CN105693746B - The Preparation Method And Their Intermediate of oxazolidinone compounds - Google Patents
The Preparation Method And Their Intermediate of oxazolidinone compounds Download PDFInfo
- Publication number
- CN105693746B CN105693746B CN201510323912.7A CN201510323912A CN105693746B CN 105693746 B CN105693746 B CN 105693746B CN 201510323912 A CN201510323912 A CN 201510323912A CN 105693746 B CN105693746 B CN 105693746B
- Authority
- CN
- China
- Prior art keywords
- formula
- compound shown
- reaction
- carries out
- solvent
- 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.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title abstract description 33
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 108
- 238000006243 chemical reaction Methods 0.000 claims description 89
- 239000002904 solvent Substances 0.000 claims description 70
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 51
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 46
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- 238000005915 ammonolysis reaction Methods 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical class O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 30
- 239000003054 catalyst Substances 0.000 claims description 29
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 26
- 238000005859 coupling reaction Methods 0.000 claims description 26
- 235000019441 ethanol Nutrition 0.000 claims description 25
- 239000003153 chemical reaction reagent Substances 0.000 claims description 21
- 238000006467 substitution reaction Methods 0.000 claims description 21
- 239000003513 alkali Substances 0.000 claims description 19
- 238000006482 condensation reaction Methods 0.000 claims description 19
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 claims description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 14
- 239000003446 ligand Substances 0.000 claims description 13
- 230000009471 action Effects 0.000 claims description 12
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 12
- 239000002798 polar solvent Substances 0.000 claims description 12
- 238000005576 amination reaction Methods 0.000 claims description 11
- 238000000746 purification Methods 0.000 claims description 11
- 238000005360 mashing Methods 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 5
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 5
- 239000001103 potassium chloride Substances 0.000 claims description 5
- 235000011164 potassium chloride Nutrition 0.000 claims description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 159000000000 sodium salts Chemical class 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 230000008859 change Effects 0.000 claims description 3
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical group I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 3
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 claims description 3
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 claims description 3
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 150000002466 imines Chemical class 0.000 claims description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
- 125000005909 ethyl alcohol group Chemical group 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000011084 recovery Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 150000002916 oxazoles Chemical class 0.000 description 30
- 239000002585 base Substances 0.000 description 25
- YHWMFDLNZGIJSD-UHFFFAOYSA-N 2h-1,4-oxazine Chemical compound C1OC=CN=C1 YHWMFDLNZGIJSD-UHFFFAOYSA-N 0.000 description 20
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 125000005605 benzo group Chemical group 0.000 description 16
- -1 Methylsilyl Chemical group 0.000 description 15
- 229940049706 benzodiazepine Drugs 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 13
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 13
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- 239000012071 phase Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical class [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 235000019253 formic acid Nutrition 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 208000007536 Thrombosis Diseases 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 150000004893 oxazines Chemical class 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 6
- 230000023555 blood coagulation Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- LFETXMWECUPHJA-UHFFFAOYSA-N methanamine;hydrate Chemical compound O.NC LFETXMWECUPHJA-UHFFFAOYSA-N 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- 239000010949 copper Substances 0.000 description 5
- 229910052802 copper Inorganic materials 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 5
- 239000011976 maleic acid Substances 0.000 description 5
- 229940098779 methanesulfonic acid Drugs 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 238000012805 post-processing Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 0 O=C1c2ccccc2N*1C[C@@]([C@]1*2c(ccc(*(CCOC3)C3=O)c3)c3OC1)OC2=O Chemical compound O=C1c2ccccc2N*1C[C@@]([C@]1*2c(ccc(*(CCOC3)C3=O)c3)c3OC1)OC2=O 0.000 description 4
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 235000006408 oxalic acid Nutrition 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 description 4
- 235000011009 potassium phosphates Nutrition 0.000 description 4
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 4
- 150000003141 primary amines Chemical class 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- UTXBJOTXFNNRDN-UHFFFAOYSA-N CC(C)(C)[Si](C)(C)[O] Chemical compound CC(C)(C)[Si](C)(C)[O] UTXBJOTXFNNRDN-UHFFFAOYSA-N 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- 102000009123 Fibrin Human genes 0.000 description 3
- 108010073385 Fibrin Proteins 0.000 description 3
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 3
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 230000010100 anticoagulation Effects 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 229950003499 fibrin Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229910052738 indium Inorganic materials 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000001488 sodium phosphate Substances 0.000 description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 description 3
- 235000011008 sodium phosphates Nutrition 0.000 description 3
- DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical class NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 3
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 2
- ROHGINRQAFHUPY-UHFFFAOYSA-N 1-n,1-n'-dimethylcyclohexane-1,1-diamine Chemical compound CNC1(NC)CCCCC1 ROHGINRQAFHUPY-UHFFFAOYSA-N 0.000 description 2
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 2
- LQOBMKYCRQDMTN-UHFFFAOYSA-N 3-(2-ethylphenyl)pentan-3-amine;hydrochloride Chemical group Cl.CCC1=CC=CC=C1C(N)(CC)CC LQOBMKYCRQDMTN-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 2
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 2
- 229940112669 cuprous oxide Drugs 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- HVZWVEKIQMJYIK-UHFFFAOYSA-N nitryl chloride Chemical compound [O-][N+](Cl)=O HVZWVEKIQMJYIK-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229940085605 saccharin sodium Drugs 0.000 description 2
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 231100000004 severe toxicity Toxicity 0.000 description 2
- 238000010583 slow cooling Methods 0.000 description 2
- 239000001119 stannous chloride Substances 0.000 description 2
- 235000011150 stannous chloride Nutrition 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N titanium dioxide Inorganic materials O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 235000010215 titanium dioxide Nutrition 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- NCPICGMTBCNSGK-UHFFFAOYSA-N 1,1,1-trimethoxy-2-(2-methoxyethoxy)ethane Chemical compound COC(COCCOC)(OC)OC NCPICGMTBCNSGK-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical class CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical class CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- 239000005725 8-Hydroxyquinoline Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical class CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 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
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- XBJFCYDKBDVADW-UHFFFAOYSA-N acetonitrile;formic acid Chemical compound CC#N.OC=O XBJFCYDKBDVADW-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 229940053202 antiepileptics carboxamide derivative Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 150000001540 azides Chemical group 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- RFKZUAOAYVHBOY-UHFFFAOYSA-M copper(1+);acetate Chemical compound [Cu+].CC([O-])=O RFKZUAOAYVHBOY-UHFFFAOYSA-M 0.000 description 1
- QNZRVYCYEMYQMD-UHFFFAOYSA-N copper;pentane-2,4-dione Chemical compound [Cu].CC(=O)CC(C)=O QNZRVYCYEMYQMD-UHFFFAOYSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- 108700003601 dimethylglycine Proteins 0.000 description 1
- JZZIHCLFHIXETF-UHFFFAOYSA-N dimethylsilicon Chemical compound C[Si]C JZZIHCLFHIXETF-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical group O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 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 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- CEAJFNBWKBTRQE-UHFFFAOYSA-N methanamine;methanol Chemical compound NC.OC CEAJFNBWKBTRQE-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- 229940078490 n,n-dimethylglycine Drugs 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- OELZFJUWWFRWLC-UHFFFAOYSA-N oxazine-1 Chemical compound C1=CC(N(CC)CC)=CC2=[O+]C3=CC(N(CC)CC)=CC=C3N=C21 OELZFJUWWFRWLC-UHFFFAOYSA-N 0.000 description 1
- YWWARDMVSMPOLR-UHFFFAOYSA-M oxolane;tetrabutylazanium;fluoride Chemical compound [F-].C1CCOC1.CCCC[N+](CCCC)(CCCC)CCCC YWWARDMVSMPOLR-UHFFFAOYSA-M 0.000 description 1
- 229960003540 oxyquinoline Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008194 pharmaceutical composition 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
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 239000012629 purifying agent Substances 0.000 description 1
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- BZWKPZBXAMTXNQ-UHFFFAOYSA-N sulfurocyanidic acid Chemical compound OS(=O)(=O)C#N BZWKPZBXAMTXNQ-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical class [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Abstract
The invention discloses a kind of preparation methods of Xin oxazolidinone compounds, while also disclosing the important intermediate compound that the preparation method is related to.Preparation method raw material provided by the present invention is cheap, and mild condition is easy to operate, safely controllable, and total recovery is high, is suitble to industrial production.
Description
Technical field
The present invention relates to medicinal chemistry art, Ju bodies She is Ji the chloro- N- of oxazolidinone compounds 5- (((3S, 3aS) -1- oxygen
Generation -7- (3- oxo-morpholines) -1,3,3a, and 4- tetrahydro benzos [b] oxazoles [3,4-d] [1,4] oxazine -3- bases) methyl) thiophene -
The Preparation Method And Their Intermediate of 2- formamides.
Background technology
Thrombotic disease, that is, thrombotic disease, refer to the lumen of vessels caused by thrombus it is narrow with occlusion, make main organs
Ischemic occurs and blocks and cause the various diseases of dysfunction, belongs to cardiovascular and cerebrovascular disease.Cardiovascular and cerebrovascular disease has become entirely
Ball causes a disease, one of the highest cause of disease of lethality.And main inducing of the thrombotic disease as cardiovascular and cerebrovascular disease, incidence are in increase year by year
Add trend.
Blood coagulation Xa factor is a kind of serine protease, can be fibrin ferment by conversion of prothrombin, be one and great face
The anticoagulation target spot of bed value has consequence in control fibrin ferment forms and activate blood coagulation waterfall.Blood coagulation Xa factor
Positioned at the joint of inside and outside source property coagulation pathway, the major catalytic II factors are factor converting to IIa.Existing for coagulation process
Bio signal amplifies, and a blood coagulation Xa factor inhibitor can inhibit the physiologic effect of 138 factor molecules, therefore, leads to
It crosses and inhibits blood coagulation Xa factor that can effectively inhibit the generation of fibrin ferment and the formation of thrombus.Blood coagulation Xa factor it is effective and special
Inhibitor potential valuable therapeutic agent can be used as to treat thromboembolic disorders.
The Shou Gong chloro- N- of Kai oxazolidinone compounds 5- (((3S, the 3aS) -1- of patent application WO 2014/110971
Oxo -7- (3- oxomorpholin -4- bases) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4-d] [1,4] oxazine -3- bases) methyl)
Thiophene-2-carboxamide derivatives, shown in structure such as formula (I).The compound has strong anticoagulation Xa factor activity, can be used as anticoagulation
Drug is diseases related for treating thrombus.
Above-mentioned patent also discloses the preparation method of compound shown in formula (I):(3R, 3aS) -7- substitutions -3- (((tertiary fourths
Base dimethyl silicon substrate) oxygen) methyl) -3a, 4- dihydrobenzos [b] oxazole [3,4-d] [1,4] (3H) -one of oxazine -1 and 3- morpholones
Coupling reaction occurs in metal palladium catalyst and under the action of containing Phosphine ligands, products therefrom is through deprotection base, sulfonylation, adjacent benzene
Intermediate (I-a) (compound shown in formula (I-a)), finally, intermediate (I- are obtained after diformyl substitution, ammonolysis four-step reaction
A) condensation reaction occurs with 5- chlorothiophene -2- formyl chlorides, obtains compound shown in formula (I).
In the preparation method, the yield of coupling reaction is relatively low, and the metal palladium catalyst price used is high, is unsuitable for amplifying
Production.In addition, intermediate (I-a) that this method is prepared is not purified to be directly used in next step condensation reaction so that condensation
The post-processing of reaction is difficult, and influences the yield of reaction.
Patent application WO 2015/043364 also discloses that compound shown in formula (I), preparation method, pharmaceutical composition and
Its purposes as anti-coagulants in treating and preventing thrombotic disease.Wherein, same in preparation method disclosed in this application
Sample is related to intermediate (I-a) and preparation method thereof:It is prepared in this after hydroxy activated, then through azide substitution, reduction reaction
Mesosome.In the synthetic method, severe toxicity, explosive sodium azide reagent are used, experimental risk is high, is unfavorable for industrial life
Production.
Invention content
The present invention relates to the preparation methods and its important intermediate of compound shown in formula (I), and this method is easy to operate, safety
Controllably, and yield is high, is suitble to industrialized production.
Present invention relates particularly to the preparation methods of compound shown in formula (I):(3R, 3aS) -7- substitutions -3- (((tertiary butyls two
Methylsilyl) oxygen) methyl) -3a, 4- dihydrobenzos [b] oxazoles [3,4-d] [Isosorbide-5-Nitrae] oxazines -1 (3H) -one after coupling reaction,
It is deprotected and obtains (3R, 3aS) -3- (methylol) -7- (3- oxo-morpholines) -3a, 4- dihydrobenzos [b] oxazoles [3,4-d] [1,
4] oxazines -1 (3H) -one, then after hydroxy activated, substitution reaction, ammonolysis reaction, acidification obtains (3S, 3aS) -3- (amino first
Base) -7- (3- oxo-morpholines) -3a, 4- dihydrobenzos [b] oxazoles [3,4-d] [salt (formula (II) of 1,4] oxazines -1 (3H) -one
Shown compound), finally with 5- chlorothiophene -2- formyl chlorides occur condensation reaction, obtain the chloro- N- of target compound 5- (((3S,
3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, and 4- tetrahydro benzos [b] oxazoles [3,4-d] [1,4] oxazine -3- bases) first
Base) thiophene-2-carboxamide derivatives.
Wherein, HX is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, malonic acid, oxalic acid, maleic acid, methanesulfonic acid or
P-methyl benzenesulfonic acid.
In preparation method of the present invention, the coupling reaction has used copper catalyst, and price is compared with catalyzing by metal palladium
Agent is low, and production cost can be reduced using copper catalyst;Meanwhile coupling reaction post-processing letter under the conditions of of the present invention
Single, yield is high.The method of the invention, which uses first to activate, to be replaced again (for example, phthalyl or o-benzoyl sulfonyl take
Generation), then hydroxyl, is converted into amido by the method for ammonolysis, is avoided using severe toxicity, explosive reagent, safer controllable.Meanwhile
In ammonolysis reaction of the present invention, the obtained acidified method at salt of crude product obtains corresponding salt so that ammonolysis is anti-
The post-processing answered is simpler, and has obtained the high midbody product of purity, is conducive to the control and production of impurity in reacting in next step
The raising of rate;Also, obtained intermediate salt is easier to preserve.In the condensation reaction of final step, using mixed solvent into
One step improves the yield of reaction;Crude product obtained by the reaction uses recrystallization purifying, easy to operate.Generally speaking, of the invention
The preparation method raw material of offer is cheap, of low cost, easy to operate, safely controllable, and total recovery is high;Especially by intermediate (I-
A) acidification is at salt so that the processing of final step reaction is simpler, yield higher, is particularly suitable for industrial production.
The invention further relates to two important intermediates of compound shown in formula (I) (chemical combination shown in formula (II) and formula (III)
Object) and preparation method thereof.
Wherein, Z is-C (=O)-or-S (=O)2-。
On the one hand, the present invention provides a kind of method preparing compound shown in formula (I) comprising:By formula (II) shownization
It closes object and carries out condensation reaction with 5- chlorothiophene -2- formyl chlorides, obtain compound shown in formula (I):
Wherein, HX is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, malonic acid, oxalic acid, maleic acid, methanesulfonic acid or
P-methyl benzenesulfonic acid.
5- chlorothiophenes -2- formyl chlorides of the present invention can be directly added dropwise in the solution of compound shown in formula (II),
Certain density solution can also be configured to the second solvent to be added dropwise.Second solvent is not specifically limited, and can be dissolved
The solvent that 5- chlorothiophene -2- formyl chlorides have no effect on reaction is included in the present invention comprising but it is not limited to toluene or dichloro
Methane etc..The certain density solution is not specifically limited, and the solution of all each concentration for not influencing reaction is included in
In the present invention.In some embodiments, the 5- chlorothiophenes-that the certain density 5- chlorothiophenes -2- formyl solutions of chlorine is 48%
2- formyl chloride toluene solutions;In further embodiments, the certain density 5- chlorothiophenes -2- formyl solutions of chlorine be 1.6M or
5- chlorothiophene -2- formyl chloride the toluene solutions of 2.1M.
5- chlorothiophenes -2- formyl chlorides of the present invention are added dropwise to the molten of compound shown in formula (II) at 0 DEG C~50 DEG C
In liquid;In some embodiments, the 5- chlorothiophene -2- formyl chlorides are added dropwise to chemical combination shown in formula (II) at 30 DEG C~50 DEG C
In the solution of object;In another embodiment, the 5- chlorothiophene -2- formyl chlorides are added dropwise to chemical combination shown in formula (II) at 0 DEG C
In the solution of object;In another embodiment, the 5- chlorothiophene -2- formyl chlorides are added dropwise to chemical combination shown in formula (II) at 35 DEG C
In the solution of object;In another embodiment, the 5- chlorothiophene -2- formyl chlorides are added dropwise to chemical combination shown in formula (II) at 45 DEG C
In the solution of object.
Condensation reaction of the present invention carries out at 0 DEG C~50 DEG C;In some embodiments, the condensation is anti-
It should be carried out at 20 DEG C~30 DEG C;In another embodiment, the condensation reaction carries out at 0 DEG C;In another embodiment,
The condensation reaction carries out at 20 DEG C;In another embodiment, the condensation reaction carries out at 25 DEG C.
Condensation reaction of the present invention carries out in the first solvent, wherein and first solvent is ether solvent,
Ketones solvent, dichloromethane, toluene, water or combination thereof.In some embodiments, first solvent is tetrahydrofuran,
Dioxane, diisopropyl ether, methyl tertiary butyl ether(MTBE), methyl ethyl ketone, methyl iso-butyl ketone (MIBK), acetone, dichloromethane, toluene, water or
Combination thereof.In further embodiments, first solvent is acetone, toluene, water or combination thereof.In other realities
It applies in example, the first solvent of the present invention is acetone, water or combination thereof.
In some embodiments, the first solvent of the present invention is the mixed solvent of acetone and water, and volume ratio is 1/2~3/
1, that is, the volume ratio of acetone and water is 1:(1/3~2).In some embodiments, first solvent is the mixing of acetone and water
Solvent, volume ratio are 1/2~3/2, that is, the volume ratio of acetone and water is 1:(2/3~2).In further embodiments, described
One solvent is the mixed solvent of acetone and water, and volume ratio is 7/10~9/10, that is, the volume ratio of acetone and water is 1:(10/9~
10/7).In further embodiments, first solvent is the mixed solvent of acetone and water, volume ratio 1/2,3/4 or 8/
11。
Condensation reaction of the present invention carries out under the action of the first alkali, and first alkali can be organic base or nothing
Machine alkali.The organic base can be triethylamine, trimethylamine, n,N-diisopropylethylamine, N- methylmorpholines, N- methyl piperazines
Pyridine, pyridine or combination thereof.The inorganic base includes, but are not limited to alkali or alkaline earth metal hydroxide, alkali metal
Or the carbonate or bicarbonate or phosphate or hydrophosphate of alkaline-earth metal alkyl oxide, alkali or alkaline earth metal, ammonia or
Combination thereof.In some embodiments, the first alkali of the present invention is organic base;In some embodiments, first alkali
For inorganic base.In some embodiments, first alkali is triethylamine, trimethylamine, n,N-diisopropylethylamine, N- methylmorphines
Quinoline, N- methyl piperidines, pyridine, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, saleratus, sodium bicarbonate, sodium phosphate,
Potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate or combination thereof.In some embodiments, the first alkali of the present invention is hydrogen
Sodium oxide molybdena, potassium hydroxide, potassium carbonate, sodium carbonate, saleratus, sodium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, phosphoric acid
Hydrogen dipotassium or combination thereof.
In method of the present invention, further comprise the purification process of compound shown in formula (I), the purification process packet
Include but be not limited to recrystallization purifying etc..Wherein, the recrystallization purifying carries out in third solvent, and the third solvent does not have
There are special limitation, any crude product that can dissolve the condensation reaction to a certain extent that crystallization simultaneously can be precipitated under certain condition
Solvent be included in the present invention.The third solvent includes but not limited to acetic acid, water or their arbitrary combination etc..One
In a little embodiments, the third solvent is acetic acid;In further embodiments, the third solvent is water;In some embodiments
In, the third solvent is the mixed solvent of acetic acid and water.In further embodiments, the third solvent is acetic acid and water
Mixed solvent, volume ratio are 1/2~3/2, i.e., the volume ratio of acetic acid and water is 1:(2/3~2).The specific mistake of the recrystallization
Journey includes:The crude product is suspended in third solvent, after heating for dissolving, cooling crystallization or anti-solvent additive process crystallization.Example
Such as, the crude product of embodiment 7 is suspended in acetic acid or water or their in the mixed solvent, after heating for dissolving, slow cooling is precipitated
Solid;Or after dissolving by heating, another solvent (can be water or acetic acid or their mixing) is added while keeping temperature,
Then solid is precipitated in slow cooling.
Condensation reaction yield of the present invention is high, and the method that post-processing uses recrystallization, and operation is simple, is suitble to
Amplification production.The present invention provides the embodiment of condensation reaction amplification synthesis, from the experimental result it is found that the reaction is in the present invention
Under conditions of described, amplification production remains to reach 77% yield.
On the one hand, the present invention provides a kind of intermediate being used for preparing compound shown in formula (I), structure such as formula (II) institute
Show:
Wherein, HX is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, malonic acid, oxalic acid, maleic acid, methanesulfonic acid or
P-methyl benzenesulfonic acid.
On the other hand, the present invention provides a kind of method preparing the compound as shown in formula (II) comprising:(1) formula
(III) ammonolysis reaction occurs for compound shown in;And the product of the ammonolysis reaction is carried out salt-forming reaction by (2), is obtained described
Compound shown in formula (II):
Wherein, Z is-C (=O)-or-S (=O)2-;HX is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, the third two
Acid, oxalic acid, maleic acid, methanesulfonic acid or p-methyl benzenesulfonic acid.
Ammonolysis reaction of the present invention carries out at 50 DEG C~100 DEG C;In some embodiments, the ammonolysis reaction exists
It is carried out at 60 DEG C~90 DEG C;In some embodiments, the ammonolysis reaction carries out at 85 DEG C;In further embodiments, institute
Ammonolysis reaction is stated to carry out at 90 DEG C;In some embodiments, the ammonolysis reaction carries out at 85 DEG C~90 DEG C.At other
In embodiment, the ammonolysis reaction carries out at the temperature at which reaction dissolvent flows back, the reflux temperature with specifically react phase
It closes, is varied from according to the difference of actual conditions.In another embodiment, the ammonolysis reaction is under the reflux temperature of ethyl alcohol
It carries out;In another embodiment, the ammonolysis reaction carries out under the reflux temperature of ethanol/water mixed solvent.
Ammonolysis reaction of the present invention carries out under the action of amination reagent, the amination reagent be ammonia, ammonium hydroxide,
Primary amine or hydrazine.Wherein, the primary amine is methylamine, ethamine, propylamine or butylamine;The hydrazine is hydrazine or hydrazine hydrate.
In some embodiments, primary amine used in the ammonolysis reaction is methylamine, wherein the methylamine can be one
Determine the methylamine solution of concentration comprising but be not limited to, certain density methylamine water solution, methylamine methanol solution, methylethylolamine is molten
Liquid or methylamine aqueous isopropanol etc..In some embodiments, the certain density methylamine solution be 40% methylamine water solution or
33% methylethylolamine solution.
In some embodiments, amination reagent used in the ammonolysis reaction is the methanol solution of ammonia.In some realities
It applies in example, the amination reagent is 33% ammonia methanol solution.
The dosage of amination reagent of the present invention is usually excessive, is the more of the mole of compound shown in formula (III)
Times.In some embodiments, the dosage of the amination reagent is 2-10 times of mole of compound shown in formula (III).One
In a little embodiments, the dosage of the amination reagent is 2-7 times of the mole of compound shown in formula (III);In other implementations
In example, the dosage of the amination reagent is 2.5 times, 5.0 times or 7.0 times of the mole of compound shown in (III).
Ammonolysis reaction of the present invention carries out in the first polar solvent, and first polar solvent is methanol, second
Alcohol, isopropanol, water or combination thereof.
Salt-forming reaction of the present invention is included in the 4th solvent, and the product of the ammonolysis reaction and acid appropriate are carried out
Reaction, obtains corresponding salt.Wherein, the 4th solvent is not specifically limited, and the product of the ammonolysis reaction can be made completely molten
The solvent that solution has no effect on into salt is included in the present invention comprising but be not limited to methanol, ethyl alcohol, isopropanol, water or it
It is arbitrary combination etc..The acid appropriate is not specifically limited, and can form stable salt with the product of the ammonolysis reaction
Acid is included in the present invention comprising but be not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, malonic acid, grass
Acid, maleic acid, methanesulfonic acid or p-methyl benzenesulfonic acid etc..The salt-forming reaction can be by being adjusted with acid pH value of solution to acid side
Formula is realized.
In some embodiments, salt-forming reaction of the present invention carries out in the 4th solvent, and the 4th solvent is
Methanol, ethyl alcohol, isopropanol, water or their arbitrary combination.In some embodiments, the salt-forming reaction includes by the ammonolysis
The product of reaction is reacted with acid HX or its solution, obtains compound shown in formula (II).In some embodiments, the acid HX
For hydrochloric acid.
In some embodiments, the salt that the product of ammonolysis reaction of the present invention is formed is hydrochloride, the hydrochloride
Salifying method includes:In the 4th solvent, product and concentrated hydrochloric acid or the solution of hydrogen chloride gas or hydrochloric acid of the ammonolysis reaction
Salt is reacted into, the solution of the hydrochloric acid includes but is not limited to the ethyl acetate solution of hydrochloric acid.In further embodiments, described
The salifying method of hydrochloride include:In the 4th solvent, the product of the ammonolysis reaction reacts into salt with concentrated hydrochloric acid.At some
In embodiment, the salifying method of the hydrochloride includes:It (can be first that the product of the ammonolysis reaction, which is dissolved in the 4th solvent,
Alcohol, ethyl alcohol, isopropanol or water etc.) in, concentrated hydrochloric acid is then added dropwise to system in acidity, target hydrochloride product is made.Wherein, it drips
The temperature of reaction system can be kept in a certain range (for example, maintaining the temperature at 0 DEG C or so or no more than 25 DEG C during adding
Or it is no more than 40 DEG C);After being added dropwise, can reduction temperature appropriate, so that the salt is precipitated as far as possible, it is unnecessary to avoid
Loss.
The product of ammonolysis reaction of the present invention is the corresponding amine of compound, i.e. chemical combination shown in formula (I-a) shown in formula (II)
Object.
Product obtained by ammonolysis reaction of the present invention takes into the mode purification process of salt, easy to operate, avoids column
The more complex operation such as chromatographic purifying.Meanwhile being reused after the purified processing of product, be conducive to the control reacted in next step
The raising of processing and yield.The salt of the high amine of purity can be prepared in salifying method of the present invention, and stability is high, compared with amine shape
The midbody product of formula is easier to preserve.
Compound shown in the formula (II) is further purified using the methods of mashing in the present invention.Wherein, the mashing is made
Solvent is not particularly limited, including but not limited to, dichloromethane, ethyl acetate, methanol, ethyl alcohol, isopropanol, diisopropyl ether
Or their arbitrary combination etc..
In some embodiments, the present invention provides a kind of intermediate being used for preparing compound shown in formula (II), structure
As shown in formula (III):
Wherein, Z is-C (=O)-or-S (=O)2-。
In some embodiments, the present invention provides a kind of methods preparing the compound as shown in formula (III) comprising:
Compound shown in formula (IV) and phthalimide or o-benzoic sulfimide or their salt are subjected to substitution reaction, obtained
To compound shown in formula (III):
Wherein, R is acetyl group, and mesyl, trifyl or 4- replace benzenesulfonyl, wherein the 4- substitutions
Substituent group in benzenesulfonyl is methyl, trifluoromethyl, nitro, chlorine or bromine;Z is-C (=O)-or-S (=O)2-。
The salt of phthalimide or o-benzoic sulfimide of the present invention is its sylvite or sodium salt.At some
In embodiment, the salt of the phthalimide or o-benzoic sulfimide is the sylvite of phthalimide.Another
In some embodiments, the salt of the phthalimide or o-benzoic sulfimide is the sodium of o-benzoic sulfimide
Salt, i.e. saccharin sodium.
The dosage of the salt of phthalimide or o-benzoic sulfimide of the present invention is chemical combination shown in formula (IV)
1 times or more times of the mole of object.In some embodiments, the salt of the phthalimide or o-benzoic sulfimide
Dosage be 1.0~2.0 times of mole of compound shown in formula (IV).In further embodiments, the phthalyl
The salt of imines or o-benzoic sulfimide is the sylvite of phthalimide, and dosage is rubbing for compound shown in formula (IV)
1.0~2.0 times of that amount;In further embodiments, the salt of the phthalimide or o-benzoic sulfimide is
The sylvite of phthalimide, dosage are 1.2 times or 1.5 times of the mole of compound shown in formula (IV).In some realities
It applies in example, the salt of the phthalimide or o-benzoic sulfimide is the sodium salt of o-benzoic sulfimide, is used
Amount is 1.0~2.0 times of the mole of compound shown in formula (IV).In some embodiments, the phthalimide or
The salt of o-benzoic sulfimide is the sodium salt of o-benzoic sulfimide, and dosage is the mole of compound shown in formula (IV)
1.5 times.
Substitution reaction of the present invention carries out at 50 DEG C~100 DEG C;In some embodiments, the substitution reaction is 65
DEG C~90 DEG C at carry out;In another embodiment, the substitution reaction carries out at 65 DEG C;In another embodiment, described to take
Generation reaction carries out at 72 DEG C;In another embodiment, the substitution reaction carries out at 75 DEG C;In another embodiment, institute
Substitution reaction is stated to carry out at 90 DEG C.
Substitution reaction of the present invention carries out in the second polar solvent, and second polar solvent is N, N- diformazans
Base formamide, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran, acetone or combination thereof.
Substitution reaction of the present invention can be carried out directly in the absence of a catalyst, can also be in catalyst
Effect is lower to be carried out.In some embodiments, the substitution reaction carries out under the action of the first catalyst, and described
One catalyst is triethyl benzyl ammonia chloride, tetrabutylammonium chloride or potassium iodide.
In some embodiments, the present invention also provides the preparation methods of compound shown in the formula (IV) comprising following
Step:
A, compound shown in formula (VII) and 3- morpholones are subjected to coupling reaction, obtain compound shown in formula (VI);
B, compound shown in formula (VI) is deprotected under the action of fluorine reagent and obtains compound shown in formula (V);
C, in non-protonic solvent, compound shown in formula (V) is reacted with RCl, obtains chemical combination shown in formula (IV)
Object;
Wherein, Hal OTf, I, Br or Cl;R is acetyl group, and mesyl, trifyl or 4- replace benzene sulfonyl
Base, wherein the substituent group in the 4- substitutions benzenesulfonyl is methyl, trifluoromethyl, nitro, chlorine or bromine.
The preparation method of compound shown in formula (IV) of the present invention, wherein in step, the coupling reaction is 60
DEG C~140 DEG C at carry out;In some embodiments, in step, the coupling reaction carries out at 90 DEG C~130 DEG C;One
In a little embodiments, in step, the coupling reaction carries out at 100 DEG C~130 DEG C;In some embodiments, in step A
In, the coupling reaction carries out at 90 DEG C~120 DEG C;In further embodiments, in step, the coupling reaction exists
It is carried out at 115 DEG C~118 DEG C.In further embodiments, temperature of the coupling reaction described in step A when reaction dissolvent flows back
Degree is lower to carry out, and the reflux temperature is slightly changed according to the difference of specific reaction condition;In further embodiments, step
Coupling reaction described in A carries out under the reflux temperature of toluene.
The preparation method of compound shown in formula (IV) of the present invention, wherein the coupling reaction described in step A is in third
It is carried out in polar solvent, the third polar solvent can be:N,N-Dimethylformamide, dimethyl sulfoxide, N- crassitudes
Ketone, toluene, dioxane, tetrahydrofuran, dimethylbenzene, glycol dimethyl ether or combination thereof.
The preparation method of compound shown in formula (IV) of the present invention, wherein the coupling reaction described in step A is second
It is carried out under the action of alkali, second alkali is potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate, sodium phosphate or combination thereof.
The preparation method of compound shown in formula (IV) of the present invention, wherein the coupling reaction described in step A is second
It being carried out under the action of catalyst, second catalyst includes the metallic catalyst that common promotion coupling reaction carries out, including
Palladium catalyst, rhodium catalyst, Raney nickel or copper catalyst etc..In some embodiments, the second catalyst of the present invention is
Copper catalyst;In further embodiments, second catalyst be copper powder, cuprous iodide, stannous chloride, cuprous sulfocyanide,
Cuprous oxide, cuprous acetate or acetylacetone copper.
The preparation method of compound shown in formula (IV) of the present invention, wherein the dosage of the second catalyst described in step A
It is 5%~20% of the mole of compound shown in formula (VII).In some embodiments, the second catalyst described in step A
Dosage is 10%~20% of the mole of compound shown in formula (VII);In further embodiments, second described in step A
The dosage of catalyst is 15% of the mole of compound shown in formula (VII).
The preparation method of compound shown in formula (IV) of the present invention, wherein coupling reaction described in step A with
It is carried out in the presence of body, the ligand is common ligand in coupling reaction, wherein the use of specific ligand is according to catalyst
Type determines that the ligand to match with second catalyst is in the scope of the invention.In some embodiments, described
Ligand is 8-hydroxyquinoline, proline, sarcosine, n,N-Dimethylglycine, N, N '-dimethyl ethylenediamine, trans--
N, N '-dimethyl cyclohexanediamine or N, N- dimethyl-ethylenediamine.
The preparation method of compound shown in formula (IV) of the present invention, wherein the dosage of the ligand described in step A is formula
(VII) the 10%~40% of the mole of compound shown in.In some embodiments, the dosage of ligand described in step A is formula
(VII) the 20%~40% of the mole of compound shown in;In further embodiments, the dosage of ligand described in step A is
The 30% of the mole of compound shown in formula (VII).
The preparation method of compound, further comprises formula (VI) shownization in step A shown in formula (IV) of the present invention
The purification process of object is closed, the purification process includes but not limited to be beaten purifying etc..Wherein, molten used in the mashing purifying
Agent is not particularly limited, including but not limited to, dichloromethane, ethyl acetate, methanol, ethyl alcohol, isopropanol, diisopropyl ether or they
It is arbitrary combination etc..
The preparation method of compound shown in formula (IV) of the present invention, wherein step A has used copper catalyst and nitrogenous matched
Body, it is cheap, and post-process the method for taking mashing and purified, it is easy to operate, it is suitable for industrial production.
The preparation method of compound shown in formula (IV) of the present invention, wherein the fluorine reagent described in step B is the tetrabutyl
Ammonium fluoride;Deprotection reaction described in step B carries out in quadripolarity solvent, and the quadripolarity solvent is tetrahydrofuran
Or glycol dimethyl ether etc..
The preparation method of compound shown in formula (IV) of the present invention, wherein the reaction of the step C is in certain reaction temperature
Degree is lower to carry out, and the reaction temperature is -20 DEG C~50 DEG C;In some embodiments, the reaction temperature of the step C is -10
DEG C~40 DEG C;In some embodiments, the reaction temperature of the step C is -10 DEG C~20 DEG C;In further embodiments, institute
The reaction temperature for stating step C is 0 DEG C~20 DEG C;In further embodiments, the reaction of the step C at ambient temperature into
Row.
The preparation method of compound shown in formula (IV) of the present invention, wherein the RCl in the step C is -20 DEG C~10
It is added dropwise at DEG C in the solution of compound shown in formula (V);In some embodiments, the RCl in the step C is at -10 DEG C~0 DEG C
Under be added dropwise in the solution of compound shown in formula (V);In further embodiments, the RCl in the step C is under condition of ice bath
It is added dropwise in the solution of compound shown in formula (V).
The preparation method of compound shown in formula (IV) of the present invention, wherein the reaction in the step C is in third alkali
In the presence of carry out, the third alkali is triethylamine, n,N-diisopropylethylamine, pyridine or combination thereof.
The preparation method of compound shown in formula (IV) of the present invention, wherein the aprotic described in the step C is molten
Agent is dichloromethane, tetrahydrofuran, n,N-Dimethylformamide, ether or combination thereof.
The preparation method of compound shown in formula (IV) of the present invention, wherein the reaction of the step C can not urged
It directly carries out, can also carry out under the effect of the catalyst in the presence of agent.In some embodiments, in the step C
Reaction carries out in the presence of third catalyst, and the third catalyst is 4-dimethylaminopyridine.
The preparation method of compound shown in formula (IV) of the present invention, wherein the method for mashing can be taken to step B institutes
Compound is purified shown in formula (IV) obtained by compound and step C shown in the formula (V) obtained, is avoided using column chromatography purifying etc.
More complex operation.Wherein, solvent used in the mashing is not particularly limited, including but not limited to, dichloromethane, acetic acid
Ethyl ester, methanol, ethyl alcohol, isopropanol, diisopropyl ether or their arbitrary combination etc..
Definition and general terms
" room temperature " refers to temperature by about 10 DEG C to about 40 DEG C in the present invention.In some embodiments, " room temperature " refers to
Be temperature by about 20 DEG C to about 30 DEG C;In other embodiments, " room temperature " refers to 20 DEG C, 22.5 DEG C, 25 DEG C,
27.5 DEG C etc..
In the context of the present invention, all numbers being disclosed that are approximation.The numerical value of each number has
It is possible that the differences such as 1%, 2%, 5%, 7%, 8% or 10%.Whenever disclosing a number with N values, any tool
There is the number within N+/- 1%, N+/- 2%, N+/- 3%, N+/- 5%, N+/- 7%, N+/- 8% or the values of N+/- 10% can be bright
It is really open, wherein " +/- " refers to adding deduct.Whenever disclosing a lower limit in a numberical range, DL and upper limit,
DU, when, any numerical value within the scope of the disclosed can be specifically disclosed.
All reaction steps reaction of the present invention is more than to a certain extent as consumption of raw materials is approximately greater than 70%
80%, it is more than 90%, is more than 95%, or post-processed after reaction raw materials have been exhausted after testing, it is such as cooling, it collects,
Extraction is filtered, separation, purified treatment or combinations thereof.Conventional method such as thin layer chromatography (TLC), efficient liquid phase can be passed through
The methods of chromatography (HPLC), gas chromatography (GC) detect the extent of reaction.May be used conventional method to reaction solution into
Row post-processing is direct plungeed into and is reacted in next step for example, by collecting crude product after reduction vaporization or conventional distil-lation reaction dissolvent;
Or crude product is directly obtained by filtration, it direct plunges into and reacts in next step;Or after standing, supernatant liquor is poured out and obtains crude product, directly
Input is connect to react in next step;Or selection organic solvent appropriate or combinations thereof is extracted, and is distilled, crystallization, column chromatography, rinse,
The purification steps such as mashing.
Each dropwise addition process of the present invention and each step reaction carry out under the conditions of certain temperature, Ren Heshi
Conjunction is used in each dropwise addition process or the temperature of each reaction process is included in the present invention.In addition, many of this field similar change
It is dynamic, equivalent replacement, or it is equal to temperature and temperature range described in the invention, it is accordingly to be regarded as the scope of the present invention.This hair
It is bright to give the preferable temperature of each dropwise addition process or temperature range, and respectively react preferable reaction temperature.
Solvent is not particularly limited used in each reaction step of the present invention, any to dissolve to a certain extent
Starting material and do not inhibit reaction solvent be included in the present invention.In addition, many similar changes of this field, are equally replaced
It changes, or is equal to solvent described in the invention, the different proportion of solvent combination and solvent combination is accordingly to be regarded as the packet of the present invention
Containing range.The present invention gives preferable solvents used in each reaction step.
Recrystallization solvent used in the present invention is not particularly limited, it is any can dissolve to a certain extent crude product and
The solvent that crystallization can be precipitated under certain condition is included in the present invention.In addition, many similar changes of this field, are equally replaced
It changes, or is equal to solvent described in the invention, the different proportion of solvent combination and solvent combination is accordingly to be regarded as the packet of the present invention
Containing range.Wherein, the solvent can be alcohols, ethers, alkanes, halogenated hydrocarbon, esters, ketone, aromatic hydrocarbons, acetonitrile,
Acetic acid, water, DMF or combination thereof.Such as water, acetic acid, methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, uncle
Butanol, petroleum ether, pentane, n-hexane, normal heptane, hexamethylene, DMF, tetrahydrofuran, ether, isopropyl ether, dioxane, first
Base tertbutyl ether, dimethoxy, diethylene glycol dimethyl ether, triglyme, dichloromethane, 1,2- dichloroethanes, chloroform,
Carbon tetrachloride, ethyl acetate, isopropyl acetate, acetone, butanone, benzene, toluene, dimethylbenzene or combination thereof.
The content of moisture, is not particularly limited in solvent of the present invention.It is any to a certain extent can be in this hair
The bright middle solvent content used, is accordingly to be regarded as solvent of the present invention.It is small if the content of moisture in solvent approximately is less than 0.05%
In 0.1%, it is less than 0.2%, is less than 0.5%, be less than 5%, be less than 10%, be less than 25%, be less than 30%, or is 0%.
In the present invention, the similar terms such as " first ", " second " are used for description purposes only, and are not understood to indicate or imply
Relative importance or the quantity for implicitly indicating indicated technical characteristic.Define " first " as a result, the feature of " second " can
To express or implicitly include at least one this feature.In the description of the present invention, unless otherwise specifically defined,
The meaning of " plurality " is at least two, such as two, three etc..
General synthetic method
In the present specification, if there are any differences, structure to be dominant between chemical name and chemical constitution.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius (DEG C).Unless other
Aspect shows reagent purchase in goods providers such as Aladdin reagent (Shanghai) Co., Ltd., and Shanghai Ling Kai medical sci-teches are limited
Company, Shanghai De Mo Pharmaceutical Technology Co., Ltd, Beijing are coupled Science and Technology Ltd., all without by further impure when use
Change.General reagent is from Chengdu Ke Long chemical reagents factory, Taizhou Hai Chuan Chemical Co., Ltd.s, the big rich limited public affairs of development in science and technology in Sichuan
Department, Zhejiang Pu Kang Chemical Co., Ltd.s are commercially available.
Spectroscopic data of the nuclear magnetic resonance is measured by 400 nuclear magnetic resonance spectrometers of Bruker Avance, with CDC13,d6-
DMSO,CD3OD,D2O or d6Acetone is solvent (report as unit of ppm), use TMS (0ppm) or chloroform (7.25ppm) as
Reference standard.When there is multiplet, following abbreviation will be used:S (singlet, unimodal), d (doublet, bimodal),
T (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of
Doublets, quartet), and dt (doublet of triplets, double triplets), td (triplet of doublets, three pairs
Weight peak), dd (doublet of doublet of doublets, in pairs doublet), ddt (doublet of doublet of
Triplets, in pairs triplet), and dddd (doublet of doublet of doublet of doublets, in pairs double two
Weight peak).Coupling constant is indicated with hertz (Hz).
By outfit G1312A binary pumps and a G1316A TCC, (column temperature is maintained at 30 to Algorithm (MS) data
DEG C) the spectrometer of Agilent6320 series LC-MS measure, G1329A automatic samplers and G1315B DAD detectors
Applied to analysis, the sources ESI are applied to LC-MS spectrometers.
Algorithm (MS) data are by being equipped with G1311A quaternary pumps and G1316A TCC (column temperature is maintained at 30 DEG C)
6120 series LC-MS of Agilent spectrometer come what is measured, G1329A automatic samplers and G1315D DAD detectors are answered
For analyzing, the sources ESI are applied to LC-MS spectrometers.
Both the above spectrometer is provided with Agilent Zorbax SB-C18 columns, and specification is 2.1 × 30mm, 5 μm.Note
Beam product is determined by sample concentration;Flow velocity is 0.6mL/min;The peak value of HPLC is by 210nm and 254nm
UV-Vis wavelength records reading.Mobile phase is that 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid are ultrapure water-soluble
Liquid (phase B).Condition of gradient elution is as shown in table 1:
Table 1:The condition of gradient elution of Algorithm mobile phase
Time (min) | A(CH3CN, 0.1%HCOOH) | B(H2O, 0.1%HCOOH) |
0-3 | 5-100 | 95-0 |
3-6 | 100 | 0 |
6-6.1 | 100-5 | 0-95 |
6.1-8 | 5 | 95 |
Compound purifying is evaluated by 1260 high performance liquid chromatography of Agilent (HPLC).Wherein, efficient liquid phase
Chromatograph is equipped with G1311B quaternary pumps, G1329B automatic samplers, G1316A TCC (column temperature is maintained at 35 DEG C) and G1315D
DAD detectors.Chromatographic column is Agilent Zorbax Extend C18 (specification be 4.6 × 150mm, 5 μm);Flow velocity is
1.0mL/min;Detection wavelength 250nm;Mobile phase and its condition of gradient elution are as shown in table 2-5:
Table 2:HPLC mobile phases and its condition of gradient elution 1
Time (min) | A (acetonitrile) | B(H2O) |
0-10 | 30-90 | 70-10 |
10-25 | 90 | 10 |
25-26 | 10 | 90 |
26-31 | 90 | 10 |
Table 3:HPLC mobile phases and its condition of gradient elution 2
Time (min) | A (acetonitrile) | B(H2O) |
0-10 | 10-30 | 90-70 |
10-15 | 30-90 | 70-10 |
15-20 | 90 | 10 |
20-21 | 10 | 90 |
21-26 | 10 | 90 |
Table 4:HPLC mobile phases and its condition of gradient elution 3
Time (min) | A (acetonitrile) | B(H2O) |
0-15 | 10-90 | 90-10 |
15-25 | 90 | 10 |
25-26 | 10 | 90 |
26-31 | 10 | 90 |
Table 5:HPLC mobile phases and its condition of gradient elution 4
Time (min) | A (acetonitrile) | B (0.05% ammonium hydroxide (pH8.0)) |
0-8 | 10-25 | 90-75 |
8-15 | 25-75 | 75-25 |
15-20 | 75 | 25 |
20-21 | 10 | 90 |
21-26 | 10 | 90 |
The use of brief word below is through the present invention:
CDC13Deuterochloroform
D2O heavy water
DMSO-d6Deuterated dimethyl sulfoxide
K2CO3Potassium carbonate
CuI cuprous iodides
HCl hydrochloric acid
EDTA ethylenediamine tetra-acetic acids
TBAF tetrabutyl ammonium fluorides
MsCl mesyl chlorides
DIEA, DIPEA N, N- diisopropylethylamine
DMF N,N-dimethylformamides
OTf trifyls
Kg kilograms
G grams
Mg milligrams
Mol moles
Mmol mMs
L liters
ML milliliters
TLC thin-layered chromatography
HPLC high performance liquid chromatographies
Following reaction scheme describes the step of preparing disclosed compound of present invention.
Compound (8) can be prepared by the method that above-mentioned reaction scheme describes, wherein R1For halogen or C1-4Alkane
Base, R2For substituted or non-substituted heterocycle, R3For substituted or non-substituted aryl or heteroaryl, Y+For Na+Or K+, n 0,1,2
Or 3, R, Z, X have meaning of the present invention.Compound (1) and R2H is in solvent appropriate, (such as phosphorus under alkaline condition
Sour potassium, potassium carbonate or cesium carbonate etc.), catalyst (such as cuprous iodide, cuprous oxide or stannous chloride etc.) and ligand (such as N,
N '-dimethyl ethylenediamine or trans--N, N '-dimethyl cyclohexanediamine etc.) in the presence of compound (2) is obtained by the reaction.Compound
(2) in the presence of fluorine-containing reagent (such as tetra-n-butyl ammonium fluoride), in polar solvent (such as tetrahydrofuran or glycol dimethyl ether)
Deprotection generates compound (3).The work of compound (3) and RCl in alkali (such as triethylamine, N, N- diisopropylethylamine or pyridine etc.)
Compound (4) is obtained by the reaction under.With compound (5) in polar solvent, substitution occurs in a heated condition for compound (4) anti-
It should obtain compound (6).Ammonolysis reaction occurs under the action of primary amine or hydrazine for compound (6), then obtains compound at salt
(7).Compound (7) and acyl chlorides (R3C (=O) Cl) it is anti-under the existence condition of alkali (such as sodium carbonate, potassium carbonate or potassium phosphate etc.)
It should obtain compound (8).
Specific implementation method
The embodiment of the invention discloses the methods of oxazolidinones class compound processed.Those skilled in the art can use for reference this
Invention content is suitably modified technological parameter to realize.In particular, it should be pointed out that all similar substitutions and modifications are to this field
It is it will be apparent that they are considered as being included in the invention for technical staff.The method of the present invention is by preferable
Embodiment is described, related personnel obviously can not depart from the content of present invention, in spirit and scope to side as described herein
Method is modified or suitably changes and combines, to realize and apply the technology of the present invention.
For a further understanding of the present invention, the following describes the present invention in detail with reference to examples.
Embodiment
Embodiment 1 (3R, 3aS) -3- (((t-Butyldimethylsilyl) oxygen) methyl) -7- (3- oxo-morpholines) -3a, 4-
Dihydrobenzo [b] oxazoles [3,4-d] [1,4] oxazines -1 (3H) -one
By the bromo- 3- of (3R, 3aS) -7- (((t-Butyldimethylsilyl) oxygen) methyl) -3a, 4- dihydrobenzos [b] oxazoles
[3,4-d] [1,4] oxazines-1 (3H) -one (J.Med.Chem., 2011,54,7493-7502) (1.96kg, 4.70mol) and 3-
Morpholone (574g, 5.60mol) is suspended in toluene (13L), and K is added2CO3(1.31kg, 9.40mol) is added under nitrogen protection
CuI (130g, 0.70mol) and N1,N2Dimethyl ethyl -1,2- diamines (124g, 1.40mol), reaction system are heated to 115 DEG C
~118 DEG C are reacted 36 hours, HPLC tracking reactions.Reaction finishes, and is cooled to room temperature, and filtering, filtrate decompression is evaporated, and concentrate is molten
In dichloromethane (10L), 1M HCl/waters solution (10L), EDETATE SODIUM salt saturated solution (10L × 2), water (10L) are used successively
Washing, organic phase decompression boil off solvent, and crude product is beaten with isopropanol (2L) and is purified, obtain white solid (1.86kg,
91.5%)
MS(ESI,pos.ion)m/z:435.2(M+1);
1H NMR(400MHz,CDCl3)δ:8.03 (d, J=8.7Hz, 1H), 6.99 (d, J=1.9Hz, 1H), 6.94 (dd,
J=8.7,1.9Hz, 1H), 4.46 (dd, J=10.4,3.1Hz, 1H), 4.33 (s, 2H), 4.31-4.26 (m, 1H), 4.15-
4.08(m,1H),4.06–3.99(m,2H),3.96–3.86(m,3H),3.75–3.69(m,2H),0.90(s,9H),0.11(d,
J=2.6Hz, 6H)
Embodiment 2 (3R, 3aS) -3- (methylol) -7- (3- oxo-morpholines) -3a, 4- dihydrobenzos [b] oxazoles [3,4-
D] [1,4] oxazines -1 (3H) -one
By (3R, 3aS) -3- (((t-Butyldimethylsilyl) oxygen) methyl) -7- (3- oxo-morpholines) -3a, 4- dihydros
[[Isosorbide-5-Nitrae] oxazines -1 (3H) -one (1.86kg, 4.30mol) is dissolved in tetrahydrofuran (5L) b] oxazoles [3,4-d] benzo, at room temperature
The TBAF tetrahydrofuran solutions (4.70L, 4.70mol) of 1M are added;It is added dropwise, stirs 1 hour at room temperature, TLC tracking reactions.
Reaction finishes, and is concentrated under reduced pressure, obtains oily liquids.Water (7L) is added into oily liquids under stiring, continues stirring 30 minutes,
Filter, filter cake wash with cold water (1L), and crude product is beaten purifying with isopropanol (3L), obtain white solid (1.35kg,
98.0%).
MS(ESI,pos.ion)m/z:321.1(M+1);
1H NMR(400MHz,DMSO-d6)δ:7.85 (d, J=8.7Hz, 1H), 7.05 (d, J=2.2Hz, 1H), 7.01
(dd, J=8.7,2.3Hz, 1H), 5.31 (s, 1H), 4.59-4.51 (m, 1H), 4.47-4.41 (m, 1H), 4.18 (s, 2H),
4.07–3.98(m,2H),3.98–3.91(m,2H),3.80–3.64(m,4H).
Embodiment 3 ((3R, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,
4-d] [1,4] oxazine -3- bases) methylmethanesulfonate ester
By (3R, 3aS) -3- (methylol) -7- (3- oxo-morpholines) -3a, 4- dihydrobenzos [b] oxazoles [3,4-d] [1,
4] oxazines -1 (3H) -one (1.35kg, 4.20mol) and DIPEA (1.09kg, 8.43mol) are added to dry DMF (6.5L)
In, in ice bath, MsCl (530g, 4.60mol) is slowly added dropwise under nitrogen protection, is added dropwise, continuation reacts 30 in ice bath
Minute, being warming up to room temperature, the reaction was continued 30 minutes, TLC tracking reactions.Reaction finishes, and pure water (7L) is added into system, in ice
It stirs 30 minutes, filters in bath, filter cake is beaten with isopropanol (4L) and is purified, and obtains white solid (1.55kg, 92.7%).
MS(ESI,pos.ion)m/z:399.1(M+1);
1H NMR(400MHz,DMSO-d6)δ:7.85 (d, J=8.7Hz, 1H), 7.07 (d, J=2.2Hz, 1H), 7.03
(dd, J=8.7,2.3Hz, 1H), 4.83-4.75 (m, 1H), 4.67-4.54 (m, 3H), 4.18 (s, 2H), 4.11-4.03 (m,
2H),3.98–3.92(m,2H),3.73–3.65(m,2H),3.28(s,3H).
4 2- of embodiment (((3S, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles
[3,4-d] [1,4] oxazine -3- bases) methyl) isoindoline -1,3- diketone
Method 1:
Potassium phthalimide (1.08kg, 5.84mol) is scattered in dry DMF (12L), is warming up to 72
DEG C, ((3R, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4-d] [Isosorbide-5-Nitrae] are added
Oxazine -3- bases) methylmethanesulfonate ester (1.55kg, 3.89mol), keep temperature to continue stirring 3 hours, HPLC tracking reactions.Instead
It should finish, system is cooled to 20 DEG C, water (12L) is added, white solid is precipitated, continues stirring 1 hour, is filtered, filter cake second
Alcohol (2L) washs, dry, obtains white solid (1.55kg, 88.7%).MS(ESI,pos.ion)m/z:450.4(M+1);
1H NMR(400MHz,DMSO-d6)δ:7.96-7.90 (m, 2H), 7.90-7.85 (m, 2H), 7.81 (d, J=
8.7Hz, 1H), 7.05 (d, J=2.2Hz, 1H), 7.00 (dd, J=8.7,2.3Hz, 1H), 4.76-4.68 (m, 1H), 4.64
(dd, J=10.4,3.1Hz, 1H), 4.22-4.15 (m, 3H), 4.14-4.00 (m, 3H), 3.95 (t, J=5.0Hz, 2H),
3.71–3.65(m,2H).
Method 2:
By potassium phthalimide (112mg, 0.61mmol) and ((3R, 3aS) -1- oxos -7- (3- oxomorpholins
Base) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4-d] [1,4] oxazine -3- bases) methylmethanesulfonate ester (200mg,
It 0.50mmol) is scattered in DMF (2mL), is heated to 65 DEG C and reacts 3 hours, HPLC tracking reactions.Reaction finishes, and system is dropped
Water (2mL) is added to 20 DEG C in temperature, stirs 1 hour, filters, dry, obtains white solid (203mg, 74.5%).
Method 3:
By potassium phthalimide (112mg, 0.61mmol) and ((3R, 3aS) -1- oxos -7- (3- oxomorpholins
Base) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4-d] [1,4] oxazine -3- bases) methylmethanesulfonate ester (200mg,
It 0.50mmol) is scattered in DMF (2mL), is heated to 90 DEG C and reacts 3 hours, HPLC tracking reactions.Reaction finishes, and system is dropped
Water (2mL) is added to 20 DEG C in temperature, stirs 1 hour, filters, dry, obtains white solid (210mg, 78.5%).
Method 4:
By potassium phthalimide (223mg, 1.21mmol), triethyl benzyl ammonia chloride (27mg, 0.12mmol)
((3R, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4-d] [1,4] oxazines -
3- yls) methylmethanesulfonate ester (400mg, 1.01mmol) is scattered in DMF (5mL), be heated to 65 DEG C and react 3 hours, HPLC with
Track reacts.Reaction finishes, and system is cooled to 20 DEG C, water (2mL) is added, is stirred 1 hour, is filtered, dry, obtains white solid
(458mg, 85.4%).
Embodiment 5 (3S, 3aS) -3- ((1,1- titanium dioxides -3- oxos benzo [d] isothiazole -2 (3H)-yl) methyl) -7-
(3- oxo-morpholines) -3a, 4- dihydrobenzos [b] oxazoles [3,4-d] [1,4] oxazines -1 (3H) -one
By saccharin sodium (770mg, 3.75mmol) and ((3R, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4-
Tetrahydro benzo [b] oxazoles [3,4-d] [1,4] oxazine -3- bases) methylmethanesulfonate ester (1.0g, 2.51mmol) is dissolved in DMF (5mL)
In, it is heated to 75 DEG C of reactions overnight.Reaction finishes, and system is cooled to 20 DEG C, water (10mL) and ethyl acetate (10mL) is added,
After liquid separation, organic phase is dried with anhydrous sodium sulfate, crude product through column chromatography (EtOAc) purify, obtain white solid (430mg,
34%).
Embodiment 6 (3S, 3aS) -3- (amino methyl) -7- (3- oxo-morpholines) -3a, 4- dihydrobenzos [b] oxazoles [3,
4-d] [1,4] oxazines -1 (3H) -one hydrochlorides
Method 1:
By 2- (((3S, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4-
D] [1,4] oxazine -3- bases) methyl) isoindoline -1,3- diketone (2.00g, 4.45mmol) is suspended in absolute ethyl alcohol (20mL)
In, 85 DEG C are heated to, 40% methylamine water solution (1.70g, 22.27mmol) is added, continues back flow reaction 1 hour, HPLC tracking
Reaction.Reaction finishes, and is cooled to room temperature, evaporated under reduced pressure solvent, and ethyl alcohol (40mL) is added into residue, and pH is adjusted with concentrated hydrochloric acid
It to 2~3, filters, filter cake is washed with ethyl alcohol (5mL), dry, obtains white solid (1.27g, 80.2%).
MS(ESI,pos.ion)m/z:320.2(M+1);
1H NMR(400MHz,D2O)δ:7.95 (d, J=8.9Hz, 1H), 7.09-7.04 (m, 2H), 4.93-4.86 (m,
1H), 4.70 (dd, J=10.5,2.9Hz, 1H), 4.39 (s, 2H), 4.24-4.18 (m, 1H), 4.16-4.09 (m, 3H),
3.83–3.77(m,2H),3.66–3.52(m,2H).
Method 2:
By 2- (((3S, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4-
D] [1,4] oxazine -3- bases) methyl) isoindoline -1,3- diketone (3.00g, 6.68mmol) is suspended in absolute ethyl alcohol (40mL)
In, 90 DEG C are heated to, 40% methylamine water solution (1.30g, 16.70mmol) is added, continues back flow reaction 1 hour, HPLC tracking
Reaction.Reaction finishes, and is cooled to room temperature, evaporated under reduced pressure solvent, and ethyl alcohol (40mL) is added into residue, and pH is adjusted with concentrated hydrochloric acid
It to 2~3, filters, filter cake is washed with ethyl alcohol (5mL), dry, obtains white solid (1.73g, 73.0%).
Method 3:
By 2- (((3S, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4-
D] [1,4] oxazine -3- bases) methyl) isoindoline -1,3- diketone (2.00g, 4.45mmol) is suspended in absolute ethyl alcohol (20mL)
In, 85 DEG C are heated to, 40% methylamine water solution (2.40g, 31.15mmol) is added, continues back flow reaction 1 hour, HPLC tracking
Reaction.Reaction finishes, and is cooled to room temperature, evaporated under reduced pressure solvent, and ethyl alcohol (40mL) is added into residue, and pH is adjusted with concentrated hydrochloric acid
It to 2~3, filters, filter cake is washed with ethyl alcohol (5mL), obtains white solid (1.31g, 82.0%).
Method 4:
By 2- (((3S, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4-
D] [1,4] oxazine -3- bases) methyl) isoindoline -1,3- diketone (3.20g, 7.13mmol) is suspended in absolute ethyl alcohol (30mL)
In, be heated to 85 DEG C, 33% methylethylolamine solution (3.60g, 35.63mmol) be added, continue back flow reaction 1 hour, HPLC with
Track reacts.Reaction finishes, and is cooled to room temperature, evaporated under reduced pressure solvent, and ethyl alcohol (24mL) is added into residue, is adjusted with concentrated hydrochloric acid
PH to 2~3.It filters, filter cake is washed with ethyl alcohol (10mL), and crude product is beaten with dichloromethane (20mL) and is purified, and obtains white solid
(2.30g, 87.0%).
Method 5:
By 2- (((3S, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos [b] oxazoles [3,4-
D] [Isosorbide-5-Nitrae] oxazine -3- bases) methyl) isoindoline -1,3- diketone (1.55kg, 3.45mol) is suspended in absolute ethyl alcohol (6L),
It is heated to reflux, 40% methylamine water solution (1.3kg, 17.3mol) is added, continue back flow reaction 1 hour, HPLC tracking reactions.Instead
It should finish, be cooled to room temperature, evaporated under reduced pressure solvent, the addition ethyl alcohol (6L) into residue, dropwise addition concentrated hydrochloric acid, adjusting pH to 2~
3.Filter, filter cake wash with ethyl alcohol (500mL), and crude product is beaten purifying with dichloromethane (9L), obtain white solid (0.8kg,
65%).
Method 6:
By (3S, 3aS) -3- ((1,1- titanium dioxides -3- oxos benzo [d] isothiazole -2 (3H)-yl) methyl) -7- (3- oxygen
For morpholinyl) -3a, [[1,4] oxazines -1 (3H) -one (400mg, 0.82mmol) are dissolved in nothing to b] oxazoles [3,4-d] to 4- dihydrobenzos
It in water-ethanol (2mL), is heated to reflux, 33% ammonia methanol solution (320mg, 5.7mmol) is added, continue back flow reaction 1 hour.
Reaction finishes, and is cooled to room temperature, evaporated under reduced pressure solvent, and ethyl alcohol (5mL) is added into residue, and concentrated hydrochloric acid is added dropwise, and adjusts pH to 2
~3.It filters, obtains white solid (280mg, 88%).
The chloro- N- of 7 5- of embodiment (((3S, 3aS) -1- oxos -7- (3- oxo-morpholines) -1,3,3a, 4- tetrahydro benzos
[b] oxazoles [3,4-d] [1,4] oxazine -3- bases) methyl) thiophene-2-carboxamide derivatives
Method 1:
By (3S, 3aS) -3- (amino methyl) -7- (3- oxo-morpholines) -3a, 4- dihydrobenzo [b] oxazoles [3,4-d]
[- 1 (3H) -one hydrochloride (800g, 2.25mol) of Isosorbide-5-Nitrae] oxazines is dissolved in water (2.2L), and acetone (1.6L) and sodium carbonate is added
(300g, 2.83mol) is heated to 35 DEG C, be added dropwise 48% 5- chlorothiophene -2- formyl chlorides toluene solution (430g,
2.37mol);It is added dropwise, is cooled to 25 DEG C and is stirred to react 0.5 hour, TLC tracking reactions.Reaction finishes, and it is small to continue stirring 2
When, it filtering, filter cake is washed with water/acetone (1L, v/v=4/1), and crude product is recrystallized with acetic acid/water (3.8L, v/v=10/9),
Obtain white solid (8.10g, 77.6%).
MS(ESI,pos.ion)m/z:464.1(M+1);
1H NMR(400MHz,DMSO-d6)δ:8.98 (t, J=5.8Hz, 1H), 7.85 (d, J=8.7Hz, 1H), 7.71
(d, J=4.1Hz, 1H), 7.20 (d, J=4.0Hz, 1H), 7.05 (d, J=2.2Hz, 1H), 7.01 (dd, J=8.7,2.3Hz,
1H), 4.64-4.52 (m, 2H), 4.17 (s, 2H), 4.12-4.00 (m, 2H), 3.98-3.91 (m, 2H), 3.73 (t, J=
5.5Hz,2H),3.70–3.64(m,2H).
Method 2:
Sodium carbonate (3.50g, 33.0mmol) is dissolved in water (30mL), (3S, 3aS) -3- (amino methyl)-is sequentially added
7- (3- oxo-morpholines) -3a, 4- dihydrobenzos [b] oxazoles [3,4-d] [- 1 (3H) -one hydrochloride of 1,4] oxazines (10.0g,
28.1mmol) with acetone (15mL), reaction system is cooled to 0 DEG C, the chloro- 2- thiophene acyl chlorides (5.30g, 29.0mmol) of 5- are added dropwise
Toluene (18mL) solution, be added dropwise, keep 0 DEG C the reaction was continued 2 hours, TLC detection reaction.Reaction finishes, and filters, obtains
White solid (13.6g, 96.1%).
Method 3:
Sodium carbonate (5.50g, 51.9mmol) is dissolved in water (40mL), (3S, 3aS) -3- (amino methyl)-is sequentially added
7- (3- oxo-morpholines) -3a, 4- dihydrobenzos [b] oxazoles [3,4-d] [- 1 (3H) -one hydrochloride of 1,4] oxazines (15.0g,
42.3mmol) with acetone (30mL), 45 DEG C are heated to, the toluene of the chloro- 2- thiophene acyl chlorides (7.80g, 43.3mmol) of 5- is added dropwise
(20mL) solution, is added dropwise, and reaction temperature is down to 20 DEG C and is stirred 1 hour, TLC tracking reactions.Reaction finishes, and is cooled to room
Temperature filters, obtains white solid (18.3g, 93.1%).
Claims (8)
1. a kind of method preparing compound shown in formula (I) comprising:By compound shown in formula (II) and 5- chlorothiophene -2- first
Acyl chlorides carries out condensation reaction, obtains compound shown in formula (I):
Wherein, HX is hydrochloric acid;
The condensation reaction carries out in the first solvent, and first solvent is the mixed solvent of acetone and water;Described first is molten
The volume ratio of acetone and water is 1/2~3/1 in agent;The condensation reaction carries out at 0 DEG C~50 DEG C;
Wherein, compound shown in formula (II) is prepared via a method which to obtain:
(1) make compound shown in formula (III) that ammonolysis reaction occur;And
(2) product of the ammonolysis reaction is subjected to salt-forming reaction, obtains compound shown in the formula (II),
Wherein, compound shown in formula (III) obtains in the following way:By compound and phthalyl shown in formula (IV)
Imines or its salt carry out substitution reaction, obtain compound shown in formula (III):
Wherein, Z is-C (=O)-;
HX is hydrochloric acid;
R is mesyl;
The ammonolysis reaction carries out under the action of amination reagent, and the amination reagent is methylamine;
The dosage of the amination reagent is 2-10 times of the mole of compound shown in the formula (III);
The ammonolysis reaction carries out in the first polar solvent, and first polar solvent is ethyl alcohol, water or combination thereof;
The ammonolysis reaction carries out at 85 DEG C~90 DEG C;
The ammonolysis reaction further comprises that the purification process of compound shown in formula (II), the purification process are that mashing purifies;
The salt-forming reaction carries out in the 4th solvent, the 4th solvent be methanol, ethyl alcohol, isopropanol, water or they
Combination;
The salt of the phthalimide is its sylvite or sodium salt;
The dosage of the salt of the phthalimide is 1.0~2.0 times of the mole of compound shown in formula (IV);
The substitution reaction carries out in the second polar solvent, and second polar solvent is n,N-Dimethylformamide;
The substitution reaction carries out at 72 DEG C;
Wherein, method acquisition is prepared by the following procedure in compound shown in formula (IV):
A, compound shown in formula (VII) and 3- morpholones are subjected to coupling reaction, obtain compound shown in formula (VI);
B, compound shown in formula (VI) is deprotected under the action of fluorine reagent and obtains compound shown in formula (V);
C, in non-protonic solvent, compound shown in formula (V) is reacted with RCl, obtains compound shown in formula (IV);
Wherein, Hal Br;
R is mesyl;
Wherein, the coupling reaction described in step A carries out at 90 DEG C~120 DEG C;
Coupling reaction described in step A carries out under the action of the second catalyst, and second catalyst is cuprous iodide,
In, the dosage of second catalyst is 5%~20% of the mole of compound shown in formula (VII);
Coupling reaction described in step A carries out in the presence of ligand, and the ligand is N, N '-dimethyl ethylenediamine, wherein
The dosage of the ligand is 10%~40% of the mole of compound shown in formula (VII);
Coupling reaction described in step A carries out under the action of the second alkali, and second alkali is:Potassium carbonate;
Coupling reaction described in step A carries out in toluene;
Step A further comprises that the purification process of compound shown in formula (VI), the purification process are that mashing purifies.
2. according to the method described in claim 1, wherein, at 0 DEG C~50 DEG C, the 5- chlorothiophene -2- formyl chlorides are dripped
It adds in the solution of compound shown in formula (II).
3. according to the method described in claim 1, wherein, at 30 DEG C~50 DEG C, the 5- chlorothiophene -2- formyl chlorides are dripped
It adds in the solution of compound shown in formula (II).
4. according to the method described in claim 1, wherein, the condensation reaction carries out at 20 DEG C~30 DEG C.
5. according to the method described in claim 1, wherein, the volume ratio of acetone and water is 7/10~9/ in first solvent
10。
6. according to the method described in claim 1, wherein, the condensation reaction carries out in the presence of the first alkali, described
First alkali is potassium carbonate, sodium carbonate or combination thereof.
7. described pure according to the method described in claim 1, wherein, further comprise the purification process of compound shown in formula (I)
Change method is recrystallization purifying.
8. according to the method described in claim 7, wherein, the recrystallization purifying carries out in third solvent, described
Three solvents are acetic acid and water.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2014102641861 | 2014-06-14 | ||
CN201410264186 | 2014-06-14 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105693746A CN105693746A (en) | 2016-06-22 |
CN105693746B true CN105693746B (en) | 2018-09-14 |
Family
ID=54832925
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510323912.7A Active CN105693746B (en) | 2014-06-14 | 2015-06-12 | The Preparation Method And Their Intermediate of oxazolidinone compounds |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN105693746B (en) |
WO (1) | WO2015188787A1 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105085542B (en) * | 2014-05-22 | 2018-01-23 | 广东东阳光药业有限公司 | The crystal formation of oxazolidinone compounds and amorphous |
CN106478658A (en) * | 2015-08-25 | 2017-03-08 | 华北制药集团新药研究开发有限责任公司 | Crystal formation D of benzoxazoles oxazines ketone compounds WA1-089 and preparation method thereof |
CN106478661A (en) * | 2015-08-25 | 2017-03-08 | 华北制药集团新药研究开发有限责任公司 | Crystal formation E of benzoxazoles oxazines ketone compounds WA1-089 and preparation method thereof |
CN107892696A (en) * | 2017-11-07 | 2018-04-10 | 南京正亮医药科技有限公司 | A kind of pharmaceutical composition for treating old cognitive disorder |
CN114685529A (en) * | 2020-12-29 | 2022-07-01 | 中国科学院上海药物研究所 | Amorphous substance of oxazolidinone compound and preparation method and application thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102260277A (en) * | 2010-05-24 | 2011-11-30 | 中国科学院上海药物研究所 | Novel benzoxazine oxazolidinone compound as well as preparation method thereof and purpose thereof |
CN102464658A (en) * | 2010-11-03 | 2012-05-23 | 天津药物研究院 | Oxazolidinone derivative and preparation method and application thereof |
CN102746288A (en) * | 2012-07-24 | 2012-10-24 | 常州制药厂有限公司 | Preparation methods of anticoagulant and key intermediate of anticoagulant |
CN102786516A (en) * | 2012-08-21 | 2012-11-21 | 湖南师范大学 | Method for synthesizing rivaroxaban |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102004002044A1 (en) * | 2004-01-15 | 2005-08-04 | Bayer Healthcare Ag | manufacturing |
WO2006043121A1 (en) * | 2004-10-20 | 2006-04-27 | Ranbaxy Laboratories Limited | Oxazolidinone derivatives as antimicrobials |
US20140378682A1 (en) * | 2011-09-08 | 2014-12-25 | Cadila Healthcare Limited | Processes and intermediates for preparing rivaroxaban |
CN103936763B (en) * | 2013-01-18 | 2017-10-31 | 中国科学院上海药物研究所 | Oxazolidinone compounds and its production and use |
WO2015043364A1 (en) * | 2013-09-29 | 2015-04-02 | 华北制药集团新药研究开发有限责任公司 | Benzoxazoleoxazine ketone compound as blood coagulation factor xa inhibitor |
-
2015
- 2015-06-12 CN CN201510323912.7A patent/CN105693746B/en active Active
- 2015-06-12 WO PCT/CN2015/081383 patent/WO2015188787A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102260277A (en) * | 2010-05-24 | 2011-11-30 | 中国科学院上海药物研究所 | Novel benzoxazine oxazolidinone compound as well as preparation method thereof and purpose thereof |
CN102464658A (en) * | 2010-11-03 | 2012-05-23 | 天津药物研究院 | Oxazolidinone derivative and preparation method and application thereof |
CN102746288A (en) * | 2012-07-24 | 2012-10-24 | 常州制药厂有限公司 | Preparation methods of anticoagulant and key intermediate of anticoagulant |
CN102786516A (en) * | 2012-08-21 | 2012-11-21 | 湖南师范大学 | Method for synthesizing rivaroxaban |
Non-Patent Citations (1)
Title |
---|
"Design, Synthesis, and Structure-Activity Relationship Studies of Highly Potent Novel Benzoxazinyl-Oxazolidinone Antibacterial Agents";Qisheng Xin et al.;《Journal of Medicinal Chemistry》;20110928;第54卷;第7493-7502页 * |
Also Published As
Publication number | Publication date |
---|---|
CN105693746A (en) | 2016-06-22 |
WO2015188787A1 (en) | 2015-12-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105693746B (en) | The Preparation Method And Their Intermediate of oxazolidinone compounds | |
JP5049013B2 (en) | Indoline compound and method for producing the same | |
JP5314730B2 (en) | Application of bicyclic heterocyclic linking compound having antiviral function and composition containing the compound in the treatment of viral diseases | |
CN110291065A (en) | A kind of new isoindoline derivative, its pharmaceutical composition and application | |
WO2003066574A1 (en) | Aromatic amino acid derivatives and medicinal compositions | |
MX2007014380A (en) | Imidazoquinolines as lipid kinase inhibitors. | |
JP2012511017A (en) | Method for preparing quinoline derivatives | |
JP2004507533A (en) | Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and methods for their production | |
JP2013189460A (en) | Xanthine oxidase inhibitor | |
CN110092740B (en) | Fused ring compound and application thereof | |
JP2012507535A (en) | Disubstituted phthalazine hedgehog pathway antagonists | |
CN113024508A (en) | Nitrogen heterocyclic ring derivative and preparation method and application thereof | |
CN100439336C (en) | Methods for producing cyclic benzamidine derivatives | |
KR20180030913A (en) | Aryl-substituted bicyclic heteroaryl compounds | |
EA016552B1 (en) | Derivatives of 7-alkynyl-1,8-naphthyridones, preparation method thereof and use of same in therapeutics | |
CZ20012529A3 (en) | Novel amidinobenzylamide derivative and use thereof as thrombin inhibitor | |
RU2137769C1 (en) | Method of preparing epoxide | |
CN112209876B (en) | Preparation method of 3-trifluoromethyl isoquinolinone derivative | |
CN113402515B (en) | Indole compound and preparation method and application thereof | |
CN115490689B (en) | Irreversible KRAS G12C Preparation and application of inhibitor | |
CN104447548B (en) | The method for synthesizing the isoquinolin of substitution | |
JP7138246B2 (en) | Crystal form of hepatitis B surface antigen inhibitor | |
JPH08188546A (en) | Chalcone derivative | |
CN106928195B (en) | A kind of synthetic method of Dabigatran etexilate key intermediate | |
JP2021531287A (en) | Heterocyclic spiro compound as a MAGL inhibitor |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CP03 | Change of name, title or address | ||
CP03 | Change of name, title or address |
Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523000 Songshan Lake Science and Technology Industrial Park, Dongguan, Guangdong (No. 1 Industrial North Road, Hubei Industrial Park, Songshan) Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd. |