CN105061425B - Synthesis method of diazabicyclo octanone sulfuric acid monoester - Google Patents
Synthesis method of diazabicyclo octanone sulfuric acid monoester Download PDFInfo
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- CN105061425B CN105061425B CN201510496134.1A CN201510496134A CN105061425B CN 105061425 B CN105061425 B CN 105061425B CN 201510496134 A CN201510496134 A CN 201510496134A CN 105061425 B CN105061425 B CN 105061425B
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- -1 diazabicyclo octanone sulfuric acid Chemical compound 0.000 title claims abstract description 37
- 238000001308 synthesis method Methods 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 94
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 239000002994 raw material Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 239000003960 organic solvent Substances 0.000 claims description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 18
- 239000003513 alkali Substances 0.000 claims description 16
- 238000010189 synthetic method Methods 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 claims description 12
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 229940125773 compound 10 Drugs 0.000 claims description 10
- 229940125797 compound 12 Drugs 0.000 claims description 10
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 10
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 9
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 229940126214 compound 3 Drugs 0.000 claims description 9
- 229940125898 compound 5 Drugs 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 125000003368 amide group Chemical group 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 239000003223 protective agent Substances 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 claims description 7
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000004220 glutamic acid Substances 0.000 claims description 6
- 235000013922 glutamic acid Nutrition 0.000 claims description 6
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical compound O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 claims description 6
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000001117 sulphuric acid Substances 0.000 claims description 4
- 235000011149 sulphuric acid Nutrition 0.000 claims description 4
- DANYXEHCMQHDNX-UHFFFAOYSA-K trichloroiridium Chemical class Cl[Ir](Cl)Cl DANYXEHCMQHDNX-UHFFFAOYSA-K 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000012448 Lithium borohydride Substances 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 3
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical group CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 2
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 2
- AQIHMSVIAGNIDM-UHFFFAOYSA-N benzoyl bromide Chemical compound BrC(=O)C1=CC=CC=C1 AQIHMSVIAGNIDM-UHFFFAOYSA-N 0.000 claims description 2
- 125000006278 bromobenzyl group Chemical group 0.000 claims description 2
- 150000001718 carbodiimides Chemical class 0.000 claims description 2
- CDHICTNQMQYRSM-UHFFFAOYSA-N di(propan-2-yl)alumane Chemical compound CC(C)[AlH]C(C)C CDHICTNQMQYRSM-UHFFFAOYSA-N 0.000 claims description 2
- 150000002460 imidazoles Chemical class 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- SJGSVFXEXGQCCY-UHFFFAOYSA-N sulfuryl dichloride;trifluoromethylbenzene Chemical compound ClS(Cl)(=O)=O.FC(F)(F)C1=CC=CC=C1 SJGSVFXEXGQCCY-UHFFFAOYSA-N 0.000 claims description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 2
- 230000006103 sulfonylation Effects 0.000 claims 4
- 238000005694 sulfonylation reaction Methods 0.000 claims 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims 2
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 claims 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims 1
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 230000005494 condensation Effects 0.000 claims 1
- 238000009833 condensation Methods 0.000 claims 1
- 238000006197 hydroboration reaction Methods 0.000 claims 1
- 239000012279 sodium borohydride Substances 0.000 claims 1
- 229910000033 sodium borohydride Inorganic materials 0.000 claims 1
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 150000007984 tetrahydrofuranes Chemical group 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 208000035143 Bacterial infection Diseases 0.000 abstract 1
- 208000022362 bacterial infectious disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 229930195712 glutamate Natural products 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 239000000243 solution Substances 0.000 description 25
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- 239000012141 concentrate Substances 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 235000002639 sodium chloride Nutrition 0.000 description 9
- 238000013517 stratification Methods 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 208000035126 Facies Diseases 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002132 β-lactam antibiotic Substances 0.000 description 3
- 229940124586 β-lactam antibiotics Drugs 0.000 description 3
- 150000003952 β-lactams Chemical class 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 229940125532 enzyme inhibitor Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- ZPVFWPFBNIEHGJ-UHFFFAOYSA-N n-hexyl methyl ketone Natural products CCCCCCC(C)=O ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- FKENQMMABCRJMK-LWOQYNTDSA-N (5r)-3,3-dimethyl-4,4,7-trioxo-4$l^{6}-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=S1(=O)C(C)(C)C(C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-LWOQYNTDSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- CWBJUPWWWOZXCY-NSHDSACASA-N CC(C)(C)NC([C@H](CCC(C1)=O)N1C(OC(C)(C)C)=O)=O Chemical compound CC(C)(C)NC([C@H](CCC(C1)=O)N1C(OC(C)(C)C)=O)=O CWBJUPWWWOZXCY-NSHDSACASA-N 0.000 description 1
- DZAHXNNEQCZPGJ-UHFFFAOYSA-N CCCCOC(OC)=O.COC(O)=O Chemical compound CCCCOC(OC)=O.COC(O)=O DZAHXNNEQCZPGJ-UHFFFAOYSA-N 0.000 description 1
- ORTDZGFNIQBSPY-UHFFFAOYSA-N CCC[N](C)(C)C Chemical compound CCC[N](C)(C)C ORTDZGFNIQBSPY-UHFFFAOYSA-N 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
- 241000192125 Firmicutes Species 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000036209 Intraabdominal Infections Diseases 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- OUHVPTUNAKUCJX-UHFFFAOYSA-N N1=CC=CC=C1.CN(C=1C=CNC1)C Chemical compound N1=CC=CC=C1.CN(C=1C=CNC1)C OUHVPTUNAKUCJX-UHFFFAOYSA-N 0.000 description 1
- 0 O[C@@](CC1)C*[C@]1C=O Chemical compound O[C@@](CC1)C*[C@]1C=O 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical class OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 239000003781 beta lactamase inhibitor Substances 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 1
- ORFOPKXBNMVMKC-DWVKKRMSSA-N ceftazidime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 ORFOPKXBNMVMKC-DWVKKRMSSA-N 0.000 description 1
- 229960000484 ceftazidime Drugs 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-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
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000012973 diazabicyclooctane Substances 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005256 sulbactam Drugs 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 150000003470 sulfuric acid monoesters Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a synthesis method of a compound diazabicyclo octanone sulfuric acid monoester for preventing and treating bacterial infection diseases. According to the synthesis method, cheap and available glutamate lactam is taken as a raw material and reacts for twelve steps, and chemical synthesis of diazabicyclo octanone sulfuric acid monoester is completed with higher total yield. According to the novel synthesis method of diazabicyclo octanone sulfuric acid monoester, the preparation method is simple and convenient, an intermediate is stable, environmental protection and economy are achieved, and the reaction is easy to control.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, particularly relate to diazabicyclo octanone sulphuric acid list
The synthetic method of ester and the like.
Background technology
Since the forties in last century uses first beta-lactam antibiotic penicillin, antibacterial is to clinic
The drug resistance problems of upper wide variety of antibiotic has become the one of clinical treatment to be threatened greatly.For many years, people
Attempt to find the scheme solving Production by Bacteria enzyme drug resistance problems, the wherein work of beta-lactamase inhibitor from many aspects
It is to be combined with bacteriogenic beta-lactamase by mechanism, is allowed to inactivate, so that antibacterial loses beta-lactam
The drug resistance of class antibiotic.This Inhibitors and the beta-lactam antibiotic use in conjunction being weak to enzyme, fully
Having played the antibacterial action of original antibiotic, this is the important means improving beta-lactam antibiotic curative effect.
Diazabicyclo octanone sulfuric acid monoester is novel ss-lactam enzyme inhibitor, it press down zymogram than his azoles bar
Smooth, sulbactam and clavulanic acid are wide.Arstwyth and AstraZeneca cooperative research and development ceftazidime and A Weiba
Smooth compound preparation, for injection, lists for 2015 first in the U.S., and it is double that A Wei Batan belongs to diaza
Cyclooctanone compound, chemical name is [(1R, 2S, 5R)-2-(amino carbonyl)-7-oxo-1,6-diazabicyclo
[3.2.1] octyl-6-yl] sulfuric acid monoester.It is the novel ss-lactam enzyme inhibitor being expected at present most, to majority
Gram positive bacteria (G+) and gram negative bacteria (G-) addicted to oxygen and anaerobism all have bactericidal action, it is adaptable to multiple
Miscellaneous intra-abdominal infection and complicated urinary tract infection (cUTI), including pyelonephritis.
AstraZeneca discloses the synthetic method of this compound in its patent WO2012172368, sees synthesis
Route 1.They are with the a-carbonyl proline of full guard as raw material, by ten single step reactions synthesis diazabicyclos
Octanone sulfuric acid monoester 1.This route can produce two isomers when synthetic intermediate 18, it is more difficult to separates, and
Affect ultimate yield.
WO2012086241 discloses with compound 21 as raw material, double by ten single step reaction synthesis diazas
The method of cyclooctanone sulfuric acid monoester 1, is shown in synthetic route 2, and this route can produce two when synthetic intermediate 22
Individual isomer, it is more difficult to separate, and affect ultimate yield.
WO2014135930 also discloses that the synthetic method of diazabicyclo octanone sulfuric acid monoester 1, sees synthesis road
Line 3, the method uses the method synthesis compound 28 identical with patent WO2012086241, compound 20
Synthesis use ammonia complex, reduce cost.The previous section of this route and patent WO2012086241
Identical, therefore, two isomers can be produced when synthetic intermediate 22, it is more difficult to separate, and affect final receipts
Rate.
Summary of the invention
Based on this, it is an object of the invention to provide the synthetic method of a kind of diazabicyclo octanone sulfuric acid monoester.
For achieving the above object, concrete technical scheme is as follows:
A kind of synthetic method of diazabicyclo octanone sulfuric acid monoester, synthetic route is as follows:
Described synthetic method comprises the following steps:
(1) in organic solvent, glutamic acid lactams 2 reacts 2-10 hour with amine under the effect of condensing agent
Obtaining compound 3, reaction temperature is 0 DEG C-50 DEG C, and the mol ratio of glutamic acid lactams 2 and amine is 1.0:1.0-5；
(2) in organic solvent, compound 3 and amido protecting agent react 1-20 hour, obtain compound 4,
Reaction temperature is 0 DEG C-50 DEG C, and the mol ratio of compound 3 and amido protecting agent is 1.0:1-5；
(3) in organic solvent, to react 1-30 with Trimethylsulfoxonium Iodide under the effect of alkali little for compound 4
Time, obtain compound 5, reaction temperature is 0 DEG C-50, compound 4, Trimethylsulfoxonium Iodide and alkali mole
Ratio is 1.0:1.0-5:1.0-5；
(4) in organic solvent, there is ring closure reaction in compound 5 under the action of an acid, reacts 1-20 hour
Obtaining compound 6, reaction temperature is room temperature-50 DEG C, and the mol ratio of compound 5 and acid is 1.0:0.01-1；
(5) in organic solvent, compound 6 and reducing agent react 1-10 hour, obtain reduzate chemical combination
Thing 7, reaction temperature is-20-30 DEG C, and the mol ratio of compound 6 and reducing agent is 1.0:1.0-5；
(6) in organic solvent, compound 7 and sulfonic acid chloride react 1-15 hour, obtain compound 8, reaction
Temperature is-20 DEG C-50 DEG C, and the mol ratio of compound 7 and sulfonic acid chloride is 1.0:1.0-5；
(7) in organic solvent, the benzyloxy amine reaction 1-20 of compound 8 and benzyloxy amine or Boc protection
Hour, obtaining compound 9, reaction temperature is 0 DEG C-50 DEG C, compound 8 and benzyloxy amine or Boc protection
The mol ratio of benzyloxy amine be 1.0:1.0-5；
(8) in organic solvent, compound 9 reacts 1-10 hour under acid effect, removes Boc protection group
Obtaining compound 10, reaction temperature is 0 DEG C-40 DEG C, and the mol ratio of compound 9 and acid is 1.0:1.0-5；
(9) in organic solvent, compound 10 and triphosgene are reacted 1-8 hour, obtain compound 11,
Reaction temperature is 0 DEG C-50 DEG C, and the mol ratio of compound 10 and triphosgene is 1.0:1.0-5；
(10) in mixed solvent, compound 11 reacts 1-30 hour with hydrogen under catalyst action,
To compound 12, reaction temperature is 0 DEG C-60 DEG C, and the mol ratio of compound 11 and catalyst is 1.0:0.01-1；
(11) in organic solvent, compound 12 and sulfur trioxide pyridine react 10-48 hour, obtain chemical combination
Thing 13, reaction temperature is 0 DEG C-50 DEG C, and the mol ratio of compound 12 and sulfur trioxide pyridine is 1.0:1.0-10；
(12) in organic solvent, compound 13 and alkali reaction 1-10 hour, obtain compound 1 diaza
Dicyclo octanone sulfuric acid monoester, reaction temperature is 0 DEG C-30 DEG C, and the mol ratio of compound 13 and alkali is 1.0:1.0-2.
Wherein in some embodiments, described in step 1, the response time of reaction is 2-4 hour, and reaction temperature is
20 DEG C-30 DEG C, the mol ratio of glutamic acid lactams and amine is 1:1-2；Described in step 2 reaction response time be
10-15 hour, reaction temperature was 20 DEG C-30 DEG C, and the mol ratio of compound 3 and amido protecting agent is 1:1-2；
Described in step 3, the response time of reaction is 10-15 hour, and reaction temperature is 20 DEG C-30 DEG C, compound 4,
The mol ratio of Trimethylsulfoxonium Iodide and alkali is 1:1.5-2.5:1.5-2.5；The response time of reaction described in step 4
For 10-15 hour, reaction temperature was 70 DEG C-90 DEG C, and the mol ratio of compound 5 and acid is 1:0.03-0.05；
Described in step 5, the response time of reaction is 1-2 hour, and reaction temperature be-20 DEG C-0 DEG C, compound 6 and and also
The mol ratio of former dose is 1:1-2；Described in step 6, the response time of reaction is 3-8 hour, and reaction temperature is
20 DEG C-30 DEG C, the mol ratio of compound 7 and sulfonic acid chloride is 1:1-2；Described in step 7 reaction response time be
8-12 hour, reaction temperature was 20 DEG C-30 DEG C, compound 8 and benzyloxy amine or the benzyloxy amine of Boc protection
Mol ratio be 1:1-2；Described in step 8, the response time of reaction is 6-10 hour, and reaction temperature is
30 DEG C-40 DEG C, the mol ratio of compound 9 and acid is 1:1-2；Described in step 9, the response time of reaction is 1-3
Hour, reaction temperature is 20 DEG C-30 DEG C, and the mol ratio of compound 10 and triphosgene is 1:1-2；Step 10
The response time of described reaction is 8-12 hour, and reaction temperature is 40 DEG C-60 DEG C, compound 11 and catalyst
Mol ratio be 1:0.01-1；Described in step 11, the response time of reaction is 22-26 hour, and reaction temperature is
20 DEG C-30 DEG C, the mol ratio of compound 12 and sulfur trioxide pyridine is 1:3-4；Described in step 12, reaction is anti-
Being 1-3 hour between Ying Shi, reaction temperature is 0 DEG C-10 DEG C, and the mol ratio of compound 13 and alkali is 1:1-2.
Wherein in some embodiments, described organic solvent is dichloromethane, oxolane, dimethyl formyl
Amine, dimethyl acetylamide, glycol dimethyl ether, 1,2-dichloroethanes, dimethyl sulfoxide, toluene, methanol,
Ethanol, acetonitrile, petroleum ether, 2,2,2 tfifluoroethyl alcohol, normal hexane or ether.
Wherein in some embodiments, described in step (1), (6), (8) and (9), organic solvent is dichloromethane,
Described in step (2), organic solvent is acetonitrile, and described in step (3), organic solvent is dimethylformamide or diformazan
Base sulfoxide, described in step (4) and (5), organic solvent is toluene, and described in step (7), organic solvent is diformazan
Yl acetamide, described in step (10), organic solvent is methanol, and described in step (11), organic solvent is tetrahydrochysene furan
Muttering, organic solvent described in step (12) is 2,2,2-trifluoroethanols.
Wherein in some embodiments, described in step (1), amine is tert-butylamine or benzylamine, and described condensing agent is 2-(7-
Azo BTA)-tetramethylurea hexafluorophosphoric acid ester (HATU), 2-(7-azo BTA)-tetramethyl
Base urea hexafluorophosphoric acid (HBTU) or carbodiimides (EDCI).
Wherein in some embodiments, described in step (2), amido protecting agent is bromobenzyl, benzoyl bromide or two
Dimethyl dicarbonate butyl ester.
Wherein in some embodiments, step (3) described reaction is carried out under conditions of inert gas shielding, institute
Stating alkali is sodium hydrogen, potassium tert-butoxide, tert-butyl lithium, imidazoles, triethylamine, diisopropylethylamine, piperidines, two
Picoline, sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS),
N-methylmorpholine, Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane (DABCO) or pyridine.
Wherein in some embodiments, step (4) described acid is: iridium chloride dimer, trifluoroacetic acid, trichlorine
Change aluminum, hydrochloric acid, p-methyl benzenesulfonic acid, sulphuric acid or nitric acid；Described in step (5), reducing agent is lithium borohydride, boron
Sodium hydride, potassium borohydride, diisopropyl aluminum hydride, Lithium Aluminium Hydride.
Wherein in some embodiments, sulfonic acid chloride described in step (6) is benzene sulfonyl chloride, to trifluoromethylbenzene sulphur
Acyl chlorides or mesyl chloride；Described in step 8, acid is iridium chloride dimer, p-methyl benzenesulfonic acid, trifluoroacetic acid, salt
Acid, sulphuric acid or nitric acid.
Wherein in some embodiments, step (10) described catalyst is palladium/carbon.
Wherein in some embodiments, step (12) described alkali is sodium hydroxide, Lithium hydrate, hydroxide
Potassium, sodium carbonate, potassium carbonate, sodium bicarbonate.
The synthetic method of diazabicyclo octanone sulfuric acid monoester of the present invention, easy and simple to handle, intermediate is steady
Fixed, environmental protection and economy, reaction is easily controlled, and described method can be used to synthesize diazabicyclo octanone sulphuric acid list
The related analogs of ester.Compared with prior art, the method for the invention, will not when synthetic intermediate 7
Producing isomer, product can be easily separated, and the yield of end product is high.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is further elaborated.
In following embodiment, conventional post-processing approach is: after having reacted, and adds suitable quantity of water in reactant liquor,
Separate organic facies and aqueous phase, merge organic facies.If it is desired, organic facies uses saturated aqueous common salt to wash successively,
Then anhydrous Na SO is used4Being dried, after filtration, decompression is spin-dried for, and obtains crude product, then through column chromatography for separation
End product is obtained after purification.
EDCI (35.7 is added in dichloromethane (300ml) solution of L-Glutimic acid (20g, 155mmol)
G, 186mmol, 1.2eq), HOBT (1.1g, 7.8mmol, 0.05eq) and tert-butylamine (16.3ml, 155
Mmol, 1eq), room temperature reaction 2h, reacts with saturated ammonium chloride solution (100ml) cancellation, concentrates, add
N-butyl alcohol (200ml) and water (100ml), stratification, aqueous phase n-butyl alcohol (200ml*2) extracts, saturated common salt
Water (100ml) washs, and anhydrous sodium sulfate is dried, and filters, and concentrates, obtains with ethyl acetate (100ml) recrystallization
Compound as white solid 3 (26.3g, 92%).1HNMR(400MHz,CDCl3): δ 5.23 (d, J=12.2
Hz, 1H), 5.18 (d, J=12.2Hz, 1H), 4.46 (dd, J=9.3Hz, J=2.4Hz, 1H), 2.55 (m,
1H),2.43(m,1H),2.21(m,1H),2.01(m,1H),1.29(s,9H)ppm.MS(m/z):185
(M++1)。
Under conditions of temperature is 0 DEG C, to the acetonitrile (300ml) of compound 3 (20g, 108.6mmol)
Solution adds N, N-diisopropylethylamine (19.7ml, 119.5mmol, 1.1eq), Bis(tert-butoxycarbonyl)oxide
(26.1g, 119.5mmol, 1.1eq) and DMAP (663mg, 5.4mmol, 0.05eq),
Room temperature reaction overnight, reacts with saturated ammonium chloride solution (100ml) cancellation, concentrates, and adds n-butyl alcohol (200ml)
With water (100ml), stratification, aqueous phase n-butyl alcohol (200ml*2) extracts, and saturated aqueous common salt (100ml) is washed
Washing, anhydrous sodium sulfate is dried, filtering and concentrating, obtains white solid chemical combination with ethyl acetate (100ml) recrystallization
Thing 4 (30.3g, 98%).1HNMR(400MHz,CDCl3): δ 5.26 (d, J=12.2Hz, 1H), 5.21
(d, J=12.2Hz, 1H), 4.51 (dd, J=9.2Hz, J=2.3Hz, 1H), 2.56 (m, 1H), 2.43 (m,
1H),2.27(m,1H),2.01(m,1H),1.41(s,9H),1.32(s,9H)ppm.MS(m/z):285
(M++1)。
Under argon shield, be sequentially added in anhydrous DMSO (100ml) Trimethylsulfoxonium Iodide (17.0g,
59.8mmol, 1.7eq) and potassium tert-butoxide (5.9g, 52.8mmol, 1.5eq) room temperature reaction 1h, then drip
Entering DMSO (75ml) solution of compound 4 (10g, 35.2mmol, 1eq), room temperature reaction is overnight, dense
Contracting, adds ethyl acetate (100ml) and water (50ml), stratification, and aqueous phase ethyl acetate (100ml*2) extracts
Taking, saturated aqueous common salt (50ml) washs, and anhydrous sodium sulfate is dried, and is concentrated to give compound as white solid 5 (12.3
G, 93%).1HNMR(400MHz,CDCl3): δ 5.71 (d, J=7.8Hz, 1H), 5.11 (d, J=12.0
Hz, 1H), 5.01 (d, J=12.0Hz, 1H), 4.28 (s, 1H), 4.15 (m, 1H), 3.25 (s, 3H), 3.21 (s,
3H),2.21-2.31(m,2H),2.01(m,1H),1.89(m,1H),1.49(s,9H)1.38(s,9H)ppm.
MS(m/z):377(M++1)。
Under argon shield, to the AlCl being heated to 80 DEG C3The toluene of (100mg, 0.75mmol, 0.035eq)
(40ml) solution drips toluene (60ml) solution of compound 5 (8g, 21.3mmol, 1.0eq), dropping
After 80 DEG C react 12h, be cooled to room temperature, with saturated ammonium chloride solution (50ml) cancellation react, dense
Contracting, adds ethyl acetate (100ml) and water (50ml), stratification, and aqueous phase ethyl acetate (100ml*2) extracts
Taking, saturated aqueous common salt (50ml) washs, and anhydrous sodium sulfate is dried, and is concentrated to give compound 6 (5.85g, 93%).1H NMR(400MHz,CDCl3): δ 5.02-5.18 (m, 2H), 4.66 (dd, J=6.4Hz, J=58Hz,
0.5H), 4.58 (dd, J=7.1Hz, J=6.4Hz, 0.5H), 4.38 (d, J=18.8Hz, 0.5H), 4.31 (d, J
=18.8Hz, 0.5H), 3.95 (d, J=18.8Hz, 0.5H), 3.91 (d, J=18.6Hz, 0.5H), 2.10-2.39
(m,4H),1.46(s,4.5H),1.39(s,4.5H),1.32(s,9H)ppm.MS(m/z):299(M++1)。
At-20 DEG C, under argon shield, to the toluene (70ml) of compound 6 (4g, 13.4mmol, 1.0eq)
Solution adds LiBH4(4M solution inTHF, 3.6ml, 1.07eq), reacts 1h, uses saturated ammonium chloride
Solution (50ml) cancellation is reacted, and concentrates, and adds ethyl acetate (100ml) and water (50ml), stratification, aqueous phase
Extracting by ethyl acetate (100ml*2), saturated aqueous common salt (50ml) washs, and anhydrous sodium sulfate is dried, and is concentrated to give
Compound 7 (3.85g, 96%).1HNMR(400MHz,CDCl3): δ 5.20 (d, J=12.0Hz, 1H),
5.01 (d, J=12.2Hz, 1H), 4.65 (d, J=4.8Hz, 0.5H), 4.61 (d, J=5.0Hz, 0.5H),
4.21-4.24(m,0.5H),4.11-4.25(m,0.5H),3.60(s,1H),2.81-2.96(m,0.5H),
2.71-2.75(m,0.5H),2.21-2.31(m,1H),1.90-2.01(m,2H),1.60-1.70(m,2H),1.48
(s,4.5H),1.43(s,4.5H),1.39(s,9H)ppm.MS(m/z):301(M++1)。
It is sequentially added into triethylamine (1.9 in dichloromethane (50ml) solution of compound 7 (3.0g, 10.0mmol)
Ml, 14.0mmol), to trifluoromethyl benzene sulfonyl chloride (1.3ml, 12.0mmol, 1.2eq) and 4-dimethylamino pyrrole
Pyridine (61.1mg, 0.5mmol), room temperature reaction 5h, react with saturated ammonium chloride solution (20ml) cancellation, concentrate,
Adding ethyl acetate (50ml) and water (20ml), stratification, aqueous phase ethyl acetate (50ml*2) extracts, full
Washing with saline solution (20ml), anhydrous sodium sulfate is dried, and is concentrated to give compound 8 (5.03g, 99%).1H NMR
(400MHz,CDCl3): δ 8.01 (d, J=8.0Hz, 2H), 7.81 (d, J=8.2Hz, 2H), 5.15 (d, J=
12.0Hz, 1H), 4.93 (d, J=11.8Hz, 1H), 4.52 (d, J=4.8Hz, 0.5H), 4.45 (d, J=5.0
Hz,0.5H),4.01-4.16(m,0.5H),3.87-3.92(m,0.5H),3.55(s,1H),2.77-2.81(m,
0.5H),2.66-2.71(m,0.5H),2.01-2.19(m,1H),1.87-1.91(m,2H),1.55-1.61(m,
2H),1.41(s,4.5H),1.33(s,4.5H),1.41(s,9H)ppm.MS(m/z):301(M++1)。
Tertiary fourth is added in DMAC (20ml) solution of N-Boc-benzyloxy amine (2.1g, 9.44mmol, 1.2eq)
Potassium alcoholate (1.06g, 9.44mmol, 1.2eq), after 30min, adds compound 8 (4.0g, 7.87mmol)
DMAC (20ml) solution, room temperature reaction 10h, react with saturated ammonium chloride solution (30ml) cancellation, concentrate,
Adding ethyl acetate (50ml) and water (20ml), stratification, aqueous phase ethyl acetate (50ml*2) extracts, full
Washing with saline solution (20ml), anhydrous sodium sulfate is dried, and is concentrated to give compound 9 (3.78g, 95%).1H NMR
(400MHz,CDCl3): δ 8.01 (d, J=8.0Hz, 2H), 7.81 (d, J=8.2Hz, 2H), 5.15 (d, J=
12.0Hz, 1H), 4.93 (d, J=11.8Hz, 1H), 4.52 (d, J=4.8Hz, 0.5H), 4.45 (d, J=5.0
Hz,0.5H),4.01-4.16(m,0.5H),3.87-3.92(m,0.5H),3.55(s,1H),2.77-2.81(m,
0.5H),2.66-2.71(m,0.5H),2.01-2.19(m,1H),1.87-1.91(m,2H),1.55-1.61(m,
2H),1.41(s,4.5H),1.33(s,4.5H),1.41(s,9H)ppm.MS(m/z):506(M++1)。
Under argon shield, in dichloromethane (20ml) solution of compound 9 (3.0g, 5.94mmol)
Add p-methyl benzenesulfonic acid (3.9ml 59.4mmol), be heated to 35 DEG C of reaction 8h, use saturated ammonium chloride solution
(20ml) cancellation reaction, stratification, aqueous phase dichloromethane (20ml*2) extracts, and merges organic facies with full
Washing with saline solution (20ml), anhydrous sodium sulfate is dried, and dissolves with acetonitrile (20ml) after concentration, and it is right to add
Toluenesulfonic acid (1.02g, 5.94mmol), room temperature reaction 1h, filters to obtain compound 10 (2.5g, 100%).1H NMR(400MHz,CDCl3):δ7.38-7.43(m,5H),4.71(s,2H),3.66(m,1H),3.21
(m,1H),3.06(m,1H),2.51(m,1H),2.14(m,1H),1.99(m,1H),1.49-1.51(m,
10H),1.29(m,1H)ppm.MS(m/z):422(M++1)。
5wt% is added in dichloromethane (20ml) solution of compound 10 (2.0g, 4.75mmol)
NaHCO3Solution (16.0mL, 9.5mmol), stirs 30min, layering, and aqueous phase is with dichloromethane (20ml*2)
Extraction, merges organic facies saturated aqueous common salt (20ml) and washs, and anhydrous sodium sulfate is dried, and filters, and filtrate is cold
But to-10 DEG C, DIPEA (2.4ml, 14.25mmol, 3.0eq) and two (trichloromethyls) are added
Carbonic ester (4.75mmol, 1eq), reacts 30min, adds 10% phosphoric acid solution (10ml), be warming up to room
Temperature, reacts 2h, layering, and aqueous phase dichloromethane (20ml*2) extracts, and merges organic facies, unsaturated carbonate hydrogen
Sodium solution (20ml) washs, and saturated aqueous common salt (20ml) washs, and anhydrous sodium sulfate is dried, and is concentrated to give chemical combination
Thing 11 (1.22g, 93%).1HNMR(400MHz,CDCl3):δ7.20-7.39(m,5H),6.50(s,1H),
5.41 (s, 1H), 5.01 (d, J=11.0Hz, 1H), 4.88 (d, J=11.2Hz, 1H), 3.90 (d, J=7.8Hz,
1H), 3.28 (s, 1H), 3.01 (d, J=11.0Hz, 1H), 2.71 (d, J=11.0Hz, 1H), 2.31 (m,
1H),1.83-1.96(m,2H),1.58(m,1H)ppm.MS(m/z):276(M++1)。
Pd/C (80mg), displacement is added in methanol (15ml) solution of compound 11 (800mg, 2.91mmol)
Hydrogen three times, is heated to 50 DEG C of reaction 10h, is filtered to remove Pd/C, is concentrated to give compound 12 (516mg, 96%).1H NMR(400MHz,CDCl3): δ 3.84 (d, J=8.0Hz, 1H), 3.69 (s, 1H), 3.15 (m, 1H),
2.96 (d, J=11.6Hz, 1H), 2.26 (m, 1H), 2.04 (m, 1H), 1.89 (m, 1H), 1.74 (m, 1H)
ppm.MS(m/z):186(M++1)。
Under argon shield, to THF (1.5ml) solution of compound 12 (40mg, 0.216mmol, 1.0eq)
Middle addition 2-picoline (0.043ml) and sulfur trioxide pyridine (0.12g, 0.756mmol, 3.5eq), room temperature
Reaction 24h, concentrates, and adds dichloromethane (1.5ml), adds 0.5M K2HPO4(0.65mL,0.32mmol)
It is subsequently adding Bu4NHSO4(80.8mg, 0.24mmol) and water (0.2ml), stratification, aqueous phase is with two
Chloromethanes (10ml*2) extracts, and merges organic facies saturated aqueous common salt (10ml) and washs, and anhydrous sodium sulfate is dried,
Concentrate, with methanol: ethyl acetate (1:5) (3ml) recrystallization obtains compound 13 (101mg, 92%).1H NMR(400MHz,D2O):δ4.06(s,1H),3.72(m,2H),3.62(m,3H),3.58-3.55(m,
3H), 3.09 (t, J=9.6Hz, 1H), 2.39 (t, J=8.6Hz, 8H), 1.96-1.75 (m, 16H), 1.52 (m,
12H)ppm.MS(m/z):288(M++1)。
In 2,2,2 tfifluoroethyl alcohol (1.5ml) solution of compound 13 (50mg, 0.099mmol, 1.0eq)
Adding Tetrafluoroboric acid (0.01mL, 0.139mmol, 1.4eq), reaction overnight, concentrates, and adds dichloromethane (2
Ml), water (1ml), NaHCO are added3(10mg, 0.119mmol, 1.2eq), 0 DEG C of reaction 1h is dense
Contract to obtain compound 1 (28mg, 100%).1H NMR(400MHz,D2O):δ4.06(s,1H),3.72(m,
2H), 3.62 (m, 3H), 3.58-3.55 (m, 3H), 3.09 (t, J=9.6Hz, 1H) ppm.MS (m/z): 288
(M++1)。
Each technical characteristic of embodiment described above can combine arbitrarily, for making description succinct, the most right
The all possible combination of each technical characteristic in above-described embodiment is all described, but, if these skills
There is not contradiction in the combination of art feature, is all considered to be the scope that this specification is recorded.
Embodiment described above only have expressed the several embodiments of the present invention, and it describes more concrete and detailed,
But can not therefore be construed as limiting the scope of the patent.It should be pointed out that, for this area
For those of ordinary skill, without departing from the inventive concept of the premise, it is also possible to make some deformation and change
Entering, these broadly fall into protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be with appended power
Profit requires to be as the criterion.
Claims (8)
1. the synthetic method of a diazabicyclo octanone sulfuric acid monoester, it is characterised in that comprise the following steps:
(1) in organic solvent, under the effect of condensing agent and amine reacts 1-10 to raw material 2 glutamic acid lactams
Hour obtaining compound 3, reaction temperature is 0 DEG C-50 DEG C, and the mol ratio of glutamic acid lactams and amine is 1:1-5；
(2) in organic solvent, compound 3 and amido protecting agent react 1-20 hour, obtain compound 4,
Reaction temperature is 0 DEG C-50 DEG C, and the mol ratio of compound 3 and amido protecting agent is 1:1-5；
(3) in organic solvent, to react 1-30 with Trimethylsulfoxonium Iodide under the effect of alkali little for compound 4
Time, obtaining compound 5, reaction temperature is 0 DEG C-50 DEG C, rubbing of compound 4, Trimethylsulfoxonium Iodide and alkali
That ratio is 1:1-5:1-5；
(4) in organic solvent, there is ring closure reaction in compound 5 under the action of an acid, reacts 1-20 hour
Obtaining compound 6, reaction temperature is 50-100 DEG C, and the mol ratio of compound 5 and acid is 1:0.01-1；
(5) in organic solvent, compound 6 and reducing agent react 1-10 hour, obtain reduzate chemical combination
Thing 7, reaction temperature is-20 DEG C-30 DEG C, and the mol ratio of compound 6 and reducing agent is 1:1-5；
(6) in organic solvent, compound 7 and sulfonylation agent react 1-15 hour, obtain compound 8,
Reaction temperature is-20 DEG C-50 DEG C, and the mol ratio of compound 7 and sulfonylation agent is 1:1-5；
(7) in organic solvent, the benzyloxy amine reaction 1-20 of compound 8 and benzyloxy amine or Boc protection
Hour, obtaining compound 9, reaction temperature is 0 DEG C-50 DEG C, compound 8 and benzyloxy amine or Boc protection
The mol ratio of benzyloxy amine be 1:1-5；
(8) in organic solvent, compound 9 reacts 1-10 hour under acid effect, removes Boc protection group
Obtaining compound 10, reaction temperature is 0 DEG C-40 DEG C, and the mol ratio of compound 9 and acid is 1:1-5；
(9) in organic solvent, compound 10 and triphosgene are reacted 1-8 hour, obtain compound 11, instead
Answering temperature is 0 DEG C-50 DEG C, and the mol ratio of compound 10 and triphosgene is 1:1-5；
(10) in mixed solvent, compound 11 reacts 1-30 hour with hydrogen under catalyst action,
To compound 12, reaction temperature is 0 DEG C-60 DEG C, and the mol ratio of compound 11 and catalyst is 1:0.01-1；
(11) in organic solvent, compound 12 and sulfur trioxide pyridine react 10-48 hour, then with
Bu4NHSO4Reaction, obtains compound 13, and reaction temperature is 0 DEG C-50 DEG C, compound 12 and sulfur trioxide
The mol ratio of pyridine is 1:1-10；
(12) in organic solvent, compound 13 and alkali reaction 1-10 hour, obtain product 1 diaza double
Cyclooctanone sulfuric acid monoester, reaction temperature is 0 DEG C-30 DEG C, and the mol ratio of compound 13 and alkali is 1:1-5；
Described product 1, raw material 2 and compound 3-13 are respectively provided with following structure:
Described in step (1), amine is tert-butylamine or benzylamine, and described condensing agent is 2-(7-azo BTA)-four
MU hexafluorophosphoric acid ester, 2-(7-azo BTA)-tetramethylurea hexafluorophosphoric acid or the condensation of carbodiimide class
Agent；
Sulfonylation agent described in step (6) is benzene sulfonyl chloride, to trifluoromethyl benzene sulfonyl chloride or mesyl chloride；
Described in step (8), acid is iridium chloride dimer, trifluoroacetic acid, hydrochloric acid, p-methyl benzenesulfonic acid, sulphuric acid or nitric acid；
B in product 1 structural formula is selected from Na+、Li+Or K+。
The synthetic method of diazabicyclo octanone sulfuric acid monoester the most according to claim 1, its feature exists
In, described in step 1, the response time of reaction is 2-4 hour, and reaction temperature is 20 DEG C-30 DEG C, in glutamic acid
The mol ratio of amide and amine is 1:1-2；Described in step 2, the response time of reaction is 10-15 hour, reaction temperature
Degree is 20 DEG C-30 DEG C, and the mol ratio of compound 3 and amido protecting agent is 1:1-2；React described in step 3
Response time be 10-15 hour, reaction temperature is 20 DEG C-30 DEG C, compound 4, Trimethylsulfoxonium Iodide
It is 1:1.5-2.5:1.5-2.5 with the mol ratio of alkali；Described in step 4, the response time of reaction is 10-15 hour,
Reaction temperature is 70 DEG C-90 DEG C, and the mol ratio of compound 5 and acid is 1:0.03-0.05；Described in step 5 instead
The response time answered is 1-2 hour, and reaction temperature is-20 DEG C-0 DEG C, compound 6 and the mol ratio of reducing agent
For 1:1-2；Described in step 6, the response time of reaction is 3-8 hour, and reaction temperature is 20 DEG C-30 DEG C, chemical combination
The mol ratio of thing 7 and sulfonylation agent is 1:1-2；Described in step 7, the response time of reaction is 8-12 hour,
Reaction temperature is 20 DEG C-30 DEG C, and the mol ratio of the benzyloxy amine of compound 8 and benzyloxy amine or Boc protection is
1:1-2；Described in step 8, the response time of reaction is 6-10 hour, and reaction temperature is 30 DEG C-40 DEG C, chemical combination
The mol ratio of thing 9 and acid is 1:1-2；Described in step 9, the response time of reaction is 1-3 hour, reaction temperature
Being 20 DEG C-30 DEG C, the mol ratio of compound 10 and triphosgene is 1:1-2；The reaction of reaction described in step 10
Time is 8-12 hour, and reaction temperature is 40 DEG C-60 DEG C, and the mol ratio of compound 11 and catalyst is
1:0.01-1；Described in step 11, the response time of reaction is 22-26 hour, and reaction temperature is 20 DEG C-30 DEG C, changes
The mol ratio of compound 12 and sulfur trioxide pyridine is 1:3-4；Described in step 12, the response time of reaction is 1-3
Hour, reaction temperature is 0 DEG C-10 DEG C, and the mol ratio of compound 13 and alkali is 1:1-2.
The synthetic method of diazabicyclo octanone sulfuric acid monoester the most according to claim 1, its feature exists
In, described organic solvent is dichloromethane, oxolane, dimethylformamide, dimethyl acetylamide, second
Glycol dimethyl ether, 1,2-dichloroethanes, dimethyl sulfoxide, toluene, methanol, ethanol, acetonitrile, petroleum ether,
2,2,2 tfifluoroethyl alcohol, normal hexane or ether.
The synthetic method of diazabicyclo octanone sulfuric acid monoester the most according to claim 3, its feature exists
In, described in step (1), (6), (8) and (9), organic solvent is dichloromethane, organic solvent described in step (2)
For acetonitrile, described in step (3), organic solvent is dimethylformamide or dimethyl sulfoxide, step (4) and (5)
Described in organic solvent be toluene, described in step (7), organic solvent is dimethyl acetylamide, institute in step (10)
Stating organic solvent is methanol, and described in step (11), organic solvent is oxolane, organic described in step (12)
Solvent is 2,2,2 tfifluoroethyl alcohol.
5. according to the synthetic method of the diazabicyclo octanone sulfuric acid monoester described in any one of claim 1-4,
It is characterized in that, described in step (2), amido protecting agent is bromobenzyl, benzoyl bromide or Bis(tert-butoxycarbonyl)oxide.
6. according to the synthetic method of the diazabicyclo octanone sulfuric acid monoester described in any one of claim 1-4,
It is characterized in that, step (3) described reaction is carried out under conditions of inert gas shielding, and described alkali is sodium hydrogen,
Potassium tert-butoxide, tert-butyl lithium, imidazoles, triethylamine, diisopropylethylamine, piperidines, lutidines,
Sodium hexamethyldisilazide, potassium hexamethyldisilazide, N-methylmorpholine, Isosorbide-5-Nitrae-diazabicylo [2.2.2]
Octane or pyridine.
7. according to the synthetic method of the diazabicyclo octanone sulfuric acid monoester described in any one of claim 1-4,
It is characterized in that, step (4) described acid is: iridium chloride dimer, p-methyl benzenesulfonic acid, trifluoroacetic acid, hydrochloric acid,
Aluminum chloride, sulphuric acid or nitric acid；Described in step (5), reducing agent is lithium borohydride, sodium borohydride, hydroboration
Potassium, diisopropyl aluminum hydride or Lithium Aluminium Hydride.
8. according to the synthetic method of the diazabicyclo octanone sulfuric acid monoester described in any one of claim 1-4,
It is characterized in that, step (10) described catalyst is palladium/carbon；Step (12) described alkali is sodium hydroxide, hydroxide
Lithium, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate.
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|---|---|---|---|---|
| WO2019075984A1 (en) * | 2017-10-18 | 2019-04-25 | 新发药业有限公司 | Method for preparing avibactam intermediate |
| KR102238179B1 (en) | 2017-12-25 | 2021-04-09 | 신파 파머슈티컬 컴퍼니 리미티드 | Simple manufacturing method of abibactam |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014135930A1 (en) * | 2013-03-08 | 2014-09-12 | Wockhardt Limited | A process for sodium salt of (2s, 5r)-2-carboxamido-7-oxo-6-sulfooxy -1,6-diaza-bicyclo[3.2.1]octane |
| WO2014141132A1 (en) * | 2013-03-14 | 2014-09-18 | Naeja Pharmaceutical Inc. | NEW HETEROCYCLIC COMPOUNDS AND THEIR USE AS ANTIBACTERIAL AGENTS AND β-LACTAMASE INHIBITORS |
| WO2015110963A1 (en) * | 2014-01-21 | 2015-07-30 | Wockhardt Limited | 2-(1,3,4-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1 ]octane derivatives and their use as antibacterial agents |
-
2015
- 2015-08-13 CN CN201510496134.1A patent/CN105061425B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014135930A1 (en) * | 2013-03-08 | 2014-09-12 | Wockhardt Limited | A process for sodium salt of (2s, 5r)-2-carboxamido-7-oxo-6-sulfooxy -1,6-diaza-bicyclo[3.2.1]octane |
| WO2014141132A1 (en) * | 2013-03-14 | 2014-09-18 | Naeja Pharmaceutical Inc. | NEW HETEROCYCLIC COMPOUNDS AND THEIR USE AS ANTIBACTERIAL AGENTS AND β-LACTAMASE INHIBITORS |
| WO2015110963A1 (en) * | 2014-01-21 | 2015-07-30 | Wockhardt Limited | 2-(1,3,4-oxadiazol-2-yl)-7-oxo-1,6-diazabicyclo[3.2.1 ]octane derivatives and their use as antibacterial agents |
Non-Patent Citations (1)
| Title |
|---|
| "Enantioselective Synthesis and Profiling of Two Novel Diazabicyclooctanone β-Lactamase Inhibitors";Hui Xiong et al.;《ACS Medicinal Chemistry Letters》;20140812;第5卷(第10期);第1143-1147页 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019075984A1 (en) * | 2017-10-18 | 2019-04-25 | 新发药业有限公司 | Method for preparing avibactam intermediate |
| EP3543236A4 (en) * | 2017-10-18 | 2020-05-27 | Xinfa Pharmaceutical Co., Ltd | Method for preparing avibactam intermediate |
| KR102238179B1 (en) | 2017-12-25 | 2021-04-09 | 신파 파머슈티컬 컴퍼니 리미티드 | Simple manufacturing method of abibactam |
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