CN105693746A - Preparation method and intermediate of oxazolidinone compound - Google Patents
Preparation method and intermediate of oxazolidinone compound Download PDFInfo
- Publication number
- CN105693746A CN105693746A CN201510323912.7A CN201510323912A CN105693746A CN 105693746 A CN105693746 A CN 105693746A CN 201510323912 A CN201510323912 A CN 201510323912A CN 105693746 A CN105693746 A CN 105693746A
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- formula
- acid
- solvent
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- -1 oxazolidinone compound Chemical class 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 118
- 238000000034 method Methods 0.000 claims description 86
- 238000006243 chemical reaction Methods 0.000 claims description 79
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 78
- 239000002904 solvent Substances 0.000 claims description 76
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 59
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 59
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 55
- 229910001868 water Inorganic materials 0.000 claims description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 44
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 238000005915 ammonolysis reaction Methods 0.000 claims description 34
- 239000003054 catalyst Substances 0.000 claims description 33
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 28
- 238000005859 coupling reaction Methods 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 28
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 24
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 24
- 238000000746 purification Methods 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 22
- 239000003153 chemical reaction reagent Substances 0.000 claims description 21
- 238000006482 condensation reaction Methods 0.000 claims description 21
- 230000000694 effects Effects 0.000 claims description 20
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 19
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 18
- 238000006467 substitution reaction Methods 0.000 claims description 18
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 16
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 16
- 239000003513 alkali Substances 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 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 239000002798 polar solvent Substances 0.000 claims description 14
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 14
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- 238000005576 amination reaction Methods 0.000 claims description 11
- 235000019253 formic acid Nutrition 0.000 claims description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 238000010009 beating Methods 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 9
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 8
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 235000011054 acetic acid Nutrition 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 8
- 239000011976 maleic acid Substances 0.000 claims description 8
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 8
- 235000006408 oxalic acid Nutrition 0.000 claims description 8
- 235000011007 phosphoric acid Nutrition 0.000 claims description 8
- 239000001117 sulphuric acid Substances 0.000 claims description 8
- 235000011149 sulphuric acid Nutrition 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 7
- 229910021529 ammonia Inorganic materials 0.000 claims description 7
- 235000011181 potassium carbonates Nutrition 0.000 claims description 7
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 7
- 235000011009 potassium phosphates Nutrition 0.000 claims description 7
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 239000001488 sodium phosphate Substances 0.000 claims description 5
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 5
- 159000000000 sodium salts Chemical class 0.000 claims description 5
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical compound O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 claims description 4
- HVZWVEKIQMJYIK-UHFFFAOYSA-N nitryl chloride Chemical compound [O-][N+](Cl)=O HVZWVEKIQMJYIK-UHFFFAOYSA-N 0.000 claims description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 4
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- ROHGINRQAFHUPY-UHFFFAOYSA-N 1-n,1-n'-dimethylcyclohexane-1,1-diamine Chemical compound CNC1(NC)CCCCC1 ROHGINRQAFHUPY-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 3
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 claims description 3
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 150000002576 ketones Chemical class 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
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- 235000011008 sodium phosphates Nutrition 0.000 claims description 3
- 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 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 2
- 108010077895 Sarcosine Proteins 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- RFKZUAOAYVHBOY-UHFFFAOYSA-M copper(1+);acetate Chemical compound [Cu+].CC([O-])=O RFKZUAOAYVHBOY-UHFFFAOYSA-M 0.000 claims description 2
- QNZRVYCYEMYQMD-UHFFFAOYSA-N copper;pentane-2,4-dione Chemical compound [Cu].CC(=O)CC(C)=O QNZRVYCYEMYQMD-UHFFFAOYSA-N 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 claims description 2
- 150000004880 oxines Chemical group 0.000 claims description 2
- 229940043230 sarcosine Drugs 0.000 claims description 2
- GVCGWXSZNUOTDW-UHFFFAOYSA-N sulfo cyanate Chemical compound OS(=O)(=O)OC#N GVCGWXSZNUOTDW-UHFFFAOYSA-N 0.000 claims description 2
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 claims 2
- 108700003601 dimethylglycine Proteins 0.000 claims 1
- 229940078490 n,n-dimethylglycine Drugs 0.000 claims 1
- 229960002429 proline Drugs 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 43
- 229960004756 ethanol Drugs 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- 239000002585 base Substances 0.000 description 18
- 238000001914 filtration Methods 0.000 description 16
- 150000003851 azoles Chemical class 0.000 description 15
- 238000010438 heat treatment Methods 0.000 description 12
- 239000012043 crude product Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 208000007536 Thrombosis Diseases 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 238000012805 post-processing Methods 0.000 description 7
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical group [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 229960000935 dehydrated alcohol Drugs 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- LFETXMWECUPHJA-UHFFFAOYSA-N methanamine;hydrate Chemical compound O.NC LFETXMWECUPHJA-UHFFFAOYSA-N 0.000 description 6
- 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 5
- 230000023555 blood coagulation Effects 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 239000010949 copper Substances 0.000 description 5
- 229910052802 copper Inorganic materials 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 4
- 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
- 238000004440 column chromatography Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 229910052763 palladium Inorganic materials 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
- DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical class NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
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- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
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- 229910052783 alkali metal Inorganic materials 0.000 description 2
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- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 2
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- 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
- JGUQDUKBUKFFRO-UHFFFAOYSA-N 1,2-dimethylglyoxyl dioxime Natural products ON=C(C)C(C)=NO JGUQDUKBUKFFRO-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 0 CC(N1c(ccc(N(CCOC2)C2=O)c2)c2OC[C@]1[C@](CNC(c1ccc(*)[s]1)=O)O)=O Chemical compound CC(N1c(ccc(N(CCOC2)C2=O)c2)c2OC[C@]1[C@](CNC(c1ccc(*)[s]1)=O)O)=O 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 235000005078 Chaenomeles speciosa Nutrition 0.000 description 1
- 240000000425 Chaenomeles speciosa Species 0.000 description 1
- 101100022323 Drosophila melanogaster Marf gene Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- IARUBEDDQGHTRC-HEIKZBPMSA-N NC[C@@H]([C@H](COc1c2)N3c1ccc2N(CCOC1)C1=O)OC3O Chemical compound NC[C@@H]([C@H](COc1c2)N3c1ccc2N(CCOC1)C1=O)OC3O IARUBEDDQGHTRC-HEIKZBPMSA-N 0.000 description 1
- RKTDHYLBPMTNRT-KPRXVCGWSA-N O=C(c1ccccc11)N(C(C2)C2([C@H](COc2c3)N4c2ccc3N(CCOC2)C2=O)OC4=O)S1(=O)=O Chemical compound O=C(c1ccccc11)N(C(C2)C2([C@H](COc2c3)N4c2ccc3N(CCOC2)C2=O)OC4=O)S1(=O)=O RKTDHYLBPMTNRT-KPRXVCGWSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 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
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 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
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 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
- 230000004913 activation Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 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
- 239000012296 anti-solvent Substances 0.000 description 1
- 229940053202 antiepileptics carboxamide derivative Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 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
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 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
- 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
- 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
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000028867 ischemia Diseases 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
- 206010025482 malaise Diseases 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- 239000000463 material Substances 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
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 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
- 230000037361 pathway Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 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
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 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
- 239000012047 saturated solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000003883 substance clean up Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 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
- 230000009424 thromboembolic effect Effects 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 238000005406 washing Methods 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of a new oxazolidinone compound, and at the same time, also discloses an important intermediate compound related with the preparation method. The preparation method provided by the invention has the advantages of cheap raw materials, mild conditions, simple operation, safety, controllability and high total yield, and is suitable for industrial production.
Description
Technical field
The present invention relates to medicinal chemistry art, it is specifically related to the chloro-N-(((3S of oxazolidinones 5-, 3aS)-1-oxo-7-(3-oxo-morpholine)-1,3,3a, 4-tetrahydro benzo [b] azoles [3,4-d] [Isosorbide-5-Nitrae] piperazine-3-base) methyl) Preparation Method And Their Intermediate of thiophene-2-carboxamide derivatives。
Background technology
Thrombotic disease and thrombotic disease, refer to that the lumen of vessels caused due to thrombosis is narrow in obturation, make main organs generation ischemia and infraction cause the various diseases of malfunction, belong to cardiovascular and cerebrovascular disease。Cardiovascular and cerebrovascular disease has become one of cause of disease that cause a disease in the whole world, fatality rate is the highest。And thrombotic disease is as the main inducing of cardiovascular and cerebrovascular disease, sickness rate is in increasing trend year by year。
Blood coagulation Xa factor is a kind of serine protease, it is possible to be thrombin by conversion of prothrombin, is the anticoagulation target spot of a great clinical value, is formed controlling thrombin and have consequence in activation blood coagulation waterfall。Blood coagulation Xa factor is positioned at the joint of inside and outside source property coagulation pathway, and the major catalytic II factor is factor converting to IIa。The bio signal existed due to coagulation process amplifies, and a blood coagulation Xa factor inhibitor can suppress the physiologic effect of 138 thrombinogen molecules, therefore, and can the formation of the effectively generation of enzyme anticoagulant and thrombosis by Xa factor anticoagulant。Effective and the special inhibitor of blood coagulation Xa factor can as potential valuable therapeutic agent to treat thromboembolic disorders。
Patent application WO2014/110971 makes public for the first time the chloro-N-(((3S of oxazolidinones 5-, 3aS)-1-oxo-7-(3-oxomorpholin-4-base)-1,3,3a, 4-tetrahydro benzo [b] azoles [3,4-d] [Isosorbide-5-Nitrae] piperazine-3-base) methyl) thiophene-2-carboxamide derivatives, shown in its structure such as formula (I)。This compound has strong anticoagulation Xa factor activity, can be used for treating thrombosis as anticoagulation medicine diseases related。
Above-mentioned patent also discloses the preparation method of compound shown in formula (I): (3R, 3aS)-7-replaces-3-(((t-Butyldimethylsilyl) oxygen) methyl)-3a, 4-dihydrobenzo [b] azoles [3, 4-d] [1, 4] there is coupling reaction in piperazine-1 (3H)-one and 3-morpholone under metal palladium catalyst and the effect containing Phosphine ligands, products therefrom is through deprotection base, sulfonylation, phthalyl replaces, intermediate (I-a) (shown in formula (I-a) compound) is obtained after aminolysis four-step reaction, finally, intermediate (I-a) and 5-chlorothiophene-2-formyl chloride generation condensation reaction, obtain compound shown in formula (I)。
In this preparation method, the yield of coupling reaction is relatively low, and the metal palladium catalyst price used is high, is unsuitable for amplifying production。Additionally, the intermediate that the method prepares (I-a) is not purified is directly used in next step condensation reaction so that the post processing difficulty of condensation reaction, and affect the yield of reaction。
Patent application WO2015/043364 also discloses that compound shown in formula (I), its preparation method, pharmaceutical composition and as anticoagulant purposes in treating and preventing thrombotic disease。Wherein, preparation method disclosed in this application also relates to intermediate (I-a) and preparation method thereof: after hydroxy activated, prepare this intermediate then through azide substitution, reduction reaction。In this synthetic method, employing severe toxicity, explosive Hydrazoic acid,sodium salt reagent, experiment is dangerous high, is unfavorable for commercial production。
Summary of the invention
The present invention relates to the preparation method of compound shown in formula (I) and important intermediate thereof, the method is simple to operate, safely controllable, and productivity is high, is suitable for industrialized production。
Present invention relates particularly to the preparation method of compound shown in formula (I): (3R, 3aS)-7-replaces-3-(((t-Butyldimethylsilyl) oxygen) methyl)-3a, 4-dihydrobenzo [b] azoles [3, 4-d] [1, 4] piperazine-1 (3H)-one is after coupling reaction, deprotection obtains (3R, 3aS)-3-(methylol)-7-(3-oxo-morpholine)-3a, 4-dihydrobenzo [b] azoles [3, 4-d] [1, 4] piperazine-1 (3H)-one, then through hydroxy activated, substitution reaction, after ammonolysis reaction, acidifying obtains (3S, 3aS)-3-(amino methyl)-7-(3-oxo-morpholine)-3a, 4-dihydrobenzo [b] azoles [3, 4-d] [1, 4] salt (shown in formula (II) compound) of piperazine-1 (3H)-one, last and 5-chlorothiophene-2-formyl chloride generation condensation reaction, obtain the chloro-N-(((3S of target compound 5-, 3aS)-1-oxo-7-(3-oxo-morpholine)-1, 3, 3a, 4-tetrahydro benzo [b] azoles [3, 4-d] [1, 4] piperazine-3-base) methyl) thiophene-2-carboxamide derivatives。
Wherein, HX is hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, malonic acid, oxalic acid, maleic acid, methanesulfonic acid or p-methyl benzenesulfonic acid。
In the preparation method that the present invention relates to, described coupling reaction employs copper catalyst, and its price relatively metal palladium catalyst is low, uses copper catalyst can reduce production cost；Meanwhile, the coupling reaction post processing under condition of the present invention is simple, and productivity is high。The method of the invention adopts first to activate and replaces (such as, phthalyl or o-benzoyl sulfonyl replace) again, and then the method for aminolysis, converts amido to hydroxyl, it is to avoid use hypertoxic, explosive reagent, safer controlled。Simultaneously, in ammonolysis reaction of the present invention, the method for the crude product acidified one-tenth salt obtained obtains corresponding salt so that the post processing of ammonolysis reaction is simpler, and obtain the midbody product that purity is high, be conducive to the control of impurity in next step reaction and the raising of productivity；Further, the intermediate salt obtained is easier to preserve。In condensation reaction in the last step, mixed solvent is used to further increase the yield of reaction；The crude product being obtained by reacting adopts recrystallization purifying, simple to operate。Generally speaking, preparation method raw material provided by the invention is cheap, with low cost, simple to operate, safely controllable, and total recovery is high；Especially intermediate (I-a) acidifying is become salt so that the process of final step reaction is simpler, productivity is higher, is particularly suitable for commercial production。
The invention still further relates to two important intermediate of compound shown in formula (I) (formula (II) and compound shown in formula (III)) and preparation method thereof。
Wherein, Z is-C (=O)-or-S (=O)2-。
On the one hand, the present invention provides one to prepare the method for compound shown in formula (I), comprising: compound shown in formula (II) and 5-chlorothiophene-2-formyl chloride are carried out condensation reaction, obtains compound shown in formula (I):
Wherein, HX is hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, malonic acid, oxalic acid, maleic acid, methanesulfonic acid or p-methyl benzenesulfonic acid。
5-chlorothiophene-2-formyl chloride of the present invention can directly drop in the solution of compound shown in formula (II), it is also possible to is configured to certain density solution with the second solvent and drips。Described second solvent is not specifically limited, and can dissolve 5-chlorothiophene-2-formyl chloride and have no effect on the solvent of reaction and be included in the present invention, and it includes but not limited to toluene or dichloromethane etc.。Described certain density solution is not specifically limited, and the solution of all each concentration not affecting reaction is included in the present invention。In certain embodiments, described certain density 5-chlorothiophene-2-formyl chloride solution is the 5-chlorothiophene-2-formyl chloride toluene solution of 48%；In further embodiments, described certain density 5-chlorothiophene-2-formyl chloride solution is the 5-chlorothiophene-2-formyl chloride toluene solution of 1.6M or 2.1M。
5-chlorothiophene-2-formyl chloride of the present invention drops in the solution of compound shown in formula (II) at 0 DEG C～50 DEG C；In certain embodiments, described 5-chlorothiophene-2-formyl chloride drops in the solution of compound shown in formula (II) at 30 DEG C～50 DEG C；In another embodiment, described 5-chlorothiophene-2-formyl chloride drops in the solution of compound shown in formula (II) at 0 DEG C；In another embodiment, described 5-chlorothiophene-2-formyl chloride drops in the solution of compound shown in formula (II) at 35 DEG C；In another embodiment, described 5-chlorothiophene-2-formyl chloride drops in the solution of compound shown in formula (II) at 45 DEG C。
Condensation reaction of the present invention carries out at 0 DEG C～50 DEG C；In certain embodiments, described condensation reaction carries out at 20 DEG C～30 DEG C；In another embodiment, described condensation reaction carries out at 0 DEG C；In another embodiment, described condensation reaction carries out at 20 DEG C；In another embodiment, described condensation reaction carries out at 25 DEG C。
Condensation reaction of the present invention carries out in the first solvent, and wherein, described first solvent is ether solvent, ketones solvent, dichloromethane, toluene, water or their combination。In certain embodiments, described first solvent is oxolane, dioxane, diisopropyl ether, methyl tertiary butyl ether(MTBE), methyl ethyl ketone, methyl iso-butyl ketone (MIBK), acetone, dichloromethane, toluene, water or their combination。In further embodiments, described first solvent is acetone, toluene, water or their combination。In further embodiments, the first solvent of the present invention is acetone, water or their combination。
In certain embodiments, the first solvent of the present invention is the mixed solvent of acetone and water, and volume ratio is 1/2～3/1, i.e. the volume ratio of acetone and water is 1:(1/3～2)。In certain embodiments, described first solvent is the mixed solvent of acetone and water, and volume ratio is 1/2～3/2, i.e. the volume ratio of acetone and water is 1:(2/3～2)。In further embodiments, described first solvent is the mixed solvent of acetone and water, and volume ratio is 7/10～9/10, i.e. the volume ratio of acetone and water is 1:(10/9～10/7)。In further embodiments, described first solvent is the mixed solvent of acetone and water, and volume ratio is 1/2,3/4 or 8/11。
Condensation reaction of the present invention is to carry out under the effect of the first alkali, and described first alkali can be organic base or inorganic base。Described organic base can be triethylamine, trimethylamine, DIPEA, N-methylmorpholine, N-methyl piperidine, pyridine or their combination。Described inorganic base includes, but are not limited to the carbonate of alkali metal or alkaline earth metal hydroxide, alkali metal or alkaline-earth metal alkyl oxide, alkali metal or alkaline-earth metal or bicarbonate or phosphate or hydrophosphate, ammonia or their combination。In certain embodiments, the first alkali of the present invention is organic base；In certain embodiments, described first alkali is inorganic base。In certain embodiments, described first alkali is triethylamine, trimethylamine, DIPEA, N-methylmorpholine, N-methyl piperidine, pyridine, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate or their combination。In certain embodiments, the first alkali of the present invention is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate or their combination。
In method of the present invention, farther including the purification process of compound shown in formula (I), described purification process includes but not limited to recrystallization purifying etc.。Wherein, described recrystallization purifying carries out in the 3rd solvent, and described 3rd solvent is not particularly limited, and any crude product that can dissolve described condensation reaction to a certain extent also can the solvent of crystallization be included in the present invention under certain condition。Described 3rd solvent includes but not limited to acetic acid, water or their combination in any etc.。In certain embodiments, described 3rd solvent is acetic acid；In further embodiments, described 3rd solvent is water；In certain embodiments, described 3rd solvent is the mixed solvent of acetic acid and water。In further embodiments, described 3rd solvent is the mixed solvent of acetic acid and water, and its volume ratio is 1/2～3/2, and namely the volume ratio of acetic acid and water is 1:(2/3～2)。The detailed process of described recrystallization includes: be suspended in the 3rd solvent by described crude product, after heating for dissolving, and cooling crystallization, or anti-solvent additive process crystallize。Such as, the crude product of embodiment 7 is suspended in acetic acid or water or their mixed solvent, after heating for dissolving, slow cooling, precipitate out solid；Or after heating for dissolving, it is simultaneously introduced another solvent (can be water or acetic acid or their mixing), then slow cooling what keep temperature, precipitates out solid。
Condensation reaction productivity of the present invention is high, and the method that post processing have employed recrystallization, and operation is simple, is suitable for amplifying production。The present invention provides this condensation reaction to amplify the embodiment of synthesis, from this experimental result it can be seen that this reaction is under condition of the present invention, amplifies production and remains to reach the productivity of 77%。
On the one hand, the present invention provides a kind of for preparing the intermediate of compound shown in formula (I), shown in its structure such as formula (II):
Wherein, HX is hydrochloric acid, hydrobromic acid, sulphuric 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 one to prepare the method for compound as shown in formula (II), comprising: (1) makes compound generation ammonolysis reaction shown in formula (III)；And the product of described ammonolysis reaction is carried out salt-forming reaction by (2), obtain compound shown in described formula (II):
Wherein, Z is-C (=O)-or-S (=O)2-；HX is hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, malonic 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 certain embodiments, described ammonolysis reaction carries out at 60 DEG C～90 DEG C；In certain embodiments, described ammonolysis reaction carries out at 85 DEG C；In further embodiments, described ammonolysis reaction carries out at 90 DEG C；In certain embodiments, described ammonolysis reaction carries out at 85 DEG C～90 DEG C。In further embodiments, described ammonolysis reaction carries out at the temperature when reaction dissolvent refluxes, and described reflux temperature is relevant to concrete reaction, is varied from according to the difference of actual conditions。In another embodiment, described ammonolysis reaction carries out under the reflux temperature of ethanol；In another embodiment, described ammonolysis reaction carries out under the reflux temperature of ethanol/water mixed solvent。
Ammonolysis reaction of the present invention is to carry out under the effect of amination reagent, and described amination reagent is ammonia, ammonia, primary amine or hydrazine。Wherein, described primary amine is methylamine, ethamine, propylamine or butylamine；Described hydrazine is hydrazine or hydrazine hydrate。
In certain embodiments, the primary amine that described ammonolysis reaction uses is methylamine, wherein, described methylamine can be certain density methylamine solution, and it includes but not limited to, certain density methylamine water solution, methylamine methanol solution, methylethylolamine solution or methylamine aqueous isopropanol etc.。In certain embodiments, described certain density methylamine solution is 40% methylamine water solution or 33% methylethylolamine solution。
In certain embodiments, the methanol solution that amination reagent is ammonia that described ammonolysis reaction uses。In certain embodiments, described amination reagent is 33% ammonia methanol solution。
It is excessive that the consumption of amination reagent of the present invention is usually, for many times of the mole of compound shown in formula (III)。In certain embodiments, the consumption of described amination reagent is shown in formula (III) 2-10 times of the mole of compound。In certain embodiments, the consumption of described amination reagent is shown in formula (III) 2-7 times of the mole of compound；In further embodiments, 2.5 times of the mole that the consumption of described amination reagent is compound shown in (III), 5.0 times or 7.0 times。
Ammonolysis reaction of the present invention carries out in the first polar solvent, and described first polar solvent is methanol, ethanol, isopropanol, water or their combination。
Salt-forming reaction of the present invention includes in the 4th solvent, the product of described ammonolysis reaction and suitable acid is reacted, obtains corresponding salt。Wherein, described 4th solvent is not specifically limited, and the product of described ammonolysis reaction can be made to be completely dissolved the solvent having no effect on into salt and be included in the present invention, and it includes, but are not limited to methanol, ethanol, isopropanol, water or their combination in any etc.。Described suitable acid is not specifically limited, and can form the acid of stable salt with the product of described ammonolysis reaction and be included in the present invention, and it includes but not limited to, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, malonic acid, oxalic acid, maleic acid, methanesulfonic acid or p-methyl benzenesulfonic acid etc.。Described salt-forming reaction can by realizing to acid mode with acid-conditioning solution pH。
In certain embodiments, salt-forming reaction of the present invention carries out in the 4th solvent, and described 4th solvent is methanol, ethanol, isopropanol, water or their combination in any。In certain embodiments, described salt-forming reaction includes reacting the product of described ammonolysis reaction with acid HX or its solution, obtains compound shown in formula (II)。In certain embodiments, described acid HX is hydrochloric acid。
In certain embodiments, the salt that the product of ammonolysis reaction of the present invention is formed is hydrochlorate, the salifying method of described hydrochlorate includes: in the 4th solvent, the product of described ammonolysis reaction becomes salt with the solution reaction of concentrated hydrochloric acid or hydrogen chloride gas or hydrochloric acid, and the solution of described hydrochloric acid includes, but are not limited to the ethyl acetate solution of hydrochloric acid。In further embodiments, the salifying method of described hydrochlorate includes: in the 4th solvent, and the product of described ammonolysis reaction reacts into salt with concentrated hydrochloric acid。In certain embodiments, the salifying method of described hydrochlorate includes: be dissolved in by the product of described ammonolysis reaction in the 4th solvent (can be methanol, ethanol, isopropanol or water etc.), then dropping concentrated hydrochloric acid is to system in acidity, prepares target hydrochloride product。Wherein, the temperature that can keep reaction system in dropping process (such as, maintains the temperature at about 0 DEG C or less than 25 DEG C or less than 40 DEG C) within the specific limits；After dropwising, it is possible to suitable reduction temperature, described salt is made to precipitate out as much as possible, it is to avoid unnecessary loss。
The product of ammonolysis reaction of the present invention is the amine that compound shown in formula (II) is corresponding, i.e. compound shown in formula (I-a)。
The product of ammonolysis reaction gained of the present invention takes into the mode purification process of salt, simple to operate, it is to avoid the more complicated operations such as column chromatography purification。, re-use after the purified process of described product meanwhile, be conducive to the control process of next step reaction and the raising of productivity。Salifying method of the present invention can prepare the salt of the high amine of purity, and its stability is high, and relatively the midbody product of amine form is easier to preserve。
The present invention adopts the methods such as making beating to be further purified compound shown in described formula (II)。Wherein, the solvent that described making beating uses is not particularly limited, and includes but not limited to, dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, diisopropyl ether or their combination in any etc.。
In certain embodiments, the present invention provides a kind of for preparing the intermediate of compound shown in formula (II), shown in its structure such as formula (III):
Wherein, Z is-C (=O)-or-S (=O)2-。
In certain embodiments; the invention provides one and prepare the method for compound as shown in formula (III); comprising: compound shown in formula (IV) and phthalimide or ortho-sulphobenzimide or their salt are carried out substitution reaction, obtain compound shown in formula (III):
Wherein, R is acetyl group, mesyl, trifyl or 4-substituted benzene sulfonyl, and wherein, the substituent group in described 4-substituted benzene sulfonyl is methyl, trifluoromethyl, nitro, chlorine or bromine；Z is-C (=O)-or-S (=O)2-。
The salt of phthalimide of the present invention or ortho-sulphobenzimide is its potassium salt or sodium salt。In certain embodiments, the salt of described phthalimide or ortho-sulphobenzimide is the potassium salt of phthalimide。In further embodiments, the salt of described phthalimide or ortho-sulphobenzimide is the sodium salt of ortho-sulphobenzimide, i.e. saccharin sodium。
The consumption of the salt of phthalimide of the present invention or ortho-sulphobenzimide is shown in formula (IV) 1 times or many times of the mole of compound。In certain embodiments, the consumption of the salt of described phthalimide or ortho-sulphobenzimide is shown in formula (IV) 1.0～2.0 times of the mole of compound。In further embodiments, the salt of described phthalimide or ortho-sulphobenzimide is the potassium salt of phthalimide, and its consumption is shown in formula (IV) 1.0～2.0 times of the mole of compound；In further embodiments, the salt of described phthalimide or ortho-sulphobenzimide is the potassium salt of phthalimide, and its consumption is 1.2 times or 1.5 times of the mole of compound shown in formula (IV)。In certain embodiments, the salt of described phthalimide or ortho-sulphobenzimide is the sodium salt of ortho-sulphobenzimide, and its consumption is shown in formula (IV) 1.0～2.0 times of the mole of compound。In certain embodiments, the salt of described phthalimide or ortho-sulphobenzimide is the sodium salt of ortho-sulphobenzimide, and its consumption is shown in formula (IV) 1.5 times of the mole of compound。
Substitution reaction of the present invention carries out at 50 DEG C～100 DEG C；In certain embodiments, described substitution reaction carries out at 65 DEG C～90 DEG C；In another embodiment, described substitution reaction carries out at 65 DEG C；In another embodiment, described substitution reaction carries out at 72 DEG C；In another embodiment, described substitution reaction carries out at 75 DEG C；In another embodiment, described substitution reaction carries out at 90 DEG C。
Substitution reaction of the present invention carries out in the second polar solvent, and described second polar solvent is DMF, dimethyl sulfoxide, acetonitrile, oxolane, acetone or their combination。
Substitution reaction of the present invention can be made directly in the absence of a catalyst, it is also possible to carries out under the effect of catalyst。In certain embodiments, described substitution reaction is to carry out under the effect of the first catalyst, and the first described catalyst is triethyl benzyl ammonia chloride, tetrabutylammonium chloride or potassium iodide。
In certain embodiments, the present invention also provides for the preparation method of compound shown in described formula (IV), and it comprises the following steps:
A, compound shown in formula (VII) and 3-morpholone are carried out coupling reaction, obtain compound shown in formula (VI)；
Shown in B, formula (VI), compound deprotection under the effect of fluorine reagent obtains compound shown in formula (V)；
C, in non-protonic solvent, compound shown in formula (V) and RCl are reacted, obtain compound shown in formula (IV)；
Wherein, Hal is OTf, I, Br or Cl；R is acetyl group, mesyl, trifyl or 4-substituted benzene sulfonyl, and wherein, the substituent group in described 4-substituted benzene sulfonyl is methyl, trifluoromethyl, nitro, chlorine or bromine。
The preparation method of compound shown in formula of the present invention (IV), wherein, in step, described coupling reaction carries out at 60 DEG C～140 DEG C；In certain embodiments, in step, described coupling reaction carries out at 90 DEG C～130 DEG C；In certain embodiments, in step, described coupling reaction carries out at 100 DEG C～130 DEG C；In certain embodiments, in step, described coupling reaction carries out at 90 DEG C～120 DEG C；In further embodiments, in step, described coupling reaction carries out at 115 DEG C～118 DEG C。In further embodiments, the coupling reaction described in step A carries out at the temperature when reaction dissolvent refluxes, and described reflux temperature is slightly changed according to the difference of concrete reaction condition；In further embodiments, the coupling reaction described in step A carries out under the reflux temperature of toluene。
The preparation method of compound shown in formula of the present invention (IV), wherein, the coupling reaction described in step A carries out in the 3rd polar solvent, and described 3rd polar solvent can be: N, dinethylformamide, dimethyl sulfoxide, N-Methyl pyrrolidone, toluene, dioxane, oxolane, dimethylbenzene, glycol dimethyl ether or their combination。
The preparation method of compound shown in formula of the present invention (IV), wherein, the coupling reaction described in step A carries out under the effect of the second alkali, and described second alkali is potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate, sodium phosphate or their combination。
The preparation method of compound shown in formula of the present invention (IV), wherein, coupling reaction described in step A carries out under the effect of the second catalyst, described 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 certain embodiments, the second catalyst of the present invention is copper catalyst；In further embodiments, described second catalyst is copper powder, Hydro-Giene (Water Science)., Cu-lyt., Cuprous sulfocyanate, Red copper oxide, cuprous acetate or acetylacetone copper。
The preparation method of compound shown in formula of the present invention (IV), wherein, the consumption of the second catalyst described in step A is shown in formula (VII) the 5%～20% of the mole of compound。In certain embodiments, the consumption of the second catalyst described in step A is shown in formula (VII) the 10%～20% of the mole of compound；In further embodiments, the consumption of the second catalyst described in step A is shown in formula (VII) the 15% of the mole of compound。
The preparation method of compound shown in formula of the present invention (IV), wherein, coupling reaction described in step A carries out under the body joined exists, described part is part conventional in coupling reaction, wherein the kind according to catalyst that uses of concrete part determines, the part matched with described second catalyst is all in the scope of the invention。In certain embodiments, described part is oxine, proline, sarcosine, DMG, N, N '-dimethyl ethylenediamine, trans-N, N '-dimethyl cyclohexanediamine or N, N-dimethyl-ethylenediamine。
The preparation method of compound shown in formula of the present invention (IV), wherein, the consumption of the part described in step A is shown in formula (VII) the 10%～40% of the mole of compound。In certain embodiments, the consumption of part described in step A is shown in formula (VII) the 20%～40% of the mole of compound；In further embodiments, the consumption of part described in step A is shown in formula (VII) the 30% of the mole of compound。
The preparation method of compound shown in formula of the present invention (IV), it farther includes the purification process of compound shown in step A Chinese style (VI), and described purification process includes but not limited to making beating purification etc.。Wherein, the solvent that described making beating purification uses is not particularly limited, and includes but not limited to, dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, diisopropyl ether or their combination in any etc.。
The preparation method of compound shown in formula of the present invention (IV), wherein, step A employs copper catalyst and containing n-donor ligand, and it is cheap, and post processing takes the method for making beating to be purified, simple to operate, it is adaptable to commercial production。
The preparation method of compound shown in formula of the present invention (IV), wherein, the fluorine reagent described in step B is tetrabutyl ammonium fluoride；Deprotection reaction described in step B carries out in quadripolarity solvent, and described quadripolarity solvent is oxolane or glycol dimethyl ether etc.。
The preparation method of compound shown in formula of the present invention (IV), wherein, the reaction of described step C carries out under certain reaction temperature, and described reaction temperature is-20 DEG C～50 DEG C；In certain embodiments, the reaction temperature of described step C is-10 DEG C～40 DEG C；In certain embodiments, the reaction temperature of described step C is-10 DEG C～20 DEG C；In further embodiments, the reaction temperature of described step C is 0 DEG C～20 DEG C；In further embodiments, the reaction of described step C carries out at ambient temperature。
The preparation method of compound shown in formula of the present invention (IV), wherein, the RCl in described step C drops in the solution of compound shown in formula (V) at-20 DEG C～10 DEG C；In certain embodiments, the RCl in described step C drops in the solution of compound shown in formula (V) at-10 DEG C～0 DEG C；In further embodiments, the RCl in described step C drops in the solution of compound shown in formula (V) under condition of ice bath。
The preparation method of compound shown in formula of the present invention (IV), wherein, the reaction in described step C is to carry out under the existence of the 3rd alkali, and described 3rd alkali is triethylamine, DIPEA, pyridine or their combination。
The preparation method of compound shown in formula of the present invention (IV), wherein, the non-protonic solvent described in described step C is dichloromethane, oxolane, DMF, ether or their combination。
The preparation method of compound shown in formula of the present invention (IV), wherein, the reaction of described step C can be made directly in the absence of a catalyst, it is also possible to carries out under the effect of catalyst。In certain embodiments, the reaction in described step C carries out under the existence of the 3rd catalyst, and described 3rd catalyst is DMAP。
The preparation method of compound shown in formula of the present invention (IV), wherein, can take the method for making beating that compound shown in the formula (IV) of compound shown in the formula (V) of step B gained and step C gained is purified, it is to avoid to use the more complicated operations such as column chromatography purification。Wherein, the solvent that described making beating uses is not particularly limited, and includes but not limited to, dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, diisopropyl ether or their combination in any etc.。
Definition and general terms
In the present invention, " room temperature " refers to temperature by about 10 DEG C to about 40 DEG C。In certain embodiments, " room temperature " refers to temperature by about 20 DEG C to about 30 DEG C；In other embodiment, " 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 numerals being disclosed that are approximation。The numerical value of each numeral likely there will be the difference such as 1%, 2%, 5%, 7%, 8% or 10%。Whenever disclosing one and having N value digital, any have N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, and N+/-8% or the numeral within N+/-10% value can be specifically disclosed, and wherein " +/-" refers to and add deduct。Whenever the lower limit disclosed in a numerical range, DL, and a upper limit, DU, time, the numerical value within any scope being in the disclosed can be specifically disclosed。
All reactions steps of the present invention are reacted to a certain degree as consumption of raw materials is approximately greater than 70%, more than 80%, more than 90%, more than 95%, or reaction raw materials carries out post processing after being exhausted after testing, such as cooling, collection, extraction, filtration, separation, purified treatment or its combination。The method detection extents of reaction such as the method such as thin layer chromatography (TLC) of routine, high performance liquid chromatography (HPLC), gas chromatography (GC) can be passed through。Reaction solution is carried out post processing by the method that can adopt routine, for instance, by being evaporated under reduced pressure or collecting crude product after conventional distil-lation reaction dissolvent, direct plunge into next step reaction；Or directly it is filtrated to get crude product, direct plunge into next step reaction；Or after standing, pour out the supernatant and obtain crude product, direct plunge into next step reaction；Or select suitable organic solvent or its combination to extract, and distillation, crystallization, column chromatography, rinse, the purification step such as making beating。
Each dropping process of the present invention and described each step reaction all carry out when uniform temperature, and any temperature being suitable for being used in each dropping process or each course of reaction is all contained in the present invention。It addition, the many similar change of this area, equivalent replacement, or it is equal to temperature described in the invention and temperature range, what be accordingly to be regarded as the present invention comprises scope。The present invention gives each dropping process preferably temperature or temperature range, and respectively react preferably reaction temperature。
The solvent that each reactions steps of the present invention uses is not particularly limited, any can dissolve to a certain extent initiation material and do not suppress reaction solvent be all contained in the present invention。It addition, the many similar change of this area, equivalent replacement, or it being equal to solvent described in the invention, solvent combines, and the different proportion of solvent combination, and what be accordingly to be regarded as the present invention comprises scope。The present invention gives the preferably solvent that each reactions steps uses。
Recrystallization solvent used in the present invention is not particularly limited, and any can dissolve crude product to a certain extent and can the solvent of crystallization be all contained in the present invention under certain condition。It addition, the many similar change of this area, equivalent replacement, or it being equal to solvent described in the invention, solvent combines, and the different proportion of solvent combination, and what be accordingly to be regarded as the present invention comprises scope。Wherein, described solvent can be alcohols, ethers, alkanes, halogenated hydrocarbon, esters, ketone, aromatic hydrocarbons, acetonitrile, acetic acid, water, DMF or their combination。Such as water, acetic acid, methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, isobutanol, the tert-butyl alcohol, petroleum ether, pentane, normal hexane, normal heptane, hexamethylene, DMF, oxolane, ether, diisopropyl ether, dioxane, methyl tertiary butyl ether(MTBE), dimethoxy, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether., dichloromethane, 1,2-dichloroethanes, chloroform, carbon tetrachloride, ethyl acetate, isopropyl acetate, acetone, butanone, benzene, toluene, dimethylbenzene or their combination。
The content of moisture in solvent of the present invention, it does not have limit especially。Any solvent that can use in the present invention to a certain extent, is accordingly to be regarded as solvent of the present invention。In solvent, the content of moisture approximately be less than 0.05%, less than 0.1%, less than 0.2%, less than 0.5%, less than 5%, less than 10%, less than 25%, less than 30%, or is 0%。
In the present invention, the similar terms such as " first ", " second " only for descriptive purposes, and it is not intended that instruction or hint relative importance or the implicit quantity indicating indicated technical characteristic。Thus, define " first ", the feature of " second " can express or implicitly include at least one this feature。In describing the invention, unless otherwise expressly limited specifically, " multiple " are meant that at least two, for instance two, three etc.。
General synthetic method
In this manual, if there is any difference between chemical name and chemical constitution, structure is dominant。
The embodiments described below, unless other aspects show that all of temperature is decided to be degree Celsius (DEG C)。Unless other aspects show, reagent is bought in goods providers such as Aladdin reagent (Shanghai) Co., Ltd., Shanghai Ling Kai Pharmaceutical Technology Co., Ltd, Shanghai De Mo Pharmaceutical Technology Co., Ltd, Beijing coupling Science and Technology Ltd., all without through being further purified during use。General reagent is from Chengdu Ke Long chemical reagent factory, Taizhou Hai Chuan Chemical Co., Ltd., and Sichuan skill Development Co., Ltd of big Boke, Zhejiang Pu Kang Chemical Co., Ltd. is commercially available。
Spectroscopic data of the nuclear magnetic resonance is measured by BrukerAvance400 nuclear magnetic resonance spectrometer, with CDC13,d6-DMSO,CD3OD,D2O or d6-acetone is solvent (report in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard。When multiplet occurs time, following abbreviation will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doubletofdoublets, quartet), dt (doubletoftriplets, double, two triplets), td (tripletofdoublets, three doublets), dd (doubletofdoubletofdoublets, doublet in pairs), ddt (doubletofdoubletoftriplets, triplet in pairs), dddd (doubletofdoubletofdoubletofdoublets, double doublet in pairs)。Coupling constant, represents with hertz (Hz)。
Algorithm (MS) data are by being equipped with what the spectrogrph of the Agilent6320 series LC-MS of G1312A binary pump and aG1316ATCC (column temperature is maintained at 30 DEG C) measured, G1329A automatic sampler and G1315BDAD detector are applied to analyze, and ESI source is applied to LC-MS spectrogrph。
Algorithm (MS) data are by being equipped with what the spectrogrph of the Agilent6120 series LC-MS of G1311A quaternary pump and G1316ATCC (column temperature is maintained at 30 DEG C) measured, G1329A automatic sampler and G1315DDAD detector are applied to analyze, and ESI source is applied to LC-MS spectrogrph。
Both the above spectrogrph is provided with AgilentZorbaxSB-C18 post, and specification is 2.1 × 30mm, 5 μm。Volume injected is to be determined by sample concentration；Flow velocity is 0.6mL/min；The UV-Vis wavelength that the peak value of HPLC is by locating at 210nm and 254nm records reading。Mobile phase be 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultra-pure water solution (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 purification is evaluated by Agilent1260 high performance liquid chromatography (HPLC)。Wherein, high performance liquid chromatograph is equipped with G1311B quaternary pump, G1329B automatic sampler, G1316ATCC (column temperature is maintained at 35 DEG C) and G1315DDAD detector。Chromatographic column is AgilentZorbaxExtendC18 (specification is 4.6 × 150mm, 5 μm)；Flow velocity is 1.0mL/min；Detection wavelength 250nm；Mobile phase and condition of gradient elution thereof are such as shown in table 2-5:
Table 2:HPLC mobile phase and condition of gradient elution 1 thereof
| 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 phase and condition of gradient elution 2 thereof
| 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 phase and condition of gradient elution 3 thereof
| 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 phase and condition of gradient elution 4 thereof
| Time (min) | A (acetonitrile) | B (0.05% ammonia (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 runs through the present invention:
CDC13Deuterochloroform
D2O heavy water
DMSO-d6Deuterated dimethyl sulfoxide
K2CO3Potassium carbonate
CuI Hydro-Giene (Water Science).
HCl salt acid
EDTA ethylenediaminetetraacetic acid
TBAF tetrabutyl ammonium fluoride
MsCl mesyl chloride
DIEA, DIPEAN, N-diisopropylethylamine
DMFN, dinethylformamide
OTf trifyl
Kg kilogram
G gram
Mg milligram
Mol mole
Mmol mM
L liter
ML milliliter
TLC thin layer chromatography
HPLC high performance liquid chromatography
Following reaction scheme describes the step of preparation disclosure compound。
Compound (8) can be prepared by the method that above-mentioned reaction scheme describes, wherein, and R1For halogen or C1-4Alkyl, R2For substituted or non-substituted heterocyclic radical, R3For substituted or non-substituted aryl or heteroaryl, Y+For Na+Or K+, n is 0,1,2 or 3, R, Z, X have implication of the present invention。Compound (1) and R2H is in suitable solvent, in the basic conditions (such as potassium phosphate, potassium carbonate or cesium carbonate etc.), at catalyst (such as Hydro-Giene (Water Science)., Red copper oxide or Cu-lyt. etc.) and part (such as N, N '-dimethyl ethylenediamine or trans-N, N '-dimethyl cyclohexanediamine etc.) existence under be obtained by reacting compound (2)。Compound (2) is in the presence of fluorine-containing reagent (such as tetra-n-butyl ammonium fluoride), and in polar solvent (such as oxolane or glycol dimethyl ether), deprotection generates compound (3)。Compound (3) and RCl are obtained by reacting compound (4) under the effect of alkali (such as triethylamine, N, N-diisopropylethylamine or pyridine etc.)。Compound (4) and compound (5), in polar solvent, occur substitution reaction to obtain compound (6) in a heated condition。Compound (6) issues raw ammonolysis reaction in the effect of primary amine or hydrazine, then becomes salt to obtain compound (7)。Compound (7) and acyl chlorides (R3C (=O) Cl) under the existence condition of alkali (such as sodium carbonate, potassium carbonate or potassium phosphate etc.), it is obtained by reacting compound (8)。
Specific implementation method
The embodiment of the invention discloses the method preparing oxazolidinones。Those skilled in the art can use for reference present invention, is suitably modified technological parameter and realizes。Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are considered as being included in the invention。The method of the present invention is described already by preferred embodiment, and method described herein substantially can be modified or suitably change and combination by related personnel in without departing from present invention, spirit and scope, realizes and applies the technology of the present invention。
In order to be further appreciated by the present invention, below in conjunction with embodiment, the present invention is described in detail。
Embodiment
Embodiment 1 (3R, 3aS)-3-(((t-Butyldimethylsilyl) oxygen) methyl)-7-(3-oxo-morpholine)-3a, 4-dihydrobenzo [b] azoles [3,4-d] [1,4] piperazine-1 (3H)-one
By (3R, 3aS) the bromo-3-of-7-(((t-Butyldimethylsilyl) oxygen) methyl)-3a, 4-dihydrobenzo [b] azoles [3,4-d] [Isosorbide-5-Nitrae] piperazine-1 (3H)-one (J.Med.Chem., 2011,54,7,493 7502) (1.96kg, 4.70mol) and 3-morpholone (574g, 5.60mol) it is suspended in toluene (13L), adds K2CO3(1.31kg, 9.40mol), adds CuI (130g, 0.70mol) and N under nitrogen protection1,N2-dimethyl ethyl-1,2-diamidogen (124g, 1.40mol), reaction system heating is reacted 36 hours to 115 DEG C～118 DEG C, and HPLC follows the tracks of reaction。React complete, being cooled to room temperature, filter, filtrate decompression is evaporated, concentrate is dissolved in dichloromethane (10L), successively with 1MHCl aqueous solution (10L), EDETATE SODIUM salt saturated solution (10L × 2), water (10L) washs, organic facies decompression boils off solvent, thick product isopropanol (2L) is pulled an oar purification, obtains white solid (1.86kg, 91.5%).
MS (ESI, pos.ion) m/z:435.2 (M+1)；
1HNMR(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-morpholine)-3a, 4-dihydrobenzo [b] azoles [3,4-d] [1,4] piperazine-1 (3H)-one
By (3R, 3aS)-3-(((t-Butyldimethylsilyl) oxygen) methyl)-7-(3-oxo-morpholine)-3a, 4-dihydrobenzo [b] azoles [3,4-d] [1,4] piperazine-1 (3H)-one (1.86kg, 4.30mol) it is dissolved in oxolane (5L), under room temperature, adds the TBAF tetrahydrofuran solution (4.70L, 4.70mol) of 1M；Dropwising, stir 1 hour under room temperature, TLC follows the tracks of reaction。React complete, concentrating under reduced pressure, obtain oily liquids。Under agitation adding water (7L) in oily liquids, continue stirring 30 minutes, sucking filtration, filter cake cold water (1L) washs, and thick product isopropanol (3L) is pulled an oar purification, obtains white solid (1.35kg, 98.0%)。
MS (ESI, pos.ion) m/z:321.1 (M+1)；
1HNMR(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-oxo-7-(3-oxo-morpholine)-1,3,3a, 4-tetrahydro benzo [b] azoles [3,4-d] [1,4] piperazine-3-base) methylmethanesulfonate ester
By (3R; 3aS)-3-(methylol)-7-(3-oxo-morpholine)-3a; 4-dihydrobenzo [b] azoles [3; 4-d] [1; 4] piperazine-1 (3H)-one (1.35kg; 4.20mol) with DIPEA (1.09kg; 8.43mol) join in dry DMF (6.5L); in ice bath, under nitrogen protection, it is slowly added dropwise MsCl (530g, 4.60mol); dropwise; continuing to react 30 minutes in ice bath, be warming up to room temperature and continue reaction 30 minutes, TLC follows the tracks of reaction。Reacting complete, add pure water (7L), stir 30 minutes, sucking filtration in ice bath in system, filter cake isopropanol (4L) is pulled an oar purification, obtains white solid (1.55kg, 92.7%)。
MS (ESI, pos.ion) m/z:399.1 (M+1)；
1HNMR(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).
Embodiment 42-(((3S, 3aS)-1-oxo-7-(3-oxo-morpholine)-1,3,3a, 4-tetrahydro benzo [b] azoles [3,4-d] [1,4] piperazine-3-base) 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, add ((3R, 3aS)-1-oxo-7-(3-oxo-morpholine)-1,3,3a, 4-tetrahydro benzo [b] azoles [3,4-d] [Isosorbide-5-Nitrae] piperazine-3-base) methylmethanesulfonate ester (1.55kg, 3.89mol), keeping temperature to continue stirring 3 hours, HPLC follows the tracks of reaction。Reacting complete, system is cooled to 20 DEG C, add water (12L), precipitate out white solid, continue stirring 1 hour, sucking filtration, filter cake ethanol (2L) washs, dry, obtains white solid (1.55kg, 88.7%)。MS (ESI, pos.ion) m/z:450.4 (M+1)；
1HNMR(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) with ((3R, 3aS)-1-oxo-7-(3-oxo-morpholine)-1,3,3a, 4-tetrahydro benzo [b] azoles [3,4-d] [Isosorbide-5-Nitrae] piperazine-3-base) methylmethanesulfonate ester (200mg, 0.50mmol) is scattered in DMF (2mL), heating to 65 DEG C of reactions 3 hours, HPLC follows the tracks of reaction。React complete, system is cooled to 20 DEG C, add water (2mL), stir 1 hour, sucking filtration, dry, obtain white solid (203mg, 74.5%)。
Method 3:
By potassium phthalimide (112mg, 0.61mmol) with ((3R, 3aS)-1-oxo-7-(3-oxo-morpholine)-1,3,3a, 4-tetrahydro benzo [b] azoles [3,4-d] [Isosorbide-5-Nitrae] piperazine-3-base) methylmethanesulfonate ester (200mg, 0.50mmol) is scattered in DMF (2mL), heating to 90 DEG C of reactions 3 hours, HPLC follows the tracks of reaction。React complete, system is cooled to 20 DEG C, add water (2mL), stir 1 hour, sucking filtration, dry, obtain white solid (210mg, 78.5%)。
Method 4:
By potassium phthalimide (223mg, 1.21mmol), triethyl benzyl ammonia chloride (27mg, 0.12mmol) with ((3R, 3aS)-1-oxo-7-(3-oxo-morpholine)-1,3,3a, 4-tetrahydro benzo [b] azoles [3,4-d] [Isosorbide-5-Nitrae] piperazine-3-base) methylmethanesulfonate ester (400mg, 1.01mmol) is scattered in DMF (5mL), heating to 65 DEG C of reactions 3 hours, HPLC follows the tracks of reaction。React complete, system is cooled to 20 DEG C, add water (2mL), stir 1 hour, sucking filtration, dry, obtain white solid (458mg, 85.4%)。
Embodiment 5 (3S, 3aS)-3-((1,1-titanium dioxide-3-oxo benzo [d] isothiazole-2 (3H)-Ji) methyl)-7-(3-oxo-morpholine)-3a, 4-dihydrobenzo [b] azoles [3,4-d] [1,4] piperazine-1 (3H)-one
By saccharin sodium (770mg, 3.75mmol) with ((3R, 3aS)-1-oxo-7-(3-oxo-morpholine)-1,3,3a, 4-tetrahydro benzo [b] azoles [3,4-d] [1,4] piperazine-3-base) methylmethanesulfonate ester (1.0g, 2.51mmol) is dissolved in DMF (5mL), heats to 75 DEG C of reactions overnight。React complete, system is cooled to 20 DEG C, add water (10mL) and ethyl acetate (10mL), after separatory, organic facies anhydrous sodium sulfate dries, and thick product is through column chromatography (EtOAc) purification, obtain white solid (430mg, 34%)。
Embodiment 6 (3S, 3aS)-3-(amino methyl)-7-(3-oxo-morpholine)-3a, 4-dihydrobenzo [b] azoles [3,4-d] [1,4] piperazine-1 (3H)-one hydrochlorate
Method 1:
By 2-(((3S, 3aS)-1-oxo-7-(3-oxo-morpholine)-1,3,3a, 4-tetrahydro benzo [b] azoles [3,4-d] [1,4] piperazine-3-base) methyl) isoindoline-1,3-diketone (2.00g, 4.45mmol) is suspended in dehydrated alcohol (20mL), and heating is to 85 DEG C, add 40% methylamine water solution (1.70g, 22.27mmol), continuing back flow reaction 1 hour, HPLC follows the tracks of reaction。React complete, be cooled to room temperature, evaporated under reduced pressure solvent, in residue, add ethanol (40mL), regulating pH to 2～3, sucking filtration with concentrated hydrochloric acid, filter cake ethanol (5mL) washs, dry, obtain white solid (1.27g, 80.2%)。
MS (ESI, pos.ion) m/z:320.2 (M+1)；
1HNMR(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-oxo-7-(3-oxo-morpholine)-1,3,3a, 4-tetrahydro benzo [b] azoles [3,4-d] [1,4] piperazine-3-base) methyl) isoindoline-1,3-diketone (3.00g, 6.68mmol) is suspended in dehydrated alcohol (40mL), and heating is to 90 DEG C, add 40% methylamine water solution (1.30g, 16.70mmol), continuing back flow reaction 1 hour, HPLC follows the tracks of reaction。React complete, be cooled to room temperature, evaporated under reduced pressure solvent, in residue, add ethanol (40mL), regulating pH to 2～3, sucking filtration with concentrated hydrochloric acid, filter cake ethanol (5mL) washs, dry, obtain white solid (1.73g, 73.0%)。
Method 3:
By 2-(((3S, 3aS)-1-oxo-7-(3-oxo-morpholine)-1,3,3a, 4-tetrahydro benzo [b] azoles [3,4-d] [1,4] piperazine-3-base) methyl) isoindoline-1,3-diketone (2.00g, 4.45mmol) is suspended in dehydrated alcohol (20mL), and heating is to 85 DEG C, add 40% methylamine water solution (2.40g, 31.15mmol), continuing back flow reaction 1 hour, HPLC follows the tracks of reaction。Reacting complete, be cooled to room temperature, evaporated under reduced pressure solvent, add ethanol (40mL) in residue, regulate pH to 2～3, sucking filtration with concentrated hydrochloric acid, filter cake ethanol (5mL) washs, and obtains white solid (1.31g, 82.0%)。
Method 4:
By 2-(((3S, 3aS)-1-oxo-7-(3-oxo-morpholine)-1,3,3a, 4-tetrahydro benzo [b] azoles [3,4-d] [1,4] piperazine-3-base) methyl) isoindoline-1,3-diketone (3.20g, 7.13mmol) is suspended in dehydrated alcohol (30mL), and heating is to 85 DEG C, add 33% methylethylolamine solution (3.60g, 35.63mmol), continuing back flow reaction 1 hour, HPLC follows the tracks of reaction。React complete, be cooled to room temperature, evaporated under reduced pressure solvent, in residue, add ethanol (24mL), regulate pH to 2～3 with concentrated hydrochloric acid。Sucking filtration, filter cake ethanol (10mL) washs, and crude product dichloromethane (20mL) is pulled an oar purification, obtains white solid (2.30g, 87.0%)。
Method 5:
By 2-(((3S, 3aS)-1-oxo-7-(3-oxo-morpholine)-1,3,3a, 4-tetrahydro benzo [b] azoles [3,4-d] [1,4] piperazine-3-base) methyl) isoindoline-1,3-diketone (1.55kg, 3.45mol) is suspended in dehydrated alcohol (6L), is heated to reflux, add 40% methylamine water solution (1.3kg, 17.3mol), continuing back flow reaction 1 hour, HPLC follows the tracks of reaction。React complete, be cooled to room temperature, evaporated under reduced pressure solvent, in residue, add ethanol (6L), drip concentrated hydrochloric acid, regulate pH to 2～3。Sucking filtration, filter cake ethanol (500mL) washs, and crude product dichloromethane (9L) is pulled an oar purification, obtains white solid (0.8kg, 65%)。
Method 6:
By (3S, 3aS)-3-((1,1-titanium dioxide-3-oxo benzo [d] isothiazole-2 (3H)-Ji) methyl)-7-(3-oxo-morpholine)-3a, 4-dihydrobenzo [b] azoles [3,4-d] [1,4] piperazine-1 (3H)-one (400mg, 0.82mmol) it is dissolved in dehydrated alcohol (2mL), it is heated to reflux, add 33% ammonia methanol solution (320mg, 5.7mmol), back flow reaction is continued 1 hour。React complete, be cooled to room temperature, evaporated under reduced pressure solvent, in residue, add ethanol (5mL), drip concentrated hydrochloric acid, regulate pH to 2～3。Sucking filtration, obtains white solid (280mg, 88%)。
The chloro-N-of embodiment 75-(((3S, 3aS)-1-oxo-7-(3-oxo-morpholine)-1,3,3a, 4-tetrahydro benzo [b] azoles [3,4-d] [1,4] piperazine-3-base) methyl) thiophene-2-carboxamide derivatives
Method 1:
By (3S, 3aS)-3-(amino methyl)-7-(3-oxo-morpholine)-3a, 4-dihydrobenzo [b] azoles [3,4-d] [1,4] piperazine-1 (3H)-one hydrochlorate (800g, 2.25mol) it is dissolved in water (2.2L), add acetone (1.6L) and sodium carbonate (300g, 2.83mol), it is heated to 35 DEG C, the toluene solution (430g, 2.37mol) of the 5-chlorothiophene-2-formyl chloride of dropping 48%；Dropwising, be cooled to 25 DEG C of stirring reactions 0.5 hour, TLC follows the tracks of reaction。React complete, continue stirring 2 hours, sucking filtration, filter cake use water/acetone (1L, v/v=4/1) washing, thick product acetic acid/water (3.8L, v/v=10/9) recrystallization, obtain white solid (8.10g, 77.6%)。
MS (ESI, pos.ion) m/z:464.1 (M+1)；
1HNMR(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:
By sodium carbonate (3.50g, 33.0mmol) be dissolved in water (30mL), it is sequentially added into (3S, 3aS)-3-(amino methyl)-7-(3-oxo-morpholine)-3a, 4-dihydrobenzo [b] azoles [3,4-d] [1,4] piperazine-1 (3H)-one hydrochlorate (10.0g, 28.1mmol) and acetone (15mL), reaction system is cooled to 0 DEG C, drips 5-chloro-2-thiophene acyl chlorides (5.30g, 29.0mmol) toluene (18mL) solution, dropwising, keep 0 DEG C to continue reaction 2 hours, TLC detects reaction。React complete, sucking filtration, obtain white solid (13.6g, 96.1%)。
Method 3:
By sodium carbonate (5.50g, 51.9mmol) be dissolved in water (40mL), it is sequentially added into (3S, 3aS)-3-(amino methyl)-7-(3-oxo-morpholine)-3a, 4-dihydrobenzo [b] azoles [3,4-d] [1,4] piperazine-1 (3H)-one hydrochlorate (15.0g, 42.3mmol) and acetone (30mL), heating, to 45 DEG C, drips 5-chloro-2-thiophene acyl chlorides (7.80g, 43.3mmol) toluene (20mL) solution, dropwising, reaction temperature is down to 20 DEG C and stirs 1 hour, TLC follows the tracks of reaction。React complete, be cooled to room temperature, sucking filtration, obtain white solid (18.3g, 93.1%)。
Claims (39)
1. prepare a method for compound shown in formula (I), comprising: compound shown in formula (II) and 5-chlorothiophene-2-formyl chloride are carried out condensation reaction, obtain compound shown in formula (I):
Wherein, HX is hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, malonic acid, oxalic acid, maleic acid, methanesulfonic acid or p-methyl benzenesulfonic acid。
2. method according to claim 1, wherein, at 0 DEG C～50 DEG C, drops to described 5-chlorothiophene-2-formyl chloride in the solution of compound shown in formula (II)。
3. method according to claim 2, wherein, at 30 DEG C～50 DEG C, drops to described 5-chlorothiophene-2-formyl chloride in the solution of compound shown in formula (II)。
4. method according to claim 1, wherein, described condensation reaction carries out at 0 DEG C～50 DEG C。
5. method according to claim 4, wherein, described condensation reaction carries out at 20 DEG C～30 DEG C。
6. method according to claim 1, wherein, described condensation reaction carries out in the first solvent, and described first solvent is ether solvent, ketones solvent, dichloromethane, toluene, water or their combination。
7. method according to claim 6, wherein, described first solvent is oxolane, dioxane, diisopropyl ether, methyl tertiary butyl ether(MTBE), methyl ethyl ketone, methyl iso-butyl ketone (MIBK), acetone, dichloromethane, toluene, water or their combination。
8. method according to claim 7, wherein, described first solvent is the mixed solvent of acetone and water。
9. method according to claim 8, wherein, in described first solvent, the volume ratio of acetone and water is 1/2～3/1。
10. method according to claim 9, wherein, in described first solvent, the volume ratio of acetone and water is 7/10～9/10。
11. method according to claim 1, wherein, described condensation reaction is to carry out under the existence of the first alkali, and described first alkali is triethylamine, trimethylamine, DIPEA, N-methylmorpholine, N-methyl piperidine, pyridine, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate or their combination。
12. method according to claim 1, wherein, farther including the purification process of compound shown in formula (I), described purification process is recrystallization purifying。
13. method according to claim 12, wherein, described recrystallization purifying carries out in the 3rd solvent, and described 3rd solvent is acetic acid, water or their combination。
14. be used for preparing an intermediate for compound shown in formula (I), shown in its structure such as formula (II):
Wherein, HX is hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, malonic acid, oxalic acid, maleic acid, methanesulfonic acid or p-methyl benzenesulfonic acid。
15. prepare a method for compound as shown in formula (II), comprising:
(1) compound generation ammonolysis reaction shown in formula (III) is made；And
(2) product of described ammonolysis reaction is carried out salt-forming reaction, obtains compound shown in described formula (II),
Wherein, Z is-C (=O)-or-S (=O)2-；
HX is hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, malonic acid, oxalic acid, maleic acid, methanesulfonic acid or p-methyl benzenesulfonic acid。
16. method according to claim 15, wherein, described ammonolysis reaction carries out at 50 DEG C～100 DEG C。
17. method according to claim 16, wherein, described ammonolysis reaction carries out at 60 DEG C～90 DEG C。
18. method according to claim 15, wherein, described ammonolysis reaction carries out under the effect of amination reagent, and described amination reagent is ammonia, ammonia, methylamine, ethamine, propylamine, butylamine, hydrazine or hydrazine hydrate。
19. method according to claim 18, wherein, the consumption of described amination reagent is shown in described formula (III) 2-10 times of the mole of compound。
20. method according to claim 15, wherein, described salt-forming reaction carries out in the 4th solvent, and described 4th solvent is methanol, ethanol, isopropanol, water or their combination。
21. method according to claim 15, it farther includes the purification process of compound shown in formula (II), and described purification process is making beating purification。
22. method according to claim 15, wherein, described ammonolysis reaction carries out in the first polar solvent, and described first polar solvent is methanol, ethanol, isopropanol, water or their combination。
23. method according to claim 15; it also includes the preparation method of compound shown in formula (III): compound shown in formula (IV) and phthalimide or ortho-sulphobenzimide or their salt are carried out substitution reaction, obtains compound shown in formula (III):
Wherein, R is acetyl group, mesyl, trifyl or 4-substituted benzene sulfonyl, and wherein, the substituent group in described 4-substituted benzene sulfonyl is methyl, trifluoromethyl, nitro, chlorine or bromine；
Z is-C (=O)-or-S (=O)2-。
24. method according to claim 23, wherein, described phthalimide or the salt of ortho-sulphobenzimide are its potassium salt or sodium salt。
25. method according to claim 23, wherein, the consumption of the salt of described phthalimide or ortho-sulphobenzimide is shown in formula (IV) 1.0～2.0 times of the mole of compound。
26. method according to claim 23, wherein, described substitution reaction carries out at 50 DEG C～100 DEG C。
27. method according to claim 26, wherein, described substitution reaction carries out at 65 DEG C～90 DEG C。
28. method according to claim 23, wherein, described substitution reaction carries out in the second polar solvent, and described second polar solvent is DMF, dimethyl sulfoxide, acetonitrile, oxolane, acetone or their combination。
29. method according to claim 23, wherein, described substitution reaction carries out under the effect of the first catalyst, and described first catalyst is triethyl benzyl ammonia chloride, tetrabutylammonium chloride or potassium iodide。
30. method according to claim 23, it also includes the preparation method of compound shown in formula (IV), it is characterised in that it comprises the following steps:
A, compound shown in formula (VII) and 3-morpholone are carried out coupling reaction, obtain compound shown in formula (VI)；
Shown in B, formula (VI), compound deprotection under the effect of fluorine reagent obtains compound shown in formula (V)；
C, in non-protonic solvent, compound shown in formula (V) and RCl are reacted, obtain compound shown in formula (IV)；
Wherein, Hal is OTf, I, Br or Cl；
R is acetyl group, mesyl, trifyl or 4-substituted benzene sulfonyl, and wherein, the substituent group in described 4-substituted benzene sulfonyl is methyl, trifluoromethyl, nitro, chlorine or bromine。
31. method according to claim 30, wherein, the coupling reaction described in step A carries out at 60 DEG C～140 DEG C。
32. method according to claim 31, wherein, described coupling reaction carries out at 90 DEG C～120 DEG C。
33. method according to claim 30, wherein, the coupling reaction described in step A carries out in the 3rd polar solvent, and described 3rd polar solvent is N, dinethylformamide, dimethyl sulfoxide, N-Methyl pyrrolidone, toluene, dioxane, oxolane, dimethylbenzene, glycol dimethyl ether or their combination。
34. method according to claim 30, wherein, the coupling reaction described in step A carries out under the effect of the second alkali, and described second alkali is: potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate, sodium phosphate or their combination。
35. method according to claim 30, wherein, the coupling reaction described in step A carries out under the effect of the second catalyst, and described second catalyst is copper powder, Hydro-Giene (Water Science)., Cu-lyt., Cuprous sulfocyanate, Red copper oxide, cuprous acetate or acetylacetone copper。
36. method according to claim 35, wherein, the consumption of described second catalyst is shown in formula (VII) the 5%～20% of the mole of compound。
37. method according to claim 30, wherein, the coupling reaction described in step A carries out under the existence of part, described part is oxine, proline, sarcosine, N, N-dimethylglycine, N, N '-dimethyl ethylenediamine, trans-N, N '-dimethyl cyclohexanediamine or N, N-dimethyl-ethylenediamine。
38. the method according to claim 37, wherein, the consumption of described part is shown in formula (VII) the 10%～40% of the mole of compound。
39. method according to claim 30, wherein, step A farther includes the purification process of compound shown in formula (VI), and described purification process is making beating purification。
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| CN2014102641861 | 2014-06-14 | ||
| CN201410264186 | 2014-06-14 |
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| CN105693746A true CN105693746A (en) | 2016-06-22 |
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| CN105085542A (en) * | 2014-05-22 | 2015-11-25 | 广东东阳光药业有限公司 | Crystal forms and amorphism of oxazolidinone compound |
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| 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 |
| 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 |
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| WO2015188787A1 (en) | 2015-12-17 |
| CN105693746B (en) | 2018-09-14 |
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