CN103183673B - The synthetic method of (S, S)-2,8-diazabicyclo [4,3,0] nonane - Google Patents
The synthetic method of (S, S)-2,8-diazabicyclo [4,3,0] nonane Download PDFInfo
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- CN103183673B CN103183673B CN201110455166.9A CN201110455166A CN103183673B CN 103183673 B CN103183673 B CN 103183673B CN 201110455166 A CN201110455166 A CN 201110455166A CN 103183673 B CN103183673 B CN 103183673B
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- compound
- acid
- nonane
- diazabicyclo
- synthetic method
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- KSCPLKVBWDOSAI-NKWVEPMBSA-N (4as,7as)-2,3,4,4a,5,6,7,7a-octahydro-1h-pyrrolo[3,4-b]pyridine Chemical compound N1CCC[C@H]2CNC[C@H]21 KSCPLKVBWDOSAI-NKWVEPMBSA-N 0.000 title claims abstract description 10
- 238000010189 synthetic method Methods 0.000 title claims description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 239000003054 catalyst Substances 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 238000000926 separation method Methods 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 9
- 150000001412 amines Chemical class 0.000 claims abstract description 8
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 7
- 229940125898 compound 5 Drugs 0.000 claims abstract description 6
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 6
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 5
- 229910015900 BF3 Inorganic materials 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 4
- 235000019260 propionic acid Nutrition 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 239000000758 substrate Substances 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- AUONNNVJUCSETH-UHFFFAOYSA-N icosanoyl icosanoate Chemical compound CCCCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCCCC AUONNNVJUCSETH-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 229940126214 compound 3 Drugs 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000005194 fractionation Methods 0.000 claims description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical group OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- UYAGPULHTNCMOT-UHFFFAOYSA-N [B].FB(F)F Chemical compound [B].FB(F)F UYAGPULHTNCMOT-UHFFFAOYSA-N 0.000 claims 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims 1
- 229910010277 boron hydride Inorganic materials 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 229940025250 camphora Drugs 0.000 claims 1
- 239000010238 camphora Substances 0.000 claims 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims 1
- 229910052737 gold Inorganic materials 0.000 claims 1
- 239000010931 gold Substances 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000011084 recovery Methods 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 229940125904 compound 1 Drugs 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000000654 additive Substances 0.000 abstract 1
- 230000000996 additive effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- -1 calcium chloride Aluminum lithium Chemical compound 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- FDHDTLFJPYRSBM-UHFFFAOYSA-N 2,3-bis(chloromethyl)pyridine Chemical compound ClCC1=CC=CN=C1CCl FDHDTLFJPYRSBM-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DFTLQVHYDAMGCG-UHFFFAOYSA-N [2-(hydroxymethyl)pyridin-3-yl]methanol Chemical compound OCC1=CC=CN=C1CO DFTLQVHYDAMGCG-UHFFFAOYSA-N 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 229960005112 moxifloxacin hydrochloride Drugs 0.000 description 2
- IDIIJJHBXUESQI-DFIJPDEKSA-N moxifloxacin hydrochloride Chemical compound Cl.COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 IDIIJJHBXUESQI-DFIJPDEKSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- MKRBAPNEJMFMHU-UHFFFAOYSA-N 1-benzylpyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1CC1=CC=CC=C1 MKRBAPNEJMFMHU-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- FCVHBUFELUXTLR-UHFFFAOYSA-N [Li].[AlH3] Chemical class [Li].[AlH3] FCVHBUFELUXTLR-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- KNVLCWQKYHCADB-UHFFFAOYSA-N chlorosulfonyloxymethane Chemical compound COS(Cl)(=O)=O KNVLCWQKYHCADB-UHFFFAOYSA-N 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000001913 cyanates Chemical class 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- NCPHGZWGGANCAY-UHFFFAOYSA-N methane;ruthenium Chemical compound C.[Ru] NCPHGZWGGANCAY-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- MXHTZQSKTCCMFG-UHFFFAOYSA-N n,n-dibenzyl-1-phenylmethanamine Chemical compound C=1C=CC=CC=1CN(CC=1C=CC=CC=1)CC1=CC=CC=C1 MXHTZQSKTCCMFG-UHFFFAOYSA-N 0.000 description 1
- XCVNDBIXFPGMIW-UHFFFAOYSA-N n-ethylpropan-1-amine Chemical compound CCCNCC XCVNDBIXFPGMIW-UHFFFAOYSA-N 0.000 description 1
- SEEYREPSKCQBBF-UHFFFAOYSA-N n-methylmaleimide Chemical compound CN1C(=O)C=CC1=O SEEYREPSKCQBBF-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 150000003456 sulfonamides Chemical group 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses the preparation method of a kind of compound 1 (S, S) 2,8 diazabicyclo [4,3,0] nonane.In existing method, all use and finally carry out chiral separation, all fail to control chirality during early stage synthesis main ring, cause last total recovery the most on the low side, had a strong impact on the synthesis cost of (S, S) 2,8 diazabicyclo [4,3,0] nonane.In organic solvent, in the presence of organic amine, benzsulfamide, under the conditions of 0 30 DEG C, prepares compound 5 with acrolein reaction to the present invention；Compound 5, in the presence of organic amine and chiral catalyst, carries out D A additive reaction with compound 4, prepares compound 6；Compound 6 is by catalytic hydrogenation, carbonyl reduction, and Deprotection, chiral separation purify the most in acid condition.The present invention fundamentally solves prior art final products and causes the problem that total recovery is low due to chiral separation, and then improves the yield of product.
Description
Technical field
The present invention relates to the preparation of Azabicyclic compound and derivant thereof, specifically a kind of (S, S)-2,8-phenodiazine
The synthetic method of miscellaneous dicyclo [4,3,0] nonane.
Background technology
(S, S)-2,8-diazabicyclo [4,3,0] nonane is colourless to light yellow viscous liquid, is synthesising bacteria anti-reflecting medicine
The important intermediate of moxifloxacin hydrochloride.Moxifloxacin hydrochloride is forth generation Development of Fluoroquinolone Antibacterials, and it has wide spectrum and resists
Bacterium effect, as the antibacterials of human and animal, can effectively treat the infection that various bacteria causes.(S, S)-2,8-bis-
The structural formula of azabicyclo [4,3,0] nonane (hereinafter referred to as compound 1) is as follows:
Patent documentation WO125425 discloses with 2, and 3-pyridinedicarboxylic acid is dehydrated in acetic anhydride, uses vinegar again with after benzylamine ammonolysis
Acid anhydride carries out cyclization；With lithium aluminium hydride reduction, carbonyl is reduced again after palladium carbon catalyst catalytic hydrogenating reduction；Finally with D-(-)-wine
Stone acid is made chiral selectors fractionation and is obtained having optically active (S, S)-2,8-diazabicyclo [4,3,0] nonane.
Patent documentation US5570597 discloses with 2, and 3-pyridinedicarboxylic acid is initiation material, carries out under hydrogen chloride is catalyzed
Esterification, the reduction of hydrogenated aluminum lithium obtains 2,3-dihydroxymethyl pyridine；React with thionyl chloride again 2,3-dichloromethyl pyridine；
React with benzsulfamide in the DMF solution of NaH again；Through hydrobromic acid, phenol, propanoic acid Deprotection；Last at catalyst action
Lower hydrogenation, chiral separation obtains compound (S, S)-octahydro-pyrrolo-[3,4-b] pyridine, and yield is 32.1%.
Patent documentation US5570597 has been made to change by patent documentation CN101514201 and patent documentation CN101657448 respectively
Enter.Patent documentation CN101514201 instead of the reducing agent hydrogenation used in patent US550597 with sodium borohydride and calcium chloride
Aluminum lithium, reductase 12,3-pyridinedicarboxylic acid methyl ester obtains 2,3-dihydroxymethyl pyridine；2,3-dichloromethyl pyridines are at potassium carbonate and iodine
With benzylamine cyclization, (4,7-is suitable)-octahydro-pyrrolo-[3, the 4-b] pyridine that hydrogenating reduction is not split, yield under change potassium effect
It is 42%.Patent documentation CN101657448 is then to be extensively that the compound Sodium ethylate used replaces NaH, replaces DMF with ethanol
Making solvent, make 2,3-dichloromethyl pyridine and the condensation of suitable substituted sulfonamide form 6-and are substituted sulfonyl-6, and 7-dihydro-
5H-pyrrolo-[3,4-b] pyridine.
Patent documentation CN1097759 discloses and with N-dimethylamino acrylic imines and N-benzyl along butyl alkene imines is
Initiation material, through alkene cycloaddition reaction, then sloughs a dimethylamine molecule；Catalyst is made successively with ruthenium charcoal and palladium charcoal, point
Twice hydrogenating reduction；With lithium aluminium hydride reduction to carbonyl reduction；Finally with D-(-)-tartaric acid makees resolution reagent chiral separation and had
There are optically active compound 1, yield about 30%.
Patent documentation US5770597 discloses with 3-alanine ethyl ester etc. as raw material: by two kinds of material dissolutions at pyridine
In be stirred at reflux, concentrate purify after successively with methyl chlorosulfuric acid, potassium cyanide replace；Through cyclization, at ZnHgCl2Carbonyl is reduced under catalysis
Base, chiral separation, debenzylation obtain target compound the most again, yield about 18%.
In above-mentioned method, all use and finally carry out chiral separation, all fail to control hands during early stage synthesis main ring
Property, causing last total recovery the most on the low side, had a strong impact on (S, S)-2, the synthesis of 8-diazabicyclo [4,3,0] nonane becomes
This.
Summary of the invention
The technical problem to be solved is the defect overcoming above-mentioned prior art to exist, it is provided that a kind of environment friend
Good, economical, high selective and (S, S)-2 of applicable industrialized production, 8-diazabicyclo [4,3,0] nonane synthetic method.
To this end, the present invention adopts the following technical scheme that: (S, S)-2, the synthesis side of 8-diazabicyclo [4,3,0] nonane
Method, its step is as follows:
A) acrylic aldehyde (compound 2) is with compound 3 in organic solvent, is catalyzed by organic amine catalyst, at 0-30 DEG C of bar
Carry out amine aldehyde condensation reaction under part and obtain compound 5；
The organic amine used is alkylamine or arylamine, such as triethylamine, methyidiethylamine, tribenzyl amine etc..In reaction
The organic solvent used is halogenated alkane, ether, ketone etc., such as dichloromethane, ether, acetone etc., the R in compound 31=methyl,
Ethyl, propyl group, isopropyl, phenyl, benzyl etc..
B) compound 5 and compound 4 are under inert gas shielding, with toluene, THF or the mixture as solvent of the former two,
It is catalyzed with organic amine and chiral catalyst, carries out D-A addition at ambient temperature and obtain chipal compounds 6；
Chiral catalyst is the cyanates such as KCN, NaCN, and chirality N-heterocyclic carbine, chirality N-heterocyclic carbine preferably under
The compound 8,9 stated,
Chiral catalyst consumption is the 5%-20% of reaction substrate, preferably 8%-12%, the R in compound 42=hydrogen, first
Base, pi-allyl, benzyl etc., R1With R2Can be the same or different.
C) chipal compounds 6 obtains compound 7 through catalytic hydrogenation, carbonyl reduction；
Reducing agent used by carbonyl reduction is metallic boron hydrides/boron trifluoride system, and wherein metallic boron hydrides is permissible
It is sodium borohydride, potassium borohydride or calcium borohydride etc.；Boron trifluoride can add in gaseous form, it is also possible to is complex
Form adds；The solvent that carbonyl reduction uses can be ether, diisopropyl ether, oxolane, 2-methyltetrahydrofuran, just oneself
Alkane, hexamethylene, petroleum ether, benzene,toluene,xylene etc., preferably oxolane, toluene；
The catalyst that catalytic hydrogenation uses is selected from palladium/carbon, Raney's nickel etc., and catalyst usage amount is the 2%-20% of substrate,
Preferably 5%-10%, the solvent that wherein catalytic hydrogenation uses is the hydrogenation atent solvents, preferably acetic acid such as acetic acid.
D) compound 7 Deprotection in acid condition, then after the separating treatment by routine, then chiral separation carries
Pure target product 1, i.e. (S, S)-2,8-diazabicyclo [4,3,0] nonane.
The reaction scheme of the present invention is as follows:
Conventional separating treatment described in the present invention can be crystallize, filter, the various conventional separation means such as extraction.
Compared with prior art, the invention have the advantages that raw material is cheap and easy to get, by specific N-heterocyclic carbine
High selective chiral intermediate is prepared in catalyst D-A addition, thus fundamentally solves prior art final products
Owing to chiral separation causes the problem that total recovery is low, and then improve the yield of product.Under suitable catalysts conditions, D-A adds
(S, the S) configuration preference become reaches more than 95%.
Detailed description of the invention
Embodiment 1
Weigh 31.4g benzsulfamide to be dissolved in 300ml oxolane, be cooled to 0 DEG C, add 10g triethylamine, stirring mixing
All with after start to drip 11.2g acrylic aldehyde, 0.5h dropping is complete, after charging, reaction temperature rises to 30 DEG C, insulation reaction
9h.It is dried with anhydrous sodium sulfate, solids removed by filtration.
Embodiment 2
In the filtrate that embodiment 1 obtains, it is passed through nitrogen, is sequentially added into 7g N-heterocyclic carbine compound 9,2gN, N-bis-different
Propylethylamine, 17.5g maleimide, stirring reaction 24h under room temperature.Concentrating under reduced pressure dries to obtain solid 47.7g, and two steps are total
Yield is 81.7%, and (S, S) isomer selective is 93%.
Embodiment 3
Under nitrogen protection, 2.4g 5% palladium/carbon, 47.7g embodiment 2 are dried solid, the 300ml acetic acid addition hydrogen obtained
Change in reactor, be passed through hydrogen and reach 9MPa to pressure, hydrogenation 10h at 80 DEG C, after being cooled to room temperature, replaces hydrogen with nitrogen
Gas.Solids removed by filtration catalyst, filtrate is adjusted pH=11-12 with the sodium hydrate aqueous solution of 20% after reclaiming acetic acid, is used
150ml × 3 chloroform extraction.Decompression Distillation recovery chloroform, vacuum drying obtains 45.6g solid, and yield is 95.0%.
Embodiment 4
In four-hole boiling flask, add solid, 150ml oxolane that 45.6g embodiment 3 obtains, stirring and dissolving, be cooled to 0
DEG C, add sodium borohydride 14.8g, keep 0 DEG C of 1h stirred below, the most slowly drip boron trifluoride ether solution 51.8g and protect
Hold temperature below 5 DEG C, drip a Bi Houji and continue insulation reaction 3h, be then warmed up to 45 DEG C of insulation 6h, be cooled to room temperature, add
100ml 2mol/L HCl solution, stirs 1h.Filter, filtrate adds 200ml toluene and 100ml 2mol/L sodium hydroxide water
Solution, after stirring 30min, stands branch vibration layer, and toluene layer anhydrous sodium sulfate is dried, and filters, and filtrate reduced in volume reclaims first
Benzene, obtains solid 38.4g, and yield is 93.1%.
Embodiment 5
The solid that 38.4g embodiment 4 obtains is dissolved in the hydrobromic acid of 150ml 48%, then in solution, adds 72ml
Propanoic acid and 14.4g phenol, be heated to reflux 8h.It is cooled to room temperature after completion of the reaction and is concentrated to dryness.Residue is dissolved in 150ml
In water, extract with the extraction of 150ml methyl tertiary butyl ether(MTBE) and 150ml ethyl acetate successively.Isolate aqueous solution, by 30% hydroxide
Sodium adjusts pH=11-12, and aqueous solution adds sodium chloride to saturated, by 100ml × 4 chloroform aqueous phase extracted.Dichloromethane subtracts after merging mutually
Obtaining 16.8g oily liquids after pushing back receipts dichloromethane, yield is 92.3%.
Embodiment 6
At 80 DEG C by 20g D-(-)-tartaric acid is dissolved in 120ml DMF, the solid of embodiment 5 gained
It is dissolved in 50ml DMF, adds after dissolving in tartaric acid/DMF solution that above-mentioned configuration is good, stir evenly, cooling
After 0 DEG C of crystallization 8h, filter and separate out solid, drain after filter cake 20ml glycol monoethyl ether drip washing.Gained filter cake proceeds to four mouthfuls
In flask, add 40ml deionized water and 100ml dichloromethane, be cooled to less than 10 DEG C, drip 30% sodium hydrate aqueous solution
Adjusting pH=9, stratification after stirring 0.5h, organic layer anhydrous sodium sulfate is dried, and filters, be concentrated under reduced pressure to give compound 1 (S,
S)-2,8-diazabicyclo [4,3,0] nonane 15.3g, yield is 911%.
Overall yield of reaction is 60.7%.
Embodiment 7
With embodiment 1,2, maleimide is changed into 35.8g N-benzylmaleimide, adds 6g azacyclo-
Carbene compound 9,2g DIPEA.Reaction obtains 65.4g solid chemical compound, and yield is 83.0%, and (S, S) is different
Structure body selectivity is 95%.
Embodiment 8
With embodiment 1,2, maleimide is changed into 20.0g N-methyl maleimide, adds 5g azacyclo-
Carbene compound 8,2gN, N-diisopropylethylamine.Reaction obtains 46.5g solid chemical compound, and yield is 76.0%, (S, S) isomery
Body selectivity is 87%.
Claims (5)
1. (S, S)-2, the synthetic method of 8-diazabicyclo [4,3,0] nonane, its step is as follows:
A) acrylic aldehyde is with compound 3 in organic solvent, is catalyzed by organic amine catalyst, carries out amine al under the conditions of 0-30 DEG C
Close reaction and obtain compound 5；
B) compound 5 and compound 4 are under inert gas shielding, with toluene, THF or the mixture as solvent of the former two, with having
Machine amine and chiral catalyst catalysis, carry out D-A addition at ambient temperature and obtain chipal compounds 6；
C) chipal compounds 6 obtains compound 7 through catalytic hydrogenation, carbonyl reduction；
D) compound 7 Deprotection in acid condition, then after the separating treatment by routine, then chiral separation purifies to obtain mesh
Mark product 1, i.e. (S, S)-2,8-diazabicyclo [4,3,0] nonane；
In above-mentioned each structural formula, R1=methyl, ethyl, propyl group, isopropyl, phenyl or benzyl；R2=hydrogen, methyl, pi-allyl or
Benzyl；
Chiral catalyst used by step b) is compound 9,
In step b), chiral catalyst consumption is the 8-12% of substrate.
Synthetic method the most according to claim 1, it is characterised in that in step c), the reducing agent used by carbonyl reduction is gold
Belonging to boron hydride/boron trifluoride system, wherein metallic boron hydrides is sodium borohydride, potassium borohydride or calcium borohydride, borontrifluoride
Boron adds in gaseous form or adds with the form of complex；The solvent that carbonyl reduction uses is ether, diisopropyl ether, tetrahydrochysene
Any one in furan, 2-methyltetrahydrofuran, normal hexane, hexamethylene, petroleum ether, benzene,toluene,xylene.
Synthetic method the most according to claim 1, it is characterised in that in step c), the catalyst that catalytic hydrogenation uses is selected from
Palladium/carbon or Raney's nickel, catalyst usage amount is the 2%-20% of substrate, and the solvent that catalytic hydrogenation uses is acetic acid.
Synthetic method the most according to claim 1, it is characterised in that in step d), the acid that Deprotection is used is salt
Any one in acid, hydrobromic acid, acetic acid, propanoic acid or the mixed acid of more than two kinds, splitting agents useful for same is tartaric acid or Camphora.
Synthetic method the most according to claim 4, it is characterised in that in step d), the acid that Deprotection is used is hydrogen bromine
Acid and the mixed acid of propanoic acid, fractionation agents useful for same be D-(-)-tartaric acid.
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