CN107417686A - A kind of synthetic method of AVM hereinafter Batan sodium - Google Patents
A kind of synthetic method of AVM hereinafter Batan sodium Download PDFInfo
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- CN107417686A CN107417686A CN201710852184.8A CN201710852184A CN107417686A CN 107417686 A CN107417686 A CN 107417686A CN 201710852184 A CN201710852184 A CN 201710852184A CN 107417686 A CN107417686 A CN 107417686A
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- Prior art keywords
- octane
- avm hereinafter
- reaction
- formamides
- synthetic method
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- 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 title claims abstract description 53
- 239000011734 sodium Substances 0.000 title claims abstract description 53
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 53
- 238000010189 synthetic method Methods 0.000 title claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 84
- -1 benzyl epoxide Chemical class 0.000 claims abstract description 62
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims abstract description 50
- 150000003053 piperidines Chemical class 0.000 claims abstract description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 17
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 13
- LIKFHECYJZWXFJ-UHFFFAOYSA-N dimethyldichlorosilane Chemical compound C[Si](C)(Cl)Cl LIKFHECYJZWXFJ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 10
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 5
- 239000000243 solution Substances 0.000 claims description 45
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 16
- 239000011259 mixed solution Substances 0.000 claims description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 239000011593 sulfur Substances 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 claims description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- JPWGUOFOCAZONZ-UHFFFAOYSA-N heptan-1-amine;hydrobromide Chemical class Br.CCCCCCCN JPWGUOFOCAZONZ-UHFFFAOYSA-N 0.000 claims description 4
- ZLSVALLKHLKICA-UHFFFAOYSA-N hexan-1-amine;hydrobromide Chemical class [Br-].CCCCCC[NH3+] ZLSVALLKHLKICA-UHFFFAOYSA-N 0.000 claims description 4
- ZUZLIXGTXQBUDC-UHFFFAOYSA-N methyltrioctylammonium Chemical compound CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC ZUZLIXGTXQBUDC-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- FECKHSTWGKTQAN-UHFFFAOYSA-N pentan-1-amine;hydrobromide Chemical compound [Br-].CCCCC[NH3+] FECKHSTWGKTQAN-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 230000008859 change Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims 1
- 239000005864 Sulphur Substances 0.000 claims 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract description 25
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 4
- 230000000977 initiatory effect Effects 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 2
- 230000006872 improvement Effects 0.000 abstract description 2
- 238000005342 ion exchange Methods 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- HWYHDWGGACRVEH-UHFFFAOYSA-N n-methyl-n-(4-pyrrolidin-1-ylbut-2-ynyl)acetamide Chemical compound CC(=O)N(C)CC#CCN1CCCC1 HWYHDWGGACRVEH-UHFFFAOYSA-N 0.000 abstract 2
- 238000003756 stirring Methods 0.000 description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 18
- 238000004809 thin layer chromatography Methods 0.000 description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 238000001514 detection method Methods 0.000 description 14
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 9
- 239000003921 oil Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 150000002118 epoxides Chemical class 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- 238000011084 recovery Methods 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- 238000010792 warming Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- QBVXKDJEZKEASM-UHFFFAOYSA-M tetraoctylammonium bromide Chemical compound [Br-].CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC QBVXKDJEZKEASM-UHFFFAOYSA-M 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- 239000003781 beta lactamase inhibitor Substances 0.000 description 3
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 3
- 238000006277 sulfonation reaction Methods 0.000 description 3
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 3
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- NDCUAPJVLWFHHB-UHNVWZDZSA-N avibactam Chemical compound C1N2[C@H](C(N)=O)CC[C@@]1([H])N(OS(O)(=O)=O)C2=O NDCUAPJVLWFHHB-UHNVWZDZSA-N 0.000 description 2
- 229960002379 avibactam Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000536 complexating effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- MGFDNLWKTJVEDZ-UHFFFAOYSA-M tributyl(hexyl)azanium;bromide Chemical compound [Br-].CCCCCC[N+](CCCC)(CCCC)CCCC MGFDNLWKTJVEDZ-UHFFFAOYSA-M 0.000 description 2
- NDIURPSCHWTXDC-UHFFFAOYSA-N 2-(4,5-dimethoxy-2-nitrophenyl)acetohydrazide Chemical compound COC1=CC(CC(=O)NN)=C([N+]([O-])=O)C=C1OC NDIURPSCHWTXDC-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000005046 Chlorosilane Substances 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- WBOHXLDSPBIPTP-UHFFFAOYSA-N N,N-dimethyl-1,8-naphthyridin-4-amine Chemical compound CN(C1=CC=NC2=NC=CC=C12)C WBOHXLDSPBIPTP-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- ASMSBEFBZWGZJT-UHFFFAOYSA-N butyl(hexyl)azanium bromide Chemical compound [Br-].C(CCCCC)[NH2+]CCCC ASMSBEFBZWGZJT-UHFFFAOYSA-N 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
- 229960003324 clavulanic acid Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 125000004989 dicarbonyl group Chemical group 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 150000002220 fluorenes Chemical class 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical compound CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 159000000000 sodium salts Chemical group 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 1
- 229960005256 sulbactam Drugs 0.000 description 1
- 229960000373 tazobactam sodium Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 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
- C07D471/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a kind of synthetic method of AVM hereinafter Batan sodium, this method is with (2S, 5R) formamide of 5 [(benzyl epoxide) amino] piperidines 2 is initiation material, under dimethyldichlorosilane effect, urea ring is built by carbonyl dimidazoles, obtain (2S, 5R) 6 (benzyl epoxide) 7 oxo 1, the formamide of 6 diazabicylos [3.2.1] octane 2, then by hydrogenation removing benzyl, sulfonating reaction is carried out with sulfonated reagent, and quaternary ammonium salt intermediate is synthesized with quaternary ammonium salt, AVM hereinafter Batan sodium is obtained finally by ion exchange.Process costs after improvement are low, easy to operate, good product quality, suitable for industrial production.The present invention is in synthetic intermediate (2S, 5R) 6 (benzyl epoxide) 7 oxo 1, during the formamide of 6 diazabicylos [3.2.1] octane 2, cheap dimethyldichlorosilane is selected, has greatly reduced production cost.
Description
Technical field
The invention belongs to medical chemistry to synthesize field, and in particular to a kind of synthetic method of AVM hereinafter Batan sodium.
Background technology
AVM hereinafter Batan, be Novexel companies research and development a kind of new beta-lactamase inhibitor, with listed three
Kind beta-lactamase inhibitor (Sulbactam, Tazobactam Sodium, clavulanic acid) is compared, and is had long-acting and is covalently tied with enzyme invertibity
The advantages that closing, and beta-lactamase will not being induced to produce.When being used in combination with all kinds of cephalos and carbapenem antibiotics, have wide
Antibacterial activity is composed, especially to the Escherichia coli containing extended spectrumβ-lactamase and klebostiella pneumoniae, contains excess
The activity of the Escherichia coli of AmpC enzymes and Escherichia coli simultaneously containing AmpC and extended spectrumβ-lactamase is significantly.2012
Year, the research such as Dubreui is found, the cefotaxime-AVM hereinafter Batan-medicine of metronidazole three combination (8:8:1) 91.8% (290/ is inhibited
316) anaerobism bacteria strain, synergy or synergy are shown to most of bacterial strains, and does not find resistant strains.Therefore, Ah
The research for tieing up the new synthesis route of Batan has very big application value.
AVM hereinafter Batan (Avibactam, NXL-104) belongs to diazabicyclo octanone compound, has two chiral centres,
It is very different with the structure of the beta-lactamase inhibitor of classics, this special structure can be recovered through back reaction, tool
There is long-acting Inhibitory activity.AVM hereinafter Batan clinically with its sodium-salt form application, its chemical name be sulfuric acid list [(1R, 2S,
5R) -2- amino carbonyls -7- oxos -1,6- azabicyclo [3.2.1] octyl- 6- yls] ester sodium salt, specific molecular structure is as follows：
CN1468242 and CN102834395 is disclosed with (2S) -5- ((benzyloxy) amino) piperidines -2- benzyl formates
The method that oxalates synthesizes AVM hereinafter Batan, its synthetic route are as follows：
The Japanese apllied patent CN103328476 of Mingzhi fruit medicine company Zhu Shi societies is disclosed with (2S, 5R) -5- ((benzyloxy)
Amino) piperidines -2- t-butyl formates are that initiation material synthesizes AVM hereinafter Batan, its synthetic route is as follows：
During AVM hereinafter Batan is synthesized, the structure of urea ring has to the yield of whole piece route and the quality of final products
Large effect, above-mentioned patent have used two phosgene during urea ring is synthesized, and not only toxicity is larger, and react bad
Control, reaction yield be not high, is unfavorable for industrial amplification production；By (2S, 5R) -5- [(benzyl epoxide) amino] piperidines -2-
During formic acid prepares (2S, 5R) -5- [(benzyl epoxide) amino] piperidines -2- formamides, it is required to first live to the former
Change, the use of activating reagent adds cost to a certain extent, and ammonolysis reaction yield is unsatisfactory.
The apllied patent CN103649051 of Astrazeneca AB discloses the synthetic route of following AVM hereinafter Batan sodium：
This method is that blocking group is former to the nitrogen on piperidine ring first from tablet held before the breast by officials methoxycarbonyl group during urea ring is synthesized
Son is protected, and the structure of urea ring is then carried out using carbonyl dimidazoles, although the method makes the step reaction yield have necessarily
Raising, but fluorenes methoxy dicarbonyl chloride is expensive, is unfavorable for large-scale application.Meanwhile this method is when carrying out sulfonating reaction,
The sulfonated reagent of selection is sulfur trioxide trimethylamine complex compound, and its weaker sulfonation performance makes reaction need longer time, and
Its higher price also adds cost to a certain extent.Then ammonium tube- nursery quaternary ammonium salt is being used as using 4-butyl ammonium
During used highly toxic 4-methyl-2 pentanone, its higher boiling point (115.8 DEG C) is unfavorable for eliminating, so as to directly
Influence the quality of next step end-product.
The content of the invention
To solve the deficiencies in the prior art, the invention provides a kind of new synthetic method of AVM hereinafter Batan sodium, the synthesis side
Method is with (2S, 5R) -5- [(benzyl epoxide) amino] piperidines -2- formamides for initiation material.
Technical scheme is as follows：
The invention provides a kind of synthetic method of AVM hereinafter Batan sodium, this method comprises the following steps：
(1) (2S, 5R) -5- [(benzyl epoxide) amino] piperidines -2- formamides in the presence of base with dimethyl dichloro silicon
Alkane reacts, and builds urea ring by carbonyl dimidazoles, obtains (2S, 5R) -6- (benzyl epoxide) -7- oxo -1,6- diazabicylos
[3.2.1] octane -2- formamides；
(2) (2S, 5R) -6- (benzyl epoxide) -7- oxo -1,6- diazabicylos [3.2.1] octane -2- formamides are being urged
Under agent catalysis, reacted with hydrogen, obtain (2S, 5R) -6- hydroxyl -7- oxos -1,6- diazabicylo [3.2.1] octanes -2-
Formamide；
(3) alkali is added into (2S, 5R) -6- hydroxyls -7- oxo -1,6- diazabicylos [3.2.1] octane -2- formamides
And sulfonated reagent, reaction obtain (2S, 5R) -6- (sulfo group epoxide) -7- oxos -1,6- diazabicylo [3.2.1] octane -2- first
Acid amides；
(4) (2S, 5R) -6- (sulfo group epoxide) -7- oxo -1,6- diazabicylos [3.2.1] octane -2- formamides and season
Ammonium salt reacts, and obtains quaternary ammonium salt intermediate；
(5) sodium iso-octoate solution is added dropwise into quaternary ammonium salt intermediate to be reacted, is filtered after precipitation solid, is dried to obtain Ah
Tie up Batan sodium.
The synthetic method (as shown in Figure 1) of AVM hereinafter Batan sodium of the present invention is first with (2S, 5R) -5- [(benzyl epoxide) amino]
Piperidines -2- formamides are initiation material, under dimethyldichlorosilane effect, build urea ring by carbonyl dimidazoles, obtain
(2S, 5R) -6- (benzyl epoxide) -7- oxos -1,6- diazabicylo [3.2.1] octane -2- formamides, it is then anti-through over hydrogenation
Benzyl should be removed, sulfonating reaction is carried out from sulfonated reagent, and quaternary ammonium salt intermediate is synthesized with quaternary ammonium salt, finally by ion
Exchange obtains AVM hereinafter Batan sodium.Process costs after improvement are low, easy to operate, product quality is good, suitable for industrial production.
Further, in step (1), alkali is triethylamine, diisopropylamine, N, N- diisopropyl ethyl amines, pyridine or 4-
Dimethylamino naphthyridine, preferably N, N- diisopropyl ethyl amines.Under selected alkalescence condition, reaction can be smoothed out, generation production
Thing.Reaction solvent for use is acetonitrile, acetone, isopropanol or tetrahydrofuran, preferably acetonitrile.
Further, in step (1), (2S, 5R) -5- [(benzyl epoxide) amino] piperidines -2- formamides and dimethyl two
The reaction temperature of chlorosilane is 0-10 DEG C, preferably 5-8 DEG C.
Further, in step (2), catalyst is palladium carbon, and preferred weight content is 10% palladium carbon；Reaction temperature is
15-35 DEG C, preferably 25-30 DEG C, reaction time 1-6h.
Further, in step (2), reaction solvent for use is isopropanol-water mixed solution, alcohol-water mixed solution, first
Alcohol-water mixed solution or Isosorbide-5-Nitrae-dioxane-water mixed solution, preferably isopropanol-water mixed solution.
Further, in step (3), sulfonated reagent is sulfur trioxide-Isosorbide-5-Nitrae dioxane complex compound, sulfonated reagent with
The rate of charge of (2S, 5R) -6- hydroxyls -7- oxo -1,6- diazabicylos [3.2.1] octane -2- formamides is 1-1.5：1, it is excellent
Select 1.2：1.The sulfonation performance of sulfur trioxide-Isosorbide-5-Nitrae dioxane complex compound is better than other sulfonated reagents, the products collection efficiency of generation compared with
It is high.
Further, in step (3), alkali be potassium carbonate, sodium carbonate, calcium carbonate, potassium hydroxide, sodium hydroxide, triethylamine,
N, N diisopropylethylamine or pyridine, preferably triethylamine.Reaction solvent for use is acetonitrile-water mixed solution, 1,4 dioxane-water
Mixed solution or isopropanol-water mixed solution, preferably isopropanol-water mixed solution.
Further, in step (3), reaction temperature is 15-35 DEG C, preferably 25-30 DEG C；Reaction time is 0.5-2h, excellent
Select 1h.
Further, in step (4), quaternary ammonium salt is ammonium bromide and tetraoctyl ammonium bromide, four pentyl ammonium bromide, four heptyl ammonium bromides, four
Hexyl ammonium bromide, tricaprylmethyl ammonium bromide or tributyl hexyl ammonium bromide, preferably ammonium bromide and tetraoctyl ammonium bromide；Reaction temperature is 25-
35 DEG C, reaction time 1-2h.Selected quaternary ammonium salt can be smoothed out reaction, generate product.
Further, in step (5), reaction solvent for use is ethanol, methanol or isopropanol, preferred alcohol.
Beneficial effects of the present invention：
(1) present invention is in synthetic intermediate (2S, 5R) -6- (benzyl epoxide) -7- oxo -1,6- diazabicylos
It is starting with (2S, 5R) -5- [(benzyl epoxide) amino] piperidines -2- formamides during [3.2.1] octane -2- formamides
Raw material, and from the cheaper dimethyldichlorosilane of price, greatly reduce production cost.
(2) present invention selects the more excellent sulfur trioxide-Isosorbide-5-Nitrae dioxane complex compound of sulfonation performance as sulfonated reagent, and
And with ammonium bromide and tetraoctyl ammonium bromide (four pentyl ammonium bromide, four heptyl ammonium bromides, four hexyl ammonium bromides, tricaprylmethyl ammonium bromide or three
Butyl hexyl ammonium bromide) it is ammonium tube- nursery quaternary ammonium salt, the reaction time is shortened, simplifies operation, improves reaction
Yield, whole piece route is set to be more suitable for industrial production.
Brief description of the drawings
Fig. 1 is the Technology Roadmap of AVM hereinafter Batan sodium synthetic method of the present invention.
Embodiment
With reference to embodiment, the present invention is expanded on further.Embodiment is raw materials used and reagent is commercially available prod.Carbonyl
Diimidazole is abbreviated as CDI, and thin-layer chromatography is represented with TLC.
Embodiment 1
A kind of synthetic method of AVM hereinafter Batan sodium comprises the following steps：
(1) acetonitrile (100mL) is measured to be added in reaction bulb, addition (2S, 5R) -5- [(benzyl epoxide) amino] piperidines -
2- formamides (10g), 5-8 DEG C of temperature control, 20mL (3eq) DIPEA is added into system, 6.4mL is then added dropwise
(1.3eq) dimethyldichlorosilane, TLC detection reactions are complete.8.5g CDI (1.3eq) are added into system, are warming up to 45 DEG C
Stirring, after TLC detection reactions completely, 9.2mL (3eq) isopropanol is added, continues to stir at 45 DEG C, after question response is complete, stops
Only stir, naturally cool to room temperature, 50mL toluene is added into system, then add 140mL 2mol/L HCl solution, treat body
After system's layering, organic phase is collected, faint yellow solid is concentrated to give, (2S, 5R) -6- (benzyls is obtained after being washed with methyl tertiary butyl ether(MTBE)
Base epoxide) -7- oxos -1,6- diazabicylo [3.2.1] octane -2- formamides (9.8g, yield 90%).
(2) each 50mL of isopropyl alcohol and water is measured, by gained (2S, 5R) -6- (benzyl epoxide) -7- oxo -1,6- diazas
Two rings [3.2.1] octane -2- formamides and 1g palladium carbons are added thereto, with the hydrogen treat mixed system until reaction is entirely
Only.Filter and remove catalyst and filter cake is washed with water, collect filtrate and be directly used in the next step.
At (3) 0 DEG C, to gained (2S, 5R) -6- hydroxyl -7- oxos -1,6- diazabicylo [3.2.1] octane -2- formyls
1mL (0.2eq) triethylamine is added in the reaction solution of amine, 7.3g (1.2eq) sulfur trioxide-Isosorbide-5-Nitrae dioxane complex compound is weighed and adds
Enter into reaction bulb, insulated and stirred 0.5h, move to room temperature continue stir 1h, obtain (2S, 5R) -6- (sulfo group epoxide) -7- oxos -
The reaction solution of 1,6- diazabicylos [3.2.1] octane -2- formamides.
(4) at room temperature, to (2S, 5R) -6- (sulfo group epoxide) -7- oxos -1,6- diazabicylo [3.2.1] octane -2-
24g (1.22eq) ammonium bromide and tetraoctyl ammonium bromide is added in the reaction solution of formamide, after stirring 1h, product is extracted with dichloromethane, with nothing
After aqueous sodium persulfate is dried, pale yellow oil is concentrated to give.
(5) pale yellow oil obtained by upper step is dissolved in 10mL ethanol, sodium iso-octoate (12g, 2eq) is added dropwise into the solution
Ethanol solution, filter after separating out solid, wash, be dried to obtain 8.3g AVM hereinafter Batan sodium.The total recovery of reaction is 72%, gained
The purity of AVM hereinafter Batan sodium product is 99.5%.
Embodiment 2
A kind of synthetic method of AVM hereinafter Batan sodium comprises the following steps：
(1) acetonitrile (100mL) is measured to be added in reaction bulb, addition (2S, 5R) -5- [(benzyl epoxide) amino] piperidines -
2- formamides (10g), 5-8 DEG C of temperature control, 20mL (3eq) DIPEA is added into system, 6.4mL is then added dropwise
(1.3eq) dimethyldichlorosilane, TLC detection reactions are complete.8.5g CDI (1.3eq) are added into system, are warming up to 45 DEG C
Stirring, after TLC detection reactions completely, 9.2mL (3eq) isopropanol is added, continues to stir at 45 DEG C, after question response is complete, stops
Only stir, naturally cool to room temperature, 50mL toluene is added into system, then add 140mL 2mol/L HCl solution, treat body
After system's layering, organic phase is collected, faint yellow solid is concentrated to give, (2S, 5R) -6- (benzyls is obtained after being washed with methyl tertiary butyl ether(MTBE)
Base epoxide) -7- oxos -1,6- diazabicylo [3.2.1] octane -2- formamides (9.8g, yield 90%).
(2) each 50mL of isopropyl alcohol and water is measured, by gained (2S, 5R) -6- (benzyl epoxide) -7- oxo -1,6- diazas
Two rings [3.2.1] octane -2- formamides and 1g palladium carbons are added thereto, with the hydrogen treat mixed system until reaction is entirely
Only.Filter and remove catalyst and filter cake is washed with water, collect filtrate and be directly used in the next step.
At (3) 0 DEG C, to gained (2S, 5R) -6- hydroxyl -7- oxos -1,6- diazabicylo [3.2.1] octane -2- formyls
1mL (0.2eq) triethylamine is added in the reaction solution of amine, 7.3g (1.2eq) sulfur trioxide-Isosorbide-5-Nitrae dioxane complex compound is weighed and adds
Enter into reaction bulb, insulated and stirred 0.5h, move to room temperature continue stir 1h, obtain (2S, 5R) -6- (sulfo group epoxide) -7- oxos -
The reaction solution of 1,6- diazabicylos [3.2.1] octane -2- formamides.
(4) at room temperature, to (2S, 5R) -6- (sulfo group epoxide) -7- oxos -1,6- diazabicylo [3.2.1] octane -2-
16.8g (1.22eq) four pentyl ammonium bromide is added in the reaction solution of formamide, after stirring 1h, product is extracted with dichloromethane, uses
After anhydrous sodium sulfate drying, pale yellow oil is concentrated to give.
(5) pale yellow oil obtained by upper step is dissolved in 10mL ethanol, sodium iso-octoate (12g, 2eq) is added dropwise into the solution
Ethanol solution, filter after separating out solid, wash, be dried to obtain 8.1g AVM hereinafter Batan sodium.The total recovery of reaction is 70%, gained
The purity of AVM hereinafter Batan sodium product is 99.4%.
Embodiment 3
A kind of synthetic method of AVM hereinafter Batan sodium comprises the following steps：
(1) acetonitrile (100mL) is measured to be added in reaction bulb, addition (2S, 5R) -5- [(benzyl epoxide) amino] piperidines -
2- formamides (10g), 5-8 DEG C of temperature control, 20mL (3eq) DIPEA is added into system, 6.4mL is then added dropwise
(1.3eq) dimethyldichlorosilane, TLC detection reactions are complete.8.5g CDI (1.3eq) are added into system, are warming up to 45 DEG C
Stirring, after TLC detection reactions completely, 9.2mL (3eq) isopropanol is added, continues to stir at 45 DEG C, after question response is complete, stops
Only stir, naturally cool to room temperature, 50mL toluene is added into system, then add 140mL 2mol/L HCl solution, treat body
After system's layering, organic phase is collected, faint yellow solid is concentrated to give, (2S, 5R) -6- (benzyls is obtained after being washed with methyl tertiary butyl ether(MTBE)
Base epoxide) -7- oxos -1,6- diazabicylo [3.2.1] octane -2- formamides (9.8g, yield 90%).
(2) each 50mL of isopropyl alcohol and water is measured, by gained (2S, 5R) -6- (benzyl epoxide) -7- oxo -1,6- diazas
Two rings [3.2.1] octane -2- formamides and 1g palladium carbons are added thereto, with the hydrogen treat mixed system until reaction is entirely
Only.Filter and remove catalyst and filter cake is washed with water, collect filtrate and be directly used in the next step.
At (3) 0 DEG C, to gained (2S, 5R) -6- hydroxyl -7- oxos -1,6- diazabicylo [3.2.1] octane -2- formyls
1mL (0.2eq) triethylamine is added in the reaction solution of amine, 7.3g (1.2eq) sulfur trioxide-Isosorbide-5-Nitrae dioxane complex compound is weighed and adds
Enter into reaction bulb, insulated and stirred 0.5h, move to room temperature continue stir 1h, obtain (2S, 5R) -6- (sulfo group epoxide) -7- oxos -
The reaction solution of 1,6- diazabicylos [3.2.1] octane -2- formamides.
(4) at room temperature, to (2S, 5R) -6- (sulfo group epoxide) -7- oxos -1,6- diazabicylo [3.2.1] octane -2-
21.8g (1.22eq) four heptyl ammonium bromide is added in the reaction solution of formamide, after stirring 1h, product is extracted with dichloromethane, uses
After anhydrous sodium sulfate drying, pale yellow oil is concentrated to give.
(5) pale yellow oil obtained by upper step is dissolved in 10mL ethanol, sodium iso-octoate (12g, 2eq) is added dropwise into the solution
Ethanol solution, filter after separating out solid, wash, be dried to obtain 8g AVM hereinafter Batan sodium.The total recovery of reaction is 69%, gained Ah
The purity for tieing up Batan sodium product is 99.4%.
Embodiment 4
A kind of synthetic method of AVM hereinafter Batan sodium comprises the following steps：
(1) acetonitrile (100mL) is measured to be added in reaction bulb, addition (2S, 5R) -5- [(benzyl epoxide) amino] piperidines -
2- formamides (10g), 5-8 DEG C of temperature control, 20mL (3eq) DIPEA is added into system, 6.4mL is then added dropwise
(1.3eq) dimethyldichlorosilane, TLC detection reactions are complete.8.5g CDI (1.3eq) are added into system, are warming up to 45 DEG C
Stirring, after TLC detection reactions completely, 9.2mL (3eq) isopropanol is added, continues to stir at 45 DEG C, after question response is complete, stops
Only stir, naturally cool to room temperature, 50mL toluene is added into system, then add 140mL 2mol/L HCl solution, treat body
After system's layering, organic phase is collected, faint yellow solid is concentrated to give, (2S, 5R) -6- (benzyls is obtained after being washed with methyl tertiary butyl ether(MTBE)
Base epoxide) -7- oxos -1,6- diazabicylo [3.2.1] octane -2- formamides (9.8g, yield 90%).
(2) each 50mL of isopropyl alcohol and water is measured, by gained (2S, 5R) -6- (benzyl epoxide) -7- oxo -1,6- diazas
Two rings [3.2.1] octane -2- formamides and 1g palladium carbons are added thereto, with the hydrogen treat mixed system until reaction is entirely
Only.Filter and remove catalyst and filter cake is washed with water, collect filtrate and be directly used in the next step.
At (3) 0 DEG C, to gained (2S, 5R) -6- hydroxyl -7- oxos -1,6- diazabicylo [3.2.1] octane -2- formyls
1mL (0.2eq) triethylamine is added in the reaction solution of amine, 7.3g (1.2eq) sulfur trioxide-Isosorbide-5-Nitrae dioxane complex compound is weighed and adds
Enter into reaction bulb, insulated and stirred 0.5h, move to room temperature continue stir 1h, obtain (2S, 5R) -6- (sulfo group epoxide) -7- oxos -
The reaction solution of 1,6- diazabicylos [3.2.1] octane -2- formamides.
(4) at room temperature, to (2S, 5R) -6- (sulfo group epoxide) -7- oxos -1,6- diazabicylo [3.2.1] octane -2-
19.3g (1.22eq) four hexyl ammonium bromide is added in the reaction solution of formamide, after stirring 1h, product is extracted with dichloromethane, uses
After anhydrous sodium sulfate drying, pale yellow oil is concentrated to give.
(5) pale yellow oil obtained by upper step is dissolved in 10mL ethanol, sodium iso-octoate (12g, 2eq) is added dropwise into the solution
Ethanol solution, filter after separating out solid, wash, be dried to obtain 7.8g AVM hereinafter Batan sodium.The total recovery of reaction is 68%, gained
The purity of AVM hereinafter Batan sodium product is 99.3%.
Embodiment 5
A kind of synthetic method of AVM hereinafter Batan sodium comprises the following steps：
(1) acetonitrile (100mL) is measured to be added in reaction bulb, addition (2S, 5R) -5- [(benzyl epoxide) amino] piperidines -
2- formamides (10g), 5-8 DEG C of temperature control, 20mL (3eq) DIPEA is added into system, 6.4mL is then added dropwise
(1.3eq) dimethyldichlorosilane, TLC detection reactions are complete.8.5g CDI (1.3eq) are added into system, are warming up to 45 DEG C
Stirring, after TLC detection reactions completely, 9.2mL (3eq) isopropanol is added, continues to stir at 45 DEG C, after question response is complete, stops
Only stir, naturally cool to room temperature, 50mL toluene is added into system, then add 140mL 2mol/L HCl solution, treat body
After system's layering, organic phase is collected, faint yellow solid is concentrated to give, (2S, 5R) -6- (benzyls is obtained after being washed with methyl tertiary butyl ether(MTBE)
Base epoxide) -7- oxos -1,6- diazabicylo [3.2.1] octane -2- formamides (9.8g, yield 90%).
(2) each 50mL of isopropyl alcohol and water is measured, by gained (2S, 5R) -6- (benzyl epoxide) -7- oxo -1,6- diazas
Two rings [3.2.1] octane -2- formamides and 1g palladium carbons are added thereto, with the hydrogen treat mixed system until reaction is entirely
Only.Filter and remove catalyst and filter cake is washed with water, collect filtrate and be directly used in the next step.
At (3) 0 DEG C, gained (2S, 5R) -6- hydroxyl -7- oxos -1,6- diazabicylo [3.2.1] octanes -2- is walked upwards
1mL (0.2eq) triethylamine is added in the reaction solution of formamide, weighs 7.3g (1.2eq) sulfur trioxide-Isosorbide-5-Nitrae dioxane complexing
Thing is added in reaction bulb, insulated and stirred 0.5h, is moved to room temperature and is continued to stir 1h, obtains (2S, 5R) -6- (sulfo group epoxide) -7-
The reaction solution of oxo -1,6- diazabicylos [3.2.1] octane -2- formamides.
(4) at room temperature, to (2S, 5R) -6- (sulfo group epoxide) -7- oxos -1,6- diazabicylo [3.2.1] octane -2-
20g (1.22eq) tricaprylmethyl ammonium bromide is added in the reaction solution of formamide, after stirring 1h, product is extracted with dichloromethane,
After anhydrous sodium sulfate drying, pale yellow oily liquid is concentrated to give.
(5) pale yellow oily liquid obtained by upper step is dissolved in 10mL ethanol, the ethanol of sodium iso-octoate is added dropwise into the solution
Solution, filter after separating out solid, wash, be dried to obtain 8.1g AVM hereinafter Batan sodium.The total recovery of reaction is 70%, gained AVM hereinafter bar
The purity of smooth sodium product is 99.3%.
Embodiment 6
A kind of synthetic method of AVM hereinafter Batan sodium comprises the following steps：
(1) acetonitrile (100mL) is measured to be added in reaction bulb, addition (2S, 5R) -5- [(benzyl epoxide) amino] piperidines -
2- formamides (10g), 5-8 DEG C of temperature control, 20mL (3eq) DIPEA is added into system, 6.4mL is then added dropwise
(1.3eq) dimethyldichlorosilane, TLC detection reactions are complete.8.5g CDI (1.3eq) are added into system, are warming up to 45 DEG C
Stirring, after TLC detection reactions completely, 9.2mL (3eq) isopropanol is added, continues to stir at 45 DEG C, after question response is complete, stops
Only stir, naturally cool to room temperature, 50mL toluene is added into system, then add 140mL 2mol/L HCl solution, treat body
After system's layering, organic phase is collected, faint yellow solid is concentrated to give, (2S, 5R) -6- (benzyls is obtained after being washed with methyl tertiary butyl ether(MTBE)
Base epoxide) -7- oxos -1,6- diazabicylo [3.2.1] octane -2- formamides (9.8g, yield 90%).
(2) each 50mL of isopropyl alcohol and water is measured, by gained (2S, 5R) -6- (benzyl epoxide) -7- oxo -1,6- diazas
Two rings [3.2.1] octane -2- formamides and 1g palladium carbons are added thereto, with the hydrogen treat mixed system until reaction is entirely
Only.Filter and remove catalyst and filter cake is washed with water, collect filtrate and be directly used in the next step.
At (3) 0 DEG C, gained (2S, 5R) -6- hydroxyl -7- oxos -1,6- diazabicylo [3.2.1] octanes -2- is walked upwards
1mL (0.2eq) triethylamine is added in the reaction solution of formamide, weighs 7.3g (1.2eq) sulfur trioxide-Isosorbide-5-Nitrae dioxane complexing
Thing is added in reaction bulb, insulated and stirred 0.5h, is moved to room temperature and is continued to stir 1h, obtains (2S, 5R) -6- (sulfo group epoxide) -7-
The reaction solution of oxo -1,6- diazabicylos [3.2.1] octane -2- formamides.
(4) at room temperature, to (2S, 5R) -6- (sulfo group epoxide) -7- oxos -1,6- diazabicylo [3.2.1] octane -2-
20g (1.22eq) tributyl hexyl ammonium bromide is added in the reaction solution of formamide, after stirring 1h, product is extracted with dichloromethane,
After anhydrous sodium sulfate drying, pale yellow oily liquid is concentrated to give.
(5) pale yellow oily liquid obtained by upper step is dissolved in 10mL ethanol, the ethanol of sodium iso-octoate is added dropwise into the solution
Solution, filter after separating out solid, wash, be dried to obtain 7.5g AVM hereinafter Batan sodium.The total recovery of reaction is 65%, gained AVM hereinafter bar
The purity of smooth sodium product is 99.2%.
Embodiment 7
A kind of synthetic method of AVM hereinafter Batan sodium comprises the following steps：
(1) acetonitrile (100mL) is measured to be added in reaction bulb, addition (2S, 5R) -5- [(benzyl epoxide) amino] piperidines -
2- formamides (10g), 5-8 DEG C of temperature control, 20mL (3eq) DIPEA is added into system, 6.4mL is then added dropwise
(1.3eq) dimethyldichlorosilane, TLC detection reactions are complete.8.5g CDI (1.3eq) are added into system, are warming up to 45 DEG C
Stirring, after TLC detection reactions completely, 9.2mL (3eq) isopropanol is added, continues to stir at 45 DEG C, after question response is complete, stops
Only stir, naturally cool to room temperature, 50mL toluene is added into system, then add 140mL 2mol/L HCl solution, treat body
After system's layering, organic phase is collected, faint yellow solid is concentrated to give, (2S, 5R) -6- (benzyls is obtained after being washed with methyl tertiary butyl ether(MTBE)
Base epoxide) -7- oxos -1,6- diazabicylo [3.2.1] octane -2- formamides (9.8g, yield 90%).
(2) each 50mL of isopropyl alcohol and water is measured, by gained (2S, 5R) -6- (benzyl epoxide) -7- oxo -1,6- diazas
Two rings [3.2.1] octane -2- formamides and 1g palladium carbons are added thereto, with the hydrogen treat mixed system until reaction is entirely
Only.Filter and remove catalyst and filter cake is washed with water, collect filtrate, solvent, which is evaporated off, under reduced pressure obtains (2S, 5R) -6- hydroxyls
Base -7- oxo -1,6- diazabicylos [3.2.1] octane -2- formamides.
(3) dissolved with 50mL water and 25mL 1,4- dioxane.1mL (0.2eq) three second is added into solution
Amine, weigh 7.3g (1.2eq) sulfur trioxide-Isosorbide-5-Nitrae dioxane complex compound and be dissolved in Isosorbide-5-Nitrae-dioxane (25mL),
At 0 DEG C, Isosorbide-5-Nitrae-dioxane solution of sulfur trioxide-Isosorbide-5-Nitrae dioxane complex compound is added drop-wise in reaction bulb, insulated and stirred
0.5h, move to room temperature and continue to stir 1h, obtain (2S, 5R) -6- (sulfo group epoxide) -7- oxos -1,6- diazabicylo [3.2.1]
The reaction solution of octane -2- formamides.
(4) at room temperature, to (2S, 5R) -6- (sulfo group epoxide) -7- oxos -1,6- diazabicylo [3.2.1] octane -2-
24g (1.22eq) ammonium bromide and tetraoctyl ammonium bromide is added in the reaction solution of formamide, after stirring 1h, product is extracted with dichloromethane, with nothing
After aqueous sodium persulfate is dried, pale yellow oily liquid is concentrated to give.
(5) pale yellow oily liquid obtained by upper step is dissolved in 10mL ethanol, the ethanol of sodium iso-octoate is added dropwise into the solution
Solution, filter after separating out solid, wash, be dried to obtain 8.2g AVM hereinafter Batan sodium.The total recovery of reaction is 71%, gained AVM hereinafter bar
The purity of smooth sodium product is 99.3%.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Any modification, equivalent substitution and simple modifications for being made in content etc., should be included in the scope of the protection.
Claims (10)
1. a kind of synthetic method of AVM hereinafter Batan sodium, it is characterised in that this method comprises the following steps：
(1) (2S, 5R) -5- [(benzyl epoxide) amino] piperidines -2- formamides are anti-with dimethyldichlorosilane in the presence of base
Should, urea ring is built by carbonyl dimidazoles, obtains (2S, 5R) -6- (benzyl epoxide) -7- oxo -1,6- diazabicylos
[3.2.1] octane -2- formamides；
(2) (2S, 5R) -6- (benzyl epoxide) -7- oxo -1,6- diazabicylos [3.2.1] octane -2- formamides are in catalyst
Under catalysis, reacted with hydrogen, obtain (2S, 5R) -6- hydroxyls -7- oxos -1,6- diazabicylo [3.2.1] octane -2- formyls
Amine；
(3) alkali and sulphur are added into (2S, 5R) -6- hydroxyls -7- oxo -1,6- diazabicylos [3.2.1] octane -2- formamides
Change reagent, reaction obtains (2S, 5R) -6- (sulfo group epoxide) -7- oxos -1,6- diazabicylo [3.2.1] octane -2- formyls
Amine；
(4) (2S, 5R) -6- (sulfo group epoxide) -7- oxo -1,6- diazabicylos [3.2.1] octane -2- formamides and quaternary ammonium salt
Reaction, obtains quaternary ammonium salt intermediate；
(5) sodium iso-octoate solution is added dropwise into quaternary ammonium salt intermediate to be reacted, is filtered after precipitation solid, is dried to obtain AVM hereinafter bar
Smooth sodium.
2. the synthetic method of AVM hereinafter Batan sodium according to claim 1, it is characterised in that in step (1), alkali is three second
Amine, diisopropylamine, N, N- diisopropyl ethyl amines, pyridine or DMAP, reaction solvent for use are acetonitrile, third
Ketone, isopropanol or tetrahydrofuran.
3. the synthetic method of AVM hereinafter Batan sodium according to claim 1, it is characterised in that in step (1), (2S, 5R) -5-
The reaction temperature of [(benzyl epoxide) amino] piperidines -2- formamides and dimethyldichlorosilane is 0-10 DEG C.
4. the synthetic method of AVM hereinafter Batan sodium according to claim 1, it is characterised in that in step (2), catalyst is palladium
Carbon, reaction temperature are 15-35 DEG C, reaction time 1-6h.
5. the synthetic method of AVM hereinafter Batan sodium according to claim 1, it is characterised in that molten used in reaction in step (2)
Agent is that isopropanol-water mixed solution, alcohol-water mixed solution, methanol-water mixed solution or 1,4- dioxane-water mixing are molten
Liquid.
6. the synthetic method of AVM hereinafter Batan sodium according to claim 1, it is characterised in that in step (3), sulfonated reagent is
Sulfur trioxide-Isosorbide-5-Nitrae dioxane complex compound, sulfonated reagent and (2S, 5R) -6- hydroxyl -7- oxo -1,6- diazabicylos
The rate of charge of [3.2.1] octane -2- formamides is 1-1.5：1.
7. the synthetic method of AVM hereinafter Batan sodium according to claim 1, it is characterised in that in step (3), alkali is carbonic acid
Potassium, sodium carbonate, calcium carbonate, potassium hydroxide, sodium hydroxide, triethylamine, DIPEA or pyridine, react solvent for use
For acetonitrile-water mixed solution, 1,4 dioxane-water mixed solution or isopropanol-water mixed solution.
8. the synthetic method of AVM hereinafter Batan sodium according to claim 1, it is characterised in that in step (3), reaction temperature is
15-35 DEG C, reaction time 0.5-2h.
9. the synthetic method of AVM hereinafter Batan sodium according to claim 1, it is characterised in that in step (4), quaternary ammonium salt four
Octyl group ammonium bromide, four pentyl ammonium bromide, four heptyl ammonium bromides, four hexyl ammonium bromides, tricaprylmethyl ammonium bromide or tributyl oneself
Base ammonium bromide, reaction temperature are 25-35 DEG C, reaction time 1-2h.
10. the synthetic method of AVM hereinafter Batan sodium according to claim 1, it is characterised in that in step (5), used in reaction
Solvent is ethanol, methanol or isopropanol.
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108409736A (en) * | 2018-05-16 | 2018-08-17 | 齐鲁天和惠世制药有限公司 | A method of spray drying prepares unformed AVM hereinafter Batan sodium |
| CN109516987A (en) * | 2018-12-26 | 2019-03-26 | 江西富祥药业股份有限公司 | A kind of AVM hereinafter Batan centre preparation |
| CN110078728A (en) * | 2019-05-23 | 2019-08-02 | 江西富祥药业股份有限公司 | A kind of AVM hereinafter Batan intermediate, preparation method and applications |
| JP2020506160A (en) * | 2017-12-25 | 2020-02-27 | 新発薬業有限公司 | A simple method for preparing avibactam |
| CN111116587A (en) * | 2019-11-29 | 2020-05-08 | 北京耀诚惠仁科技有限公司 | Preparation method of avibactam intermediate compound |
| CN111732587A (en) * | 2020-06-05 | 2020-10-02 | 北京耀诚惠仁科技有限公司 | Abamebactam intermediate compound gemini quaternary ammonium disulfonate and preparation method thereof |
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| CN113105455A (en) * | 2020-01-10 | 2021-07-13 | 天津科伦药物研究有限公司 | Preparation method of crystal form B avibactam sodium |
| CN113387950A (en) * | 2020-03-11 | 2021-09-14 | 天津科伦药物研究有限公司 | Method for refining avibactam sodium intermediate |
| CN115073458A (en) * | 2022-07-04 | 2022-09-20 | 山东致泰医药技术有限公司 | Preparation method of avibactam sodium |
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| CN108409736A (en) * | 2018-05-16 | 2018-08-17 | 齐鲁天和惠世制药有限公司 | A method of spray drying prepares unformed AVM hereinafter Batan sodium |
| CN109516987A (en) * | 2018-12-26 | 2019-03-26 | 江西富祥药业股份有限公司 | A kind of AVM hereinafter Batan centre preparation |
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| CN113105455B (en) * | 2020-01-10 | 2024-05-17 | 四川科伦药物研究院有限公司 | Preparation method of crystal form B avibactam sodium |
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| CN111732587A (en) * | 2020-06-05 | 2020-10-02 | 北京耀诚惠仁科技有限公司 | Abamebactam intermediate compound gemini quaternary ammonium disulfonate and preparation method thereof |
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