -1,3 of 100mL 2-, the benzole soln of 2- dioxaphospholane (4.69g, 32.88mmol) adds
Enter into the solution of compound 7, reaction 3.5h is stirred at room temperature, be filtered to remove deposition salt, filtrate is concentrated to give intermediate product, by
Between product be dissolved in 24mL concentration be 3.8M trimethylamines acetonitrile solution in, 50 DEG C reaction 16h.Reaction solution is concentrated, silicagel column purifying.
Eluant, eluent is chloroform/methanol/water (v/v/v=32/9/1~20/15/1), obtains 8.35g compounds 8, yield 65%.
1H NMR(DMSO-d6) δ 0.89 (t, J=6.4Hz, 3H), 1.10-1.50 (m, 28H), 2.50-2.65 (m, 1H),
2.84 (dd, J=10.2,4.4Hz, 1H), 3.05-3.27 (m, 3H), 3.18 (s, 9H), 3.50-3.65 (m, 2H), 3.75-
3.95(m,2H),4.10-4.30(m,2H),7.15-7.40(m,9H),7.45-7.55(m,6H).
13C NMR(DMSO-d6)δ14.15,22.70,26.07,29.38,29.56,29.68,29.74,31.93,
44.93,54.29,59.18,64.87,66.22,67.20,69.35,70.80,126.70,127.94,129.65,144.88.
The concrete operations of step 8 are that compound 8 (1.2g, 7.62mmol) is dissolved in 12mL MeCN and 1.2mL MeOH
In, 0.3mL pyridines are added, are stirred.By AgNO3MeCN (1.8mL) solution of (0.55g, 3.24mmol) is added to reaction solution
In, react 1h.Ether is added into reaction solution, suction filtration is cleaned with acetonitrile/ether (v/v=1/1), be dried in vacuo, obtain 0.6g
Compound 9, yield 61%.
The concrete operations of step 9 are that compound 9 (115mg, 0.19mmol) is dissolved in 2mL MeCN, add KI
(38mg, 0.38mmol), DMAP (46mg, 0.38mmol) and acetic anhydride (39mg, 0.38mmol), reaction 16h obtain product.With
CHCl3/ MeOH obtains target product 2-S-PAF, yield 61% as eluant, eluent, column chromatographic isolation and purification.
1H NMR(CDCl3) δ 0.88 (t, J=6.4Hz, 3H), 0.89 (t, J=6.4Hz, 3H), 1.20-1.42 (m,
32H), 1.42-1.60 (m, 2H), 1.60-1.80 (m, 2H), 1.96-2.18 (m, 4H), 2.54 (t, J=7.6Hz, 2H),
2.72-2.92(m,6H),3.30-3.47(m,2H),3.40(s,9H),3.48-3.68(m,2H),3.75-4.03(m,5H),
4.26-4.42(m,2H),5.24-5.50(m,8H).
13C NMR(CDCl3)δ14.09,14.13,22.59,22.71,25.46,25.66,26.11,26.43,27.24,
29.33,29.38,29.58,29.70,29.74,31.53,31.94,43.63,44.20,54.51,59.24,64.24,
66.52,69.20,71.47,127.53,127.83,128.07,128.34,128.65,128.68,129.10,130.52,
198.98.
Embodiment 2, a kind of synthesis of 2-S-PAF derivatives
The present embodiment gives synthetic route referring to Fig. 3, and the concrete operations of step 1~8 are referring to embodiment 1.
The concrete operations of step 9 are that compound 9 (30mg, 0.05mmol) is dissolved in 2mL MeCN, add KI
(8.3mg, 0.05mmol), DMAP (6mg, 0.05mmol) and 16 phosgenes (137mg, 0.5mmol), 16~24h of reaction are obtained
To product.Use CHCl3/ MeOH obtains 2-S-PAF derivatives, yield 61% as eluant, eluent, column chromatographic isolation and purification.
1H NMR(CDCl3) δ 0.88 (t, J=6.4Hz, 3H), 0.89 (t, J=6.4Hz, 3H), 0.91 (t, J=6.4Hz,
3H),1.20-1.42(m,64H),1.42-1.60(m,2H),1.60-1.80(m,2H),1.96-2.18(m,4H),2.33(t,J
=7.6Hz, 2H), 2.54 (t, J=7.6Hz, 2H), 2.72-2.92 (m, 6H), 3.30-3.47 (m, 2H), 3.40 (s, 9H),
3.48-3.68(m,2H),3.75-4.03(m,5H),4.26-4.42(m,2H),5.24-5.50(m,8H).
Further narration has been done to the present invention above in conjunction with embodiment, but the present invention is not limited to above-mentioned embodiment,
In the knowledge that one skilled in the relevant art possesses, it can also be made on the premise of present inventive concept is not departed from
Various change.
Claims (10)
1. platelet activating factor derivative, it has the chemical constitution of formula (I)：
Wherein, substituent R represents acyl group.
2. platelet activating factor derivative according to claim 1, it is characterised in that the substituent R represents fat
Race's acyl group.
3. platelet activating factor derivative according to claim 1, it is characterised in that the substituent R represents chain
Aliphatic acyl radical, R=CnH2n+1CO-, n are positive integer and represent the length of carbochain.
4. the synthetic method of platelet activating factor derivative, it uses following reaction scheme：
Step 1, into the solvent dissolved with compound 1, hexadecane derivative is added, is reacted, obtained in the presence of base reagent
Compound 2；
Step 2, the acidic hydrolysis of compound 2, obtains compound 3；
Step 3, the terminal hydroxyl of selective protection compound 3, obtains compound 4；
Step 4, compound 4 is generated into leaving group in a solvent, thio reagents is added into intermediate, obtain compound 5；
Step 5, the deacetylate in the presence of a base of compound 5, obtains compound 6；
Step 6, compound 6 adds reaction reagent BF in dichloromethane solution3Et2O, carries out trityl transport reaction, obtains
To compound 7；
Step 7, in the solvent dissolved with compound 7, catalyst is added, reaction is complete, obtains compound 8；
Step 8, into the reaction dissolvent of compound 8, add protection group catalyst, obtain compound 9；
Step 9, compound 9 is reacted with acylating reagent, obtains target product I.
5. the synthetic method of platelet activating factor derivative according to claim 4, it is characterised in that the step 1
Described in base reagent be one kind or its mixed base in NaH, KH, KOH, NaOH, NaOt-Bu, the hexadecane derivative is
One kind in cetyl sulphonic acid ester, 1- bromohexadecanes, 1- iodohexadecanes；Acid described in step 2 needed for acidic hydrolysis
It is one kind or its mixed acid in hydrochloric acid, acetic acid, sulfuric acid, p-methyl benzenesulfonic acid, camphorsulfonic acid.
6. the synthetic method of platelet activating factor derivative according to claim 4, it is characterised in that the step 3
Reaction dissolvent be MeCN/ tetrahydrofurans (v/v=1/5), used catalyst be triethylamine, pyridine, 4- dimethylamino-pyridine,
One kind or its mixture in 2,6- lutidines, used terminal hydroxyl protection reagent is triphenylchloromethane, three
One kind or its mixture in phenyl bromomethane.
7. the synthetic method of platelet activating factor derivative according to claim 4, it is characterised in that the step 4
Catalyst be triethylamine, solvent is dichloromethane, and the reagent of generation leaving group is methane sulfonyl chloride, paratoluensulfonyl chloride, right
Nitrobenzene sulfonyl chloride, ortho-nitrophenyl sulfonic acid chloride, one kind in 2,4- dinitrophenyl chloride benzene or its mixture；The centre
The reaction dissolvent of body is dimethylformamide, and used thio reagents are thiacetate.
8. the synthetic method of platelet activating factor derivative according to claim 4, it is characterised in that the step 5
Reaction dissolvent be methanol/tetrahydrofuran (v/v=2/1), base reagent used is the methanol solution of 28% sodium methoxide, or solid
Sodium methoxide, solid sodium ethanol, or lithium hydroxide/hydrogen peroxide system；The solvent of the step 6 be benzene,toluene,xylene,
One kind or its mixture in hexamethylene, dichloromethane, dichloroethanes, 1,1,2,2- tetrachloroethanes, used catalyst
For alchlor, boron trifluoride, BFEE, one kind or its mixture in zinc chloride.
9. the synthetic method of platelet activating factor derivative according to claim 4, it is characterised in that the step 7
Reaction dissolvent be one kind or its mixture in benzene,toluene,xylene, hexamethylene, the catalyst is triethylamine；Step
8 reaction dissolvent is one kind or its mixture in tetrahydrofuran, acetonitrile, pyridine, it is described fall protection group catalyst be nitric acid
One kind or its mixture in silver, silver acetate, silver trifluoroacetate.
10. the synthetic method of platelet activating factor derivative according to claim 4, it is characterised in that the step 9
Reaction dissolvent be one kind or its mixture in dichloromethane, tetrahydrofuran, acetonitrile, pyridine, used catalyst is iodate
Potassium, one kind in 4- dimethylamino-pyridine or its mixture, the acylating reagent is acid anhydrides, one kind of acyl chlorides or it is mixed
Compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710218907.9A CN106967113A (en) | 2017-04-05 | 2017-04-05 | Platelet activating factor derivative and its synthetic method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710218907.9A CN106967113A (en) | 2017-04-05 | 2017-04-05 | Platelet activating factor derivative and its synthetic method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106967113A true CN106967113A (en) | 2017-07-21 |
Family
ID=59336564
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710218907.9A Pending CN106967113A (en) | 2017-04-05 | 2017-04-05 | Platelet activating factor derivative and its synthetic method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106967113A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04346797A (en) * | 1991-05-24 | 1992-12-02 | Shinotesuto:Kk | Measurement of acetylhydrolase activity of platelet activating factor |
| JPH06116279A (en) * | 1991-05-24 | 1994-04-26 | Shinotesuto:Kk | New ether type thiophospholipid compound and its production |
| US5663405A (en) * | 1994-09-20 | 1997-09-02 | Shionogi & Co., Ltd. | Process of producing ether-type thio-phospholipids |
-
2017
- 2017-04-05 CN CN201710218907.9A patent/CN106967113A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04346797A (en) * | 1991-05-24 | 1992-12-02 | Shinotesuto:Kk | Measurement of acetylhydrolase activity of platelet activating factor |
| JPH06116279A (en) * | 1991-05-24 | 1994-04-26 | Shinotesuto:Kk | New ether type thiophospholipid compound and its production |
| US5663405A (en) * | 1994-09-20 | 1997-09-02 | Shionogi & Co., Ltd. | Process of producing ether-type thio-phospholipids |
Non-Patent Citations (3)
| Title |
|---|
| BHATIA, SURESH K. ET AL: "Stereospecific synthesis of 2-substituted ether Phospholipids", 《SYNTHESIS》 * |
| FUJI, MASAHIRO ET AL: "A Stereoselective and Highly Practical Synthesis of Cytosolic Phospholipase A2 Substrate,2-S-Arachidonoyl-1-O-hexadecyl-sn-2-thioglycero-3-O-phosphocholine", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| MURATA, MASAKAZU ET AL: "Synthesis of 2-thio-platelet activating factor and related compounds", 《CHEMICAL & PHARMACEUTICAL BULLETIN》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10730904B2 (en) | Method for liquid-phase synthesis of nucleic acid | |
| AU2016204770B2 (en) | Asymmetric Auxiliary Group | |
| US9029534B2 (en) | Methods for preparing anti-viral nucleotide analogs | |
| CN102282155B (en) | The synthetic method of the nucleic acid of phosphorus atoms modification | |
| CN103476784B (en) | Method for producing oligonucleotide | |
| EP2883866B1 (en) | INTERMEDIATE FOR SYNTHESIS OF 1-(2-DEOXY-2-FLUORO-4-THIO-beta-D-ARABINOFURANOSYL) CYTOSINE, INTERMEDIATE FOR SYNTHESIS OF THIONUCLEOSIDE, AND METHODS FOR PRODUCING THESE INTERMEDIATES | |
| CZ298592A3 (en) | Pyrimidine nucleoside derivatives exhibiting anti-tumor activity,their preparation and use | |
| JP2020523378A (en) | Synthesis of phosphate derivatives | |
| WO2009125841A1 (en) | Process for production of ethynylthymidine compound using 5-methyluridine as starting raw material | |
| WO2005033121A2 (en) | Synthesis of 2-aralkyloxyadenosines, 2-alkoxyadenosines, and their analogs | |
| JP6204223B2 (en) | Method for producing thiopyranose compound, etc. | |
| EP3684780A1 (en) | Floxuridine synthesis | |
| CN106967113A (en) | Platelet activating factor derivative and its synthetic method | |
| WO2015188782A1 (en) | Method for preparing sofosbuvir | |
| CN109053496A (en) | A kind of synthetic method of 3-Boc- aminomethyl cyclobutanone | |
| US5663405A (en) | Process of producing ether-type thio-phospholipids | |
| JPS60226873A (en) | 1,3-benzoxazole derivative and its preparation | |
| PT673947E (en) | PSYCHOFURANOSE AND PSYCHOPYRANOSE DERIVATIVES | |
| US20060135466A1 (en) | Synthesis of 2-aralkyloxyadenosines, 2-alkoxyadenosines, and their analogs | |
| Sakakibara et al. | First synthesis of [6-15N]-cladribine using ribonucleoside as a starting material | |
| Kim et al. | Efficient Synthesis of Novel 4'-Trifluoromethyl-5'-norcarbocyclic Purine Phosphonic Acid Analogs by Using the Ruppert-Prakash Reaction | |
| Dimagno | Heavily fluorinated sugar analogs | |
| CN101684134A (en) | Synthetic process of 5-[3-(biotin acylamino hexanoyl)-amido]-propenyl-2'-deoxycholic-5'-uridine triphosphate lithium salt | |
| JPH01139593A (en) | Isotope-labeled aldononitrile derivative | |
| CN102803236A (en) | Synthesis of TTX intermediates |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170721 |