CN104163821A - Diazabicyclo compound preparation method - Google Patents
Diazabicyclo compound preparation method Download PDFInfo
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- CN104163821A CN104163821A CN201410120316.4A CN201410120316A CN104163821A CN 104163821 A CN104163821 A CN 104163821A CN 201410120316 A CN201410120316 A CN 201410120316A CN 104163821 A CN104163821 A CN 104163821A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 81
- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 239000002904 solvent Substances 0.000 claims abstract description 78
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 30
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical group 0.000 claims abstract description 7
- 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 16
- 238000001953 recrystallisation Methods 0.000 claims description 13
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000012805 post-processing Methods 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- -1 sec.-propyl Chemical group 0.000 claims description 9
- 229910001413 alkali metal ion Inorganic materials 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 230000001476 alcoholic effect Effects 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 150000002576 ketones Chemical class 0.000 claims description 7
- 230000006340 racemization Effects 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 claims description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 150000008282 halocarbons Chemical class 0.000 claims description 6
- 150000002825 nitriles Chemical class 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 229960005112 moxifloxacin hydrochloride Drugs 0.000 claims description 4
- 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 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 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 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229910052728 basic metal Inorganic materials 0.000 claims description 2
- 150000003818 basic metals Chemical class 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 229910001424 calcium ion Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 229910001416 lithium ion Inorganic materials 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 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
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229910001415 sodium ion Inorganic materials 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- 229910001414 potassium ion Inorganic materials 0.000 claims 1
- 230000003287 optical effect Effects 0.000 abstract description 12
- 150000003839 salts Chemical class 0.000 abstract description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 abstract 2
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 37
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- RRBLNPCNHNHAFW-NEPJUHHUSA-N (4ar,7as)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione Chemical compound O=C([C@H]1NCCC[C@H]1C1=O)N1CC1=CC=CC=C1 RRBLNPCNHNHAFW-NEPJUHHUSA-N 0.000 description 23
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 23
- 238000003756 stirring Methods 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- 229930182470 glycoside Natural products 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 8
- 150000002338 glycosides Chemical class 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- RRBLNPCNHNHAFW-NWDGAFQWSA-N (4as,7ar)-6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione Chemical compound O=C([C@@H]1NCCC[C@@H]1C1=O)N1CC1=CC=CC=C1 RRBLNPCNHNHAFW-NWDGAFQWSA-N 0.000 description 5
- 238000010583 slow cooling Methods 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- 229960003702 moxifloxacin Drugs 0.000 description 3
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- FNEQHKCQXDKYEO-UHFFFAOYSA-N 1-benzylpyrrole Chemical compound C1=CC=CN1CC1=CC=CC=C1 FNEQHKCQXDKYEO-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 125000005233 alkylalcohol group Chemical group 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- KSJDOQFYNPUQDU-BZWNWTOPSA-N (2r,3r,4s,5r)-2,3,4,5,6-pentahydroxyhexanoic acid;hydrate Chemical compound O.OC[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KSJDOQFYNPUQDU-BZWNWTOPSA-N 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- RRBLNPCNHNHAFW-UHFFFAOYSA-N 6-benzyl-1,2,3,4,4a,7a-hexahydropyrrolo[3,4-b]pyridine-5,7-dione Chemical compound O=C1C2CCCNC2C(=O)N1CC1=CC=CC=C1 RRBLNPCNHNHAFW-UHFFFAOYSA-N 0.000 description 1
- VTUCTUJARFDFHH-UHFFFAOYSA-N 7a-benzyl-2,3,4,4a-tetrahydro-1h-pyrrolo[3,4-b]pyridine-5,7-dione Chemical compound N1CCCC2C(=O)NC(=O)C21CC1=CC=CC=C1 VTUCTUJARFDFHH-UHFFFAOYSA-N 0.000 description 1
- 206010001076 Acute sinusitis Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The present invention discloses a diazabicyclo compound preparation method. The preparation method of a compound represented by a formula (IIIa) comprises the step of in a solvent, carrying out a salt forming reaction on a compound represented by a formula I and a resolution agent, wherein the resolution agent is a compound represented by a formula (IIa). The preparation method of a compound represented by a formula (IIIb) comprises the step of in a solvent, carrying out a salt forming reaction on the compound represented by the formula I and a resolution agent, wherein the resolution agent is a compound represented by a formula (IIb). In the compound IIa and/or IIb, R is C1-C20 alkyl, or C6-C10 aryl substituted by one or more selected from following substituents or unsubstituted C6-C10 aryl, halogen, or C1-C4 alkyl substituted by halogen or unsubstituted C1-C4 alkyl. The diazabicyclo compound prepared by the preparation method of the present invention has characteristics of high optical purity, high yield and low cost, and is suitable for industrial production. The formulas (I), (IIa), (IIb), (IIIa) and (IIIb) are shown as follows.
Description
Technical field
The present invention relates to a kind of preparation method of diazabicyclo compounds.
Background technology
Moxifloxacin hydrochloride, its structural formula is as follows, and it is that the 4th generation 8-methoxyl group quinoline is coughed up ketone antimicrobial drug, is used for the treatment of acute sinusitis, acute episode of chronic bronchitis, community acquired pneumonia and Skin and soft tissue infection.Moxifloxacin has a broad antifungal spectrum, and long half time, tissue penetration is strong, and liver, the two-way excretion of kidney have good pharmacokinetics and good security and tolerance.Moxifloxacin, was used in Discussion on Chinese Listed in Germany and U.S.'s listing in 1999 for 2002.
Bayer A.G discloses Moxifloxacin intermediate (1S in patent EP550903 in 1993, 6R)-8-benzyl-7, 9-dioxo-2, the synthetic method of 8-diazabicyclo [4.3.0] nonane, in this patent, disclose and adopted 8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane is after D-tartrate or the fractionation of L-TARTARIC ACID chemistry, obtain (1S, 6R)-8-benzyl-7, 9-dioxo-2, the D-tartrate of 8-diazabicyclo [4.3.0] nonane, then through recrystallization with after dissociating, obtain (1S, 6R)-8-benzyl-7, 9-dioxo-2, 8-diazabicyclo [4.3.0] nonane.But in this preparation method, the compound optical purity making is not high.
A kind of (1S is disclosed in US Patent No. 6566523,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4,3,0] preparation method of nonane, concrete operations are: cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane and (-)-2,3:4,6-bis-isopropylidenes-2-keto-L-gulonic acid (gulonic acid) monohydrate salify in butanone.This preparation method splits rear products therefrom, its optical purity ee99.6%, and the yield that still makes compound is low.Meanwhile, the method resolving agent price is more expensive, and resolving agent is unstable under acidic condition, is unfavorable for recovery, causes resolving agent institute's accounting in raw materials consumption too high, to scale production, makes troubles.
Summary of the invention
Technical problem to be solved by this invention is in order to overcome that the optical purity of the Moxifloxacin hydrochloride intermediate that existing preparation method makes is not high enough, yield is low, cost is high and not to be suitable for the defect of industrialized production, and a kind of preparation method of diazabicyclo compounds is provided.Diazabicyclo compounds optical purity that preparation method of the present invention makes is high, yield is high, cost is low, is more suitable for suitability for industrialized production.
The invention provides a kind of preparation method suc as formula the diazabicyclo compounds shown in IIIa or IIIb:
Wherein, the described preparation method suc as formula the compound shown in IIIa, it comprises the following step: in solvent, will carry out salt-forming reaction as follows suc as formula the compound shown in I and resolving agent, make suc as formula the compound shown in IIIa; Described resolving agent is suc as formula the compound shown in IIa;
The described preparation method suc as formula the compound shown in IIIb, it comprises the following step: in solvent, will carry out salt-forming reaction as follows suc as formula the compound shown in I and resolving agent, make suc as formula the compound shown in IIIb; Described resolving agent is suc as formula the compound shown in IIb;
In Compound I Ia and/or IIb, R is C
1～C
20alkyl, or by the one or more replacements in following substituting group or unsubstituted C
6～C
10aryl: halogen, or replaced or do not replace C by halogen
1～C
4alkyl.
Wherein, described C
1～C
20alkyl be preferably C
1～C
4alkyl.Described C
1～C
4alkyl be preferably methyl, ethyl, propyl group, sec.-propyl, n-propyl or normal-butyl.Described C
6～C
10aryl be preferably phenyl.The C of described replacement
6～C
10aryl be preferably p-methylphenyl.Described halogen is preferably fluorine, chlorine, bromine or iodine.
Wherein, described is more preferably tolysulfonyl L-benzene glycosides propylhomoserin suc as formula the compound shown in IIa, and it is a kind of good resolving agent, cheap and easy to get, and easily, to ph stability, recovery is convenient in preparation.
Wherein, suc as formula the compound shown in I, can be cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane, it is (1S, 6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane and (1R, 6S)-8-benzyl-7,9-dioxo-2, the mixture that 8-diazabicyclo [4.3.0] nonane forms.
Wherein, the described preparation method suc as formula the compound shown in IIIa or IIIb, preferably comprises the following step: in solvent, under sour existence, will carry out salt-forming reaction suc as formula the compound shown in I and resolving agent.
In preparation method suc as formula the diazabicyclo compounds shown in IIIa or IIIb, the method of described salt-forming reaction and condition can be this area this type of react conventional method and condition, and the present invention is following condition particularly preferably: described preferred solvents ground is water and/or organic solvent.Described organic solvent is preferably one or more in alcoholic solvent, esters solvent, ether solvent, ketones solvent, nitrile solvents, halogenated hydrocarbon solvent and aromatic hydrocarbon solvent.Described alcoholic solvent is preferably C
1～C
4alkyl alcohol (preferred C
1～C
4monobasic alkyl alcohol).Described C
1～C
4alkyl alcohol be preferably one or more in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol and the trimethyl carbinol.Described esters solvent is preferably one or more in ethyl acetate, isopropyl acetate and n-butyl acetate.Described ether solvent is preferably one or more in tetrahydrofuran (THF), 2-methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, ether and methyl tertiary butyl ether.Described ketones solvent is preferably one or more of acetone, butanone and 4-methyl-2 pentanone.Described nitrile solvents is preferably acetonitrile.Described halogenated hydrocarbon solvent is preferably methylene dichloride and/or 1,2-ethylene dichloride.Described aromatic hydrocarbon solvent is preferably toluene.Described acid is preferably organic acid and/or mineral acid.Described organic acid is preferably one or more in formic acid, acetic acid, propionic acid and phenylformic acid, is preferably acetic acid.Described mineral acid is preferably one or more in hydrochloric acid, phosphoric acid and sulfuric acid.The described mol ratio suc as formula the compound shown in I and described resolving agent is preferably 1:0.1～1:5, is more preferably 1:0.3～1:1.Described sour and mol ratio suc as formula the compound shown in I is preferably 0:1～10:1, is more preferably 0:1～1:1.Described solvent is 1mL/g～50mL/g with the volume mass suc as formula the compound shown in I than preferably, is more preferably 3mL/g～20mL/g.The temperature of described reaction is preferably 35～120 ℃, i.e. the temperature of solvent refluxing under normal pressure.The process of described reaction is preferably usingd reaction solution and is formed homogeneous, transparent solution as the terminal of reaction.
In the present invention's one better embodiment, the described preparation method suc as formula the diazabicyclo compounds shown in IIIa or IIIb comprises the following step: by suc as formula after the compound shown in I and solvent, then mix with resolving agent, carry out salt-forming reaction; Preferably, by suc as formula after the compound shown in I and solvent, then after mixing with resolving agent, at 35～120 ℃, carry out salt-forming reaction.The time of described salt-forming reaction preferably clarifies by being stirred to reaction solution after adding resolving agent, more preferably, stirs until reaction solution clarification at 35～120 ℃.As preferably, by suc as formula after the compound shown in I and solvent, then mix with resolving agent and acid, carry out the kind of salt-forming reaction acid and consumption ditto described in.
In preparation method suc as formula the diazabicyclo compounds shown in IIIa or IIIb, after described salt-forming reaction finishes, preferably also can comprise post-processing step.The method of described post-processing step and condition can be method and the condition of this area post-processing step routine, preferably, the reaction solution of salt-forming reaction are carried out to filtration treatment, obtain filter cake and filtrate, and filter cake is the crude product suc as formula the compound shown in IIIa or IIIb.
In the present invention's one better embodiment, described post-processing step comprises the following step: after described salt-forming reaction finishes, be cooled to-20～60 ℃ (preferably 0～25 ℃), crystallization.The time of described crystallization is preferably with crystallize out in reaction solution,, be generally 1～24 hour; For example can under agitation condition, be incubated crystallization in 1～24 hour.
In preparation method suc as formula the diazabicyclo compounds shown in IIIa or IIIb, described post-processing step also can comprise and be further purified processing.The method of described purifying and condition can be conventional method and the condition of this area purifying, are preferably recrystallization.Described recrystallization preferably comprises the following step: by after crude product and solvent suc as formula the compound shown in IIIa or IIIb, and crystallization, suction filtration, obtains filter cake, filtration cakes torrefaction.Wherein, the preferred solvents of described recrystallization ground, for the solvent described in salt-forming reaction, is more preferably alcoholic solvent.Described solvent is 2～15mL/g with the volume mass of crude product suc as formula the compound shown in IIIa or IIIb than preferably.The temperature of described recrystallization is preferably 25～120 ℃.The crystallization that described recrystallization obtains mixes with the alkaline aqueous solution that pH value is 8～11, must be suc as formula compound shown in IVa or IVb, and wherein IVa is the main intermediate of preparing Moxifloxacin hydrochloride;
In preparation method suc as formula the diazabicyclo compounds shown in IIIa or IIIb, the described preparation method suc as formula the compound shown in I, it comprises the following step: under the effect of highly basic, to carry out racemization reaction as follows suc as formula the compound shown in IVb, make suc as formula the compound shown in I;
Described racemization reaction, preferably, comprises the following step:
(1) by described suc as formula filtrate that in the preparation method of the diazabicyclo compounds shown in IIIa, post-processing step obtains, through reclaiming solvent, reaction after the alkaline aqueous solution that is 8～11 with pH value mixes, the product that must be main component suc as formula the compound shown in IVb;
(2) product of step (1) is carried out to racemization reaction under the effect of highly basic.
In above-mentioned steps (2), can in solvent, not carry out, can in solvent, carry out yet.Described solvent can be the solvent of this area routine, is preferably water and/or organic solvent.Described organic solvent is preferably one or more in alcoholic solvent, esters solvent, ether solvent, ketones solvent, nitrile solvents, aromatic hydrocarbon solvent and halogenated hydrocarbon solvent.Described alcoholic solvent is preferably C
1～C
4alkyl alcohol (preferred C
1～C
4monobasic alkyl alcohol).Described C
1～C
4alkyl alcohol be preferably one or more in methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol and the trimethyl carbinol.Described esters solvent is preferably one or more in ethyl acetate, isopropyl acetate and n-butyl acetate.Described ether solvent is preferably one or more in tetrahydrofuran (THF), methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane, ether and methyl tertiary butyl ether.Described ketones solvent is preferably one or more in acetone, butanone and 4-methyl-2 pentanone.Described nitrile solvents is preferably acetonitrile.Described aromatic hydrocarbon solvent is preferably toluene.Described halogenated hydrocarbon solvent is preferably methylene dichloride and/or 1,2-ethylene dichloride.Described highly basic is preferably one or more in inorganic strong alkali, alkali and alkaline earth metal ions.Described inorganic strong alkali is preferably MOH, ROM and MNH
2in one or more, M is alkalimetal ion or alkaline-earth metal ions, R is C
1～C
4alkyl.Described alkalimetal ion is preferably lithium ion (Li
+), sodium ion (Na
+) or potassium ion (K
+).Described alkaline-earth metal ions is preferably calcium ion (Ca
2+).Described C
1～C
4alkyl be preferably methyl, ethyl, propyl group, butyl or the tertiary butyl.Described basic metal is preferably lithium (Li), sodium (Na) or potassium (K).Described alkaline-earth metal is preferably calcium (Ca).The quality of described highly basic is 0.05%～1%, and described per-cent refers to that the quality of highly basic accounts for the per-cent suc as formula the compound quality shown in IVb.The volume mass with suc as formula the compound shown in I of described solvent is 0～50mL/g than preferably, is more preferably 0.1～10mL/g.The temperature of described reaction is preferably 10～30 ℃.The time of described reaction can be this area, and this type of reacts the conventional time, is generally 0.1～12 hour.
The mechanism of above-mentioned racemization may be as follows:
By the filtrate that in the preparation method suc as formula the diazabicyclo compounds shown in III a, post-processing step obtains, through reclaiming solvent, after alkali is free, obtain with (the 1R shown in structural formula as I Vb, 6S)-8-benzyl-7,9-dioxo-2, the product that 8-diazabicyclo [4.3.0] nonane is main component.This product comprises pure (1R, 6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane, through highly basic, process, obtain the possible structure of fragrant heterocycle intermediate N benzyl-pyrrole negative ion VII(comparatively stable in solvent), after this ion is again protonated, obtain (1S, 6R)-8-benzyl-7,9-dioxo 2,8-diazabicyclo [4.3.0] nonane (IVa) and (1R, 6S)-8-benzyl-7,9-dioxo 2,8-diazabicyclo [4.3.0] nonane (IVb) is in equal proportions or close product, for splitting again.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
In the present invention, room temperature refers to 10～30 ℃, and normal pressure refers to 0.8atm～1.2atm.
Agents useful for same of the present invention and raw material be commercially available obtaining all.
Positive progressive effect of the present invention is:
1, resolving agent is sulphonyl benzene glycosides threonine derivative, as preferred tolysulfonyl L-benzene glycosides propylhomoserin, is a kind of good resolving agent, cheap and easy to get, and preparation easily, is white solid compound, water-soluble hardly, and to ph stability, recovery is convenient.Therefore, can reduce raw materials consumption, thereby reduce production costs, reduce pollution.Simultaneously, fractured operation is easy, after fractionation, directly obtain required configuration and obtain (1S, 6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane Ν-tolysulfonyl benzene glycosides propylhomoserin diastereoisomeric salt, after recrystallization, the target compound chemical purity and the optical purity that obtain are very high, simple to operate.
2, split crystalline mother solution, through highly basic, process, obtain suc as formula the compound shown in I, for splitting, cost reduces environmental pollution, environmental protection simultaneously again.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to ordinary method and condition, or selects according to catalogue.
Embodiment 1
20g cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane is in 250mL reaction flask, add 150mL Virahol, stirring treats that it all dissolves, and adds 2.5g acetic acid and 10g (S)-tolysulfonyl benzene glycosides propylhomoserin, is warming up to backflow, then slow cooling is to room temperature, and stirring is spent the night.Second day, filters, and obtains crystallization, by a small amount of isopropyl alcohol wash, obtain (1S, 6R)-8-benzyl-7,9-dioxy-2,8-diazabicyclo [4.3.0] nonane * (S)-tolysulfonyl benzene glycosides propylhomoserin salt, through Virahol recrystallization, obtain white solid 17.7g, yield 79%, optical purity 99.5%ee.
Embodiment 2
5g cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane is in 100mL reaction flask, add 50mL propyl carbinol, stir and treat that it all dissolves, add 1g water and 3.2g (S)-tolysulfonyl benzene glycosides propylhomoserin, be warming up to 80 ℃, then slow cooling is to room temperature, and stirring is spent the night.Second day, filters, and obtains crystallization, by a small amount of isopropyl alcohol wash, obtains (1S, 6R)-8-benzyl-7,9-dioxo 2,8-diazabicyclo [4.3.0] nonane * (S)-tolysulfonyl benzene glycosides propylhomoserin salt 4.4g, yield 78%, optical purity 96.5%ee.
Embodiment 3
5g cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane is in 100mL reaction flask, add 50mL Virahol, stir and treat that it all dissolves, add 0.5g acetic acid and 3.3g (S)-benzene sulfonyl benzene glycosides propylhomoserin, be warming up to 80 ℃, then slow cooling is to room temperature, and stirring is spent the night.Second day, filters, and obtains crystallization, by a small amount of isopropyl alcohol wash, obtain (1S, 6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane * (S)-tolylsulfonyl benzene glycosides propylhomoserin salt, through Virahol recrystallization, obtain white solid 4.2g, yield 75%, optical purity 97.5%ee.
Embodiment 4
5g cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane is in 100mL reaction flask, add 25mL Virahol and 25mL toluene, stirring treats that it all dissolves, and adds 0.5g acetic acid and 3g (S)-tolysulfonyl benzene glycosides propylhomoserin, is warming up to backflow, then slow cooling is to room temperature, and stirring is spent the night.Second day, filters, and obtains crystallization, by a small amount of isopropyl alcohol wash, obtains (1S, 6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane * (S)-tolysulfonyl benzene glycosides propylhomoserin salt 4.4g, yield 79%, optical purity 96.9%ee.
Embodiment 5
5g cis-8-benzyl-7,9-dioxo 2,8-diazabicyclo [4.3.0] nonane is in 100mL reaction flask, add 50mL propyl carbinol, stir and treat that it all dissolves, add 1g water and 3.2g (R)-tolysulfonyl benzene glycosides propylhomoserin, be warming up to 80 ℃, then slow cooling is to room temperature, and stirring is spent the night.Second day, filters, and obtains crystallization, by a small amount of isopropyl alcohol wash, obtains (1R, 6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane * (R)-tolysulfonyl benzene glycosides propylhomoserin salt 4.4g, yield 79%, optical purity 96.7%ee.
Embodiment 6
2g (1S, 6R)-8-benzyl-7,9-dioxo 2,8-diazabicyclo [4.3.0] nonane and (1R, 6S)-8-benzyl-7,9-dioxo 2, the mixture (1:4) of 8-diazabicyclo [4.3.0] nonane is answered in bottle in 10ml, add 5ml tetrahydrofuran (THF), add 0.1g NaH, stirring is spent the night, and pours 20ml water into, use methylene dichloride extracting, organic phase is through anhydrous Na
2sO
4dry, underpressure distillation, obtains 1.9g (1S, 6R)-8-benzyl-7,9-dioxo 2,8-diazabicyclo [4.3.0] nonane and (1R, 6S)-8-benzyl-7,9-dioxo 2, the mixture (49:51) of 8-diazabicyclo [4.3.0] nonane.
Embodiment 7
2g (1R, 6S)-8-benzyl-7,9-dioxo 2,8-diazabicyclo [4.3.0] nonane, in 10mL reaction flask, adds 5mL methyltetrahydrofuran, adds 0.1g NaH, and stirring is spent the night, and pours 20mL water into, uses methylene dichloride extracting, and organic phase is through anhydrous Na
2sO
4dry, underpressure distillation, obtains 1.95g (1S, 6R)-8-benzyl-7,9-dioxo 2,8-diazabicyclo [4.3.0] nonane and (1R, 6S)-8-benzyl-7,9-dioxo 2, the mixture (50:50) of 8-diazabicyclo [4.3.0] nonane.
Embodiment 8
2g (1S, 6R)-8-benzyl-7,9-dioxy-2, assorted dicyclo [4.3.0] nonane of 8-bis-Gas and (1R, 6S)-8-benzyl-7,9-dioxy-2, the mixture (1.1:3.9) of 8-diazabicyclo [4.3.0] nonane is in 10mL reaction flask, add 5mL1,2-glycol dimethyl ether, adds 0.2g sodium ethylate, stirring is spent the night, pour 20mL water into, use methylene dichloride extracting, organic phase is through anhydrous Na
2sO
4dry, underpressure distillation, obtains 1.8g (1S, 6R)-8-benzyl-7,9-dioxy-2, assorted dicyclo [4.3.0] nonane of 8-bis-Gas and (1R, 6S)-8-benzyl-7,9-dioxy-2, the mixture (48:52) of assorted dicyclo [4.3.0] nonane of 8-bis-Gas.
Embodiment 9
2g (1S, 6R)-8-benzyl-7,9-dioxo 2,8-diazabicyclo [4.3.0] nonane and (1R, 6S)-8-benzyl-7,9-dioxo-2, the mixture (1:6) of 8-diazabicyclo [4.3.0] nonane is in 10mL reaction flask, add 4mL toluene and 1mL Virahol, add 0.1g sodium Metal 99.5, stirring is spent the night, and pours 20mL water into, use methylene dichloride extracting, organic phase is through anhydrous Na
2sO
4dry, underpressure distillation, obtains 1.8g (1S, 6R)-8-benzyl-7,9-dioxo 2,8-diazabicyclo [4.3.0] nonane and (1R, 6S)-8-benzyl-7,9-dioxo-2, the mixture (50:50) of 8-diazabicyclo [4.3.0] nonane.
Embodiment 10
2g (1S, 6R)-8-benzyl-7,9-dioxo 2,8-diazabicyclo [4.3.0] nonane and (1R, 6S)-8-benzyl-7,9-dioxo 2, the mixture (1:4) of 8-diazabicyclo [4.3.0] nonane is answered in bottle in 10mL, add 5mL methyl tertbutyl mystery, add 0.2g LDA, stirring is spent the night, and pours 20mL water into, use methylene dichloride extracting, organic phase is through anhydrous Na
2sO
4dry, underpressure distillation, obtains 1.9g (1S, 6R)-8-benzyl-7,9-dioxy-2,8-dioxa dicyclo [4.3.0] nonane and (1R, 6S)-8-benzyl-7,9-dioxy-2, the mixture (49:51) of 8-dioxa dicyclo [4.3.0] nonane.
Embodiment 11
2g (1S, 6R)-8-benzyl-7,9-dioxo 2,8-diazabicyclo [4.3.0] nonane and (1R, 6S)-8-benzyl-7,9-dioxo-2, the mixture (1:4) of 8-diazabicyclo [4.3.0] nonane is answered in bottle in 10mL, add 5mL1,4-dioxane, adds 0.1g NaNH
2, stirring is spent the night, and pours 20mL water into, uses methylene dichloride extracting, and organic phase is through anhydrous Na
2sO
4dry, underpressure distillation, obtains 1.9g (1S, 6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo [4.3.0] nonane and (1R, 6S)-8-benzyl-7,9-dioxo-2, the mixture (49:51) of 8-diazabicyclo [4.3.0] nonane.
The mensuration reference Tetrahedron:Asymmetry of HPLC optical purity, 2011,22,379-380.
Press synthetic target compound (1S, the 6R)-8-of EP550903 report method benzyl-7,9-dioxo 2,8-diazabicyclo [4.3.0] nonane, the product making with preparation method of the present invention carries out chirality HPLC analysis, and both retention time are consistent, determine product configuration.
Claims (12)
1. suc as formula a preparation method for the diazabicyclo compounds shown in IIIa or IIIb, it is characterized in that:
The described preparation method suc as formula the compound shown in IIIa, it comprises the following step: in solvent, will carry out salt-forming reaction as follows suc as formula the compound shown in I and resolving agent, make suc as formula the compound shown in IIIa; Described resolving agent is suc as formula the compound shown in IIa;
The described preparation method suc as formula the compound shown in IIIb, it comprises the following step: in solvent, will carry out salt-forming reaction as follows suc as formula the compound shown in I and resolving agent, make suc as formula the compound shown in IIIb; Described resolving agent is suc as formula the compound shown in IIb;
In IIa and/or IIb, R is C
1～C
20alkyl, or by the one or more replacements in following substituting group or unsubstituted C
6～C
10aryl: halogen, or replaced or do not replace C by halogen
1～C
4alkyl.
2. preparation method as claimed in claim 1, is characterized in that, described C
1～C
20alkyl be C
1～C
4alkyl; Preferably, described C
1～C
4alkyl be methyl, ethyl, propyl group, sec.-propyl, n-propyl or normal-butyl; And/or, described C
6～C
10aryl be phenyl; And/or, the C of described replacement
6～C
10aryl be p-methylphenyl; And/or described halogen is fluorine, chlorine, bromine or iodine.
3. preparation method as claimed in claim 1, is characterized in that, it comprises the following step: in solvent, under sour existence, will carry out salt-forming reaction suc as formula the compound shown in I and resolving agent.
4. preparation method as claimed in claim 1, is characterized in that, by suc as formula after the compound shown in I and solvent, then mixes with resolving agent, or mixes with resolving agent and acid, carries out salt-forming reaction; Preferably, by suc as formula after the compound shown in I and solvent, then after mixing with resolving agent, at 35～120 ℃, carry out salt-forming reaction.
5. preparation method as claimed in claim 4, is characterized in that: described solvent is water and/or organic solvent; And/or described acid is organic acid and/or mineral acid; And/or the described mol ratio suc as formula the compound shown in I and described resolving agent is 1:0.1～1:5; And/or described sour and mol ratio suc as formula the compound shown in I is 0:1～10:1, while having acid to exist, this mol ratio is greater than 0:1.
6. preparation method as claimed in claim 5, is characterized in that, described organic solvent is one or more in alcoholic solvent, esters solvent, ether solvent, ketones solvent, nitrile solvents, halogenated hydrocarbon solvent and aromatic hydrocarbon solvent; And/or described organic acid is one or more in formic acid, acetic acid, propionic acid and phenylformic acid; And/or described mineral acid is one or more in hydrochloric acid, phosphoric acid and sulfuric acid.
7. preparation method as claimed in claim 1, is characterized in that, after described salt-forming reaction finishes, also further comprises post-processing step; And/or described post-processing step is: the reaction solution of salt-forming reaction is carried out to filtration treatment, obtain filter cake and filtrate, filter cake is the crude product of formula III a or formula III b compound.
8. preparation method as claimed in claim 7, it is characterized in that: described post-processing step also further comprises recrystallization, described recrystallization preferably comprises the following step: by after crude product and solvent suc as formula the compound shown in IIIa or IIIb, crystallization, suction filtration, obtain filter cake, filtration cakes torrefaction; Wherein, the solvent of described recrystallization as claimed in claim 6; And/or the crystallization that described recrystallization obtains mixes with the alkaline aqueous solution that pH value is 8～11, must, suc as formula compound shown in IVa or IVb, wherein, suc as formula the compound shown in IVa, be the main intermediate of preparing Moxifloxacin hydrochloride;
9. preparation method as claimed in claim 8, is characterized in that comprising the following step:
Under the effect of highly basic, described carried out to racemization reaction as follows suc as formula the compound shown in IVb, make suc as formula the compound shown in I, for splitting again;
10. preparation method as claimed in claim 9, is characterized in that: described racemization reaction comprises the following step:
(1) by described suc as formula filtrate that in the preparation method of the diazabicyclo compounds shown in IIIa, post-processing step obtains, through reclaiming solvent, reaction after the alkaline aqueous solution that is 8～11 with pH value mixes, the product that must be main component suc as formula compound shown in IVb;
(2) product of step (1) is carried out to racemization reaction under the effect of highly basic.
11. preparation methods as claimed in claim 10, is characterized in that, step (2) is carried out in solvent-free or solvent, and described solvent is water and/or organic solvent; And/or described highly basic is one or more in inorganic strong alkali, alkali and alkaline earth metal ions.
12. preparation methods as claimed in claim 11, is characterized in that, described organic solvent is one or more in alcoholic solvent, esters solvent, ether solvent, ketones solvent, nitrile solvents, aromatic hydrocarbon solvent and halogenated hydrocarbon solvent; Described inorganic strong alkali is MOH, ROM and MNH
2in one or more, M is alkalimetal ion or alkaline-earth metal ions, R is C
1～C
4alkyl; Described basic metal is lithium, sodium or potassium; Described alkaline-earth metal is calcium;
And/or described alkalimetal ion is lithium ion, sodium ion or potassium ion;
And/or described alkaline-earth metal ions is calcium ion;
And/or the quality of described highly basic is 0.05%～1%, described per-cent refers to that the quality of highly basic accounts for the per-cent suc as formula the compound quality shown in IVb;
And/or volume mass ratio described solvent and suc as formula the compound shown in I is 0～50mL/g;
And/or the temperature of described reaction is 10～30 ℃.
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| CN104803999A (en) * | 2015-03-27 | 2015-07-29 | 九江中星医药化工有限公司 | Preparation method of moxifloxacin side chain intermediate |
| CN112707901A (en) * | 2020-12-07 | 2021-04-27 | 泰安汉威集团有限公司 | Preparation method of compound A |
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| US6566523B1 (en) * | 1999-06-16 | 2003-05-20 | Bayer Aktiengesellschaft | Method for the enantiomer separation of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane |
| CN102408427A (en) * | 2011-10-22 | 2012-04-11 | 浙江普洛康裕制药有限公司 | Preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane |
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| US5792869A (en) * | 1994-11-04 | 1998-08-11 | Yamakawa Chemical Industry Co., Ltd | Process for preparing optically active piperazine derivatives and Intermediates for preparation |
| US6566523B1 (en) * | 1999-06-16 | 2003-05-20 | Bayer Aktiengesellschaft | Method for the enantiomer separation of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane |
| US6392044B1 (en) * | 1999-07-06 | 2002-05-21 | Bayer Aktiengesellschaft | Racemization of R,S-dioxo-benzylpyrrolopiperidine |
| CN102408427A (en) * | 2011-10-22 | 2012-04-11 | 浙江普洛康裕制药有限公司 | Preparation method for moxifloxacin intermediate (1S, 6R)-8-benzyl-7, 9-dioxy-2, 8-diazabicyclo [4.3.0] nonane |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104803999A (en) * | 2015-03-27 | 2015-07-29 | 九江中星医药化工有限公司 | Preparation method of moxifloxacin side chain intermediate |
| CN112707901A (en) * | 2020-12-07 | 2021-04-27 | 泰安汉威集团有限公司 | Preparation method of compound A |
| CN112707901B (en) * | 2020-12-07 | 2022-03-22 | 泰安汉威集团有限公司 | Preparation method of compound A |
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