CN110078728A - A kind of AVM hereinafter Batan intermediate, preparation method and applications - Google Patents
A kind of AVM hereinafter Batan intermediate, preparation method and applications Download PDFInfo
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- CN110078728A CN110078728A CN201910434365.8A CN201910434365A CN110078728A CN 110078728 A CN110078728 A CN 110078728A CN 201910434365 A CN201910434365 A CN 201910434365A CN 110078728 A CN110078728 A CN 110078728A
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- Prior art keywords
- alkyl
- avm hereinafter
- hereinafter batan
- preparation
- alkaline agent
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 26
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 26
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 25
- -1 alkyl pyridine Chemical compound 0.000 claims abstract description 24
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 19
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims abstract description 19
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 14
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 125000005270 trialkylamine group Chemical group 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 36
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 14
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims description 10
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 claims description 10
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 6
- 229910001415 sodium ion Inorganic materials 0.000 claims description 6
- OOHAUGDGCWURIT-UHFFFAOYSA-N n,n-dipentylpentan-1-amine Chemical compound CCCCCN(CCCCC)CCCCC OOHAUGDGCWURIT-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 150000003222 pyridines Chemical class 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 13
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000012805 post-processing Methods 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- 150000001875 compounds Chemical class 0.000 description 17
- 229910052739 hydrogen Inorganic materials 0.000 description 17
- 239000001257 hydrogen Substances 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 229960004756 ethanol Drugs 0.000 description 14
- 235000019441 ethanol Nutrition 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 239000012071 phase Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 12
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 11
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 11
- 238000004321 preservation Methods 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 9
- 235000011130 ammonium sulphate Nutrition 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 238000001556 precipitation Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 8
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 7
- 238000005352 clarification Methods 0.000 description 7
- 229960000935 dehydrated alcohol Drugs 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- 238000009413 insulation Methods 0.000 description 7
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical class O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 4
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 3
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 3
- 239000001099 ammonium carbonate Substances 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003781 beta lactamase inhibitor Substances 0.000 description 3
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 159000000000 sodium salts Chemical group 0.000 description 3
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical compound CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000006277 sulfonation reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 150000003952 β-lactams Chemical group 0.000 description 2
- LVFGWOQWXQLVRO-XJDKXYGGSA-N (6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetyl]amino]-8-oxo-3-(pyridin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;[(2s,5r)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl] hydrogen sulfate Chemical compound NC(=O)[C@@H]1CC[C@H]2N(OS(O)(=O)=O)C(=O)N1C2.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 LVFGWOQWXQLVRO-XJDKXYGGSA-N 0.000 description 1
- NFDXQGNDWIPXQL-UHFFFAOYSA-N 1-cyclooctyldiazocane Chemical group C1CCCCCCC1N1NCCCCCC1 NFDXQGNDWIPXQL-UHFFFAOYSA-N 0.000 description 1
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960002379 avibactam Drugs 0.000 description 1
- 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 1
- 229940091875 avycaz Drugs 0.000 description 1
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 1
- 229960003644 aztreonam Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- AJSHDAOMUKXVDC-UHFFFAOYSA-N butan-1-amine;sulfuric acid Chemical compound CCCC[NH3+].OS([O-])(=O)=O AJSHDAOMUKXVDC-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229960004261 cefotaxime Drugs 0.000 description 1
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 1
- ZCCUWMICIWSJIX-NQJJCJBVSA-N ceftaroline fosamil Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OCC)C=2N=C(NP(O)(O)=O)SN=2)CC=1SC(SC=1)=NC=1C1=CC=[N+](C)C=C1 ZCCUWMICIWSJIX-NQJJCJBVSA-N 0.000 description 1
- 229960004828 ceftaroline fosamil 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
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 229960003324 clavulanic acid Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 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
- 230000001629 suppression Effects 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 238000005406 washing Methods 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 AVM hereinafter Batan intermediates and preparation method thereof, comprising: in the presence of alkaline agent, compound II is reacted with sulfonated reagent, is then reacted again with alkaline agent, obtains the AVM hereinafter Batan intermediate；The alkaline agent is trialkylamine, pyridine, alkyl pyridine, N- Alkylpiperidine, dialkyl aniline or dialkyl benzylamine, in which: alkyl is C in the trialkylamine5‑8Alkyl, alkyl is C in alkyl pyridine1‑4Alkyl, alkyl is C in N- Alkylpiperidine1‑4Alkyl, alkyl is C in dialkyl aniline1‑4Alkyl, alkyl is C in dialkyl benzylamine1‑4Alkyl.It is compared with the traditional method, the present invention can directly be reacted with one step of sulfonated reagent using the alkaline agent of appropriate alkalinity instead of traditional alkaline agent, and post-processing is simple, be more suitable for industrial mass production.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of AVM hereinafter Batan intermediate [(1R, 2S, 5R) -2- (amino
Carbonyl) -7- oxo -1,6- diazabicyclo [3.2.1] octyl- 6- yl] ammonium sulfate, preparation method and applications.
Background technique
AVM hereinafter Batan (avibactam) is a kind of novel non-beta-lactam structure beta-lactamase inhibitor, and wide
Spectrum cephalosporin cefotaxime (ceftazidime) is combined for treating complexity intraperitoneal infection (cIAI) and complexity urinary tract
It infects (cUTI), the drug combination has obtained FDA approval listing, trade name Avycaz at present.Combination with other antibiotic is (such as
Ceftaroline Fosamil, aztreonam etc.) it is in clinical research.3 beta-lactams that AVM hereinafter Batan lists than before
Enzyme inhibitor-clavulanic acid, Sulbactam, Tazobactam-effect are stronger, and range is wider, to A class, C class and part D class β-interior acyl
Amine enzyme inhibition is significant.
AVM hereinafter Batan has diazabicyclooctane skeleton, different from classical beta-lactamase inhibitor structure, it is certainly
Body structure can restore through back reaction, have long-acting inhibition enzyme effect.In addition, classical beta-lactamase inhibitor is to C fermentoid
Do not have or with faint inhibiting effect, but AVM hereinafter Batan inhibits C class enzyme effect significant, suppression zymogram is wider.AVM hereinafter Batan exists
Clinically with its sodium-salt form application, entitled sulfuric acid list [(1R, 2S, 5R) -2- amino carbonyl -7- oxo -1, the 6- azepine of chemistry
Two rings [3.2.1] octyl- 6- base ester sodium salt, specific structure are as follows:
About the synthesis of AVM hereinafter Batan, there are more document reports, such as: CN103649051B, CN105758367A,
CN106699756A, CN106699756A etc..
It is using sulfur trioxide trimethylamine complex compound or SO mostly in current technique3.DMF these sulfur trioxides are waited
Complex and (1R, 2S, 5R) -6- hydroxyl -7- oxo -1,6- diazacyclo [3.2.1] octane -2- formamide, then again
With 4-butyl ammonium at salt.However sulfur trioxide trimethylamine complex compound or SO3.DMF the complex price of these equal sulfur trioxides
Costly, huge resistance is brought to the industrialized production of the compound.
In some existing techniques, use chlorosulfonic acid for sulfonated reagent, the sulfonated reagent price is relatively low.But it generates
Sulfoacid compound can not need to be converted to ammonium salt first with reagents such as ammonium hydrogen carbonate, obtain with 4-butyl ammonium directly at salt
The ammonium salt arrived just can thus need two-step reaction with tetrabutylammonium reactant salt, cumbersome, and yield is lower.
Summary of the invention
The present invention provides a kind of AVM hereinafter Batan intermediate [(1R, 2S, 5R) -2- (amino carbonyl) -7- oxo -1,6- two
Azabicyclo [3.2.1] octyl- 6- yl] ammonium sulfate (III) with and preparation method thereof, this method step is few, easy to operate.
The present invention discloses a kind of methods using above-mentioned intermediate preparation AVM hereinafter Batan.
A kind of AVM hereinafter Batan intermediate, including one of structure shown in following formula or a variety of:
A is trialkylamine, pyridine, alkyl pyridine, N- Alkylpiperidine, dialkyl aniline or dialkyl benzylamine, in which: described
Alkyl is C in trialkylamine5-8Alkyl, alkyl is C in alkyl pyridine1-4Alkyl, alkyl is C in N- Alkylpiperidine1-4Alkane
Base, alkyl is C in dialkyl aniline1-4Alkyl, alkyl is C in dialkyl benzylamine1-4Alkyl.The i.e. described A+It can derive from
It being capable of shape after trialkylamine, pyridine, alkyl pyridine, N- Alkylpiperidine, dialkyl aniline or dialkyl benzylamine or other reactions
At trialkylamine, pyridine, alkyl pyridine, N- Alkylpiperidine, the compound of dialkyl aniline or dialkyl benzylamine.
Preferably, the A is benzyl dimethylamine, 4- picoline, triamylamine.
A kind of preparation method of AVM hereinafter Batan intermediate, comprising: in the presence of alkaline agent, compound II ((1R, 2S, 5R) -6-
Hydroxyl -7- oxo -1,6- diazacyclo [3.2.1] octane -2- formamide) it is reacted with sulfonated reagent, then reacted again with alkaline agent,
Obtain the AVM hereinafter Batan intermediate ([(1R, 2S, 5R) -2- (amino carbonyl) -7- oxo -1,6- diazabicyclo [3.2.1]
Octyl- 6- yl] ammonium sulfate)；
The compound II structure is as follows:
The alkaline agent be trialkylamine, pyridine, alkyl pyridine, N- Alkylpiperidine, dialkyl aniline or dialkyl benzylamine,
In: alkyl is C in the trialkylamine5-8Alkyl, alkyl is C in alkyl pyridine1-4Alkyl, alkyl is in N- Alkylpiperidine
C1-4Alkyl, alkyl is C in dialkyl aniline1-4Alkyl, alkyl is C in dialkyl benzylamine1-4Alkyl.
Preferably, the sulfonated reagent is one of chlorosulfonic acid, sulfuric acid or a variety of.Further preferably chlorosulfonic acid.
Preferably, the alkaline agent is one of benzyl dimethylamine, 4- picoline, triamylamine or a variety of.
Preferably, the molar ratio of the alkaline agent and the compound II are (2~6): 1.Further preferably (3~4):
1；It is still more preferably 4:1.
Preferably, the molar ratio of the sulfonated reagent and the compound II are (1~3): 1.Further preferably
(1.5~2): 1；Molar ratio still more preferably for the sulfonated reagent and the compound II is 2:1.
Preferably, reaction temperature is -10~30 DEG C.Further preferred reaction temperature is -5~10 DEG C, further
Preferred reaction temperature is 0~5 DEG C.
Preferably, reaction dissolvent is methylene chloride, chloroform, tetrahydrofuran, acetonitrile, acetone, ethyl acetate etc..
Preferably, the alkaline agent is benzyl dimethylamine；
The molar ratio of the alkaline agent and the compound II are (3~4): 1；The sulfonated reagent is with the compound II's
Molar ratio is (1.5~2): 1；Reaction temperature is -5~10 DEG C.
The rear product of sulfonating reaction is directly reacted with alkaline agent, after the reaction was completed, can will be produced by simply extracting
Object [(1R, 2S, 5R) -2- (amino carbonyl) -7- oxo -1,6- diazabicyclo [3.2.1] octyl- 6- yl] ammonium sulfate is from system
It extracts, before extraction, can choose and in advance remove reaction dissolvent.Extractant can choose methylene chloride etc..After extraction,
Merge organic phase, remove extractant, isopropyl ether is added, the product of high-purity can both be precipitated: [(1R, 2S, 5R) -2- (amino carbonyl
Base) -7- oxo -1,6- diazabicyclo [3.2.1] octyl- 6- yl] ammonium sulfate.
The method of the preparation AVM hereinafter Batan of AVM hereinafter Batan intermediate described in a kind of any of the above-described technical solution, by the AVM hereinafter bar
Smooth intermediate is handled to obtain AVM hereinafter Batan with sodium ion.
Preferably, the sodium ion is received from isooctyl acid.
Preferably, the compound II is by (1R, 2S, 5R) -6- benzyloxy -7- oxo -1,6- diazacyclo [3.2.1]
Octane -2- formamide direct hydrogenation restores to obtain.(1R, 2S, 5R) -6- benzyloxy -7- oxo -1,6- diazacyclo [3.2.1]
Octane -2- formamide can use palladium carbon as catalyst and carry out hydrogenating reduction, and after reaction, direct filtration washing is obtained by filtration
Filtrate can directly carry out above-mentioned reaction, it can the reaction dissolvent consumption for saving above-mentioned reaction also saves hydrogenating reduction
Post-processing operation afterwards.
The reaction dissolvent that catalytic hydrogenation uses can be methylene chloride, chloroform, tetrahydrofuran, acetonitrile, acetone, ethyl acetate
Deng.Reaction temperature is 20~40 DEG C, and further preferably the hydrogenation temperature is 25~35 DEG C.Reaction time is 3~5h.
Preferably, a kind of method for preparing AVM hereinafter Batan, comprising: with oxo -1 (1R, 2S, 5R) -6- benzyloxy -7-,
6- diazacyclo [3.2.1] octane -2- formamide is raw material.By hydrogenation, sulfonation prepare AVM hereinafter Batan intermediate [(1R, 2S,
5R) -2- (amino carbonyl) -7- oxo -1,6- diazabicyclo [3.2.1] octyl- 6- yl] ammonium sulfate, then with sodium ion exchange at
Sodium salt.This method reaction condition is mild, and centre, which is reduced, uses ammonium salt salt-forming steps, easy to operate.
A kind of AVM hereinafter Batan intermediate [(1R, 2S, 5R) -2- (amino carbonyl) -7- oxo -1,6- diazabicyclo
[3.2.1] octyl- 6- yl] ammonium sulfate (III) preparation method, this method contains following steps:
(1) compound I takes off benzyl generation compound II under the catalysis of palladium charcoal；
(2) compound II, which reacts to react with alkali again with sulfonated reagent in the presence of alkaline agent, generates compound III；
(3) compound III is processed into compound IV with sodium ion.
By taking alkaline agent is benzyl dimethylamine as an example, reaction process are as follows:
Be compared with the traditional method, the present invention using appropriate alkalinity alkaline agent, instead of traditional alkaline agent (such as instead of bicarbonate
Ammonium), it can directly be reacted with one step of sulfonated reagent, not need other [(1R, 2S, the 5R)-for operating, obtaining at salinization
2- (amino carbonyl) -7- oxo -1,6- diazabicyclo [3.2.1] octyl- 6- yl] ammonium sulfate can directly react with sodium salt, after
Processing is simple, is more suitable for industrial mass production.
Meanwhile the present invention cooperates new alkaline agent, we can be reacted using the more economic sulfonated reagent of price, from
The production pressure of enterprise is greatly reduced in cost.
Alkaline agent of the invention also has both the function of acid binding agent simultaneously, does not need additional add while as reactant
Add acid binding agent, avoids the residual of acid binding agent impurity, reduce post-processing difficulty.
Detailed description of the invention
The nuclear magnetic spectrogram that Fig. 1 is the compound II that embodiment obtains-hydrogen spectrum；
The nuclear magnetic spectrogram that Fig. 2 is the compound II that embodiment obtains-carbon spectrum；
The nuclear magnetic spectrogram that Fig. 3 is the compound III that embodiment obtains-hydrogen spectrum；
The nuclear magnetic spectrogram that Fig. 4 is the compound III that embodiment obtains-carbon spectrum.
Specific embodiment
Embodiment 1:
((1R, 2S, 5R) -6- benzyloxy -7- oxo -1,6- diazacyclo [3.2.1] is pungent by investment compound I in reaction flask
Alkane -2- formamide) 5g (18mmol), acetone 50ml, palladium charcoal 0.5g, with nitrogen replace at least 3 times, with hydrogen replace 3 times, 25~
At 35 DEG C, it is passed through hydrogen heat-insulation 3h, TLC detects fully reacting, is replaced 3 times with nitrogen, filters, and elutes filter cake, filtrate with acetonitrile
0 DEG C is cooled to, is added benzyl dimethylamine 9.7g (72mmol), is added dropwise chlorosulfonic acid 4.2g (36mmol).Heat preservation 2h, fully reacting,
Reaction solution is decompressed to dry, is added methylene chloride 50ml, pure water 30ml, split-phase, and water phase is extracted primary with 20ml methylene chloride, merges
Organic phase is decompressed to dry, addition isopropyl ether 20ml, there is solid precipitation, and suction filtration is eluted, 35 DEG C of baking materials obtain compound with isopropyl ether
III ([(1R, 2S, 5R) -2- (amino carbonyl) -7- oxo -1,6- diazabicyclo [3.2.1] octyl- 6- yl] sulfuric acid benzyl diformazan
Ammonium) 5.8g, yield 80%, content > 99%.Wherein compound II nuclear-magnetism is as follows:1H NMR(400MHz,DMSO)δ9.70(s,
1H), 7.31 (d, J=44.8Hz, 2H), 3.64 (d, J=7.2Hz, 1H), 3.57 (s, 1H), 3.00 (d, J=11.5Hz, 1H),
2.86 (d, J=11.6Hz, 1H), 2.07 (dd, J=13.8,7.1Hz, 1H), 1.92-1.82 (m, 1H), 1.76-1.52 (m,
2H), map is shown in Fig. 1.13C NMR(101MHz,DMSO)δ172.19(s),167.51(s),59.50(s),59.11(s),47.64
(s), 40.54 (s), 40.42 (d, J=21.0Hz), 40.15 (s), 40.15-39.61 (m), 39.49 (s), 39.28 (s),
20.84 (s), 18.38 (s), map is shown in Fig. 2.Compound III nuclear-magnetism is as follows:1H NMR(400MHz,DMSO)δ7.57–7.15
(m, 7H), 4.26 (s, 2H), 3.98 (s, 1H), 3.68 (d, J=6.0Hz, 1H), 2.96 (dd, J=37.1,11.6Hz, 2H),
2.72 (s, 6H), 2.05 (d, J=7.2Hz, 1H), 1.83 (d, J=3.5Hz, 1H), 1.63 (t, J=9.7Hz, 2H), map is shown in
Fig. 3.13C NMR(101MHz,DMSO)δ172.00(s),166.58(s),131.35(s),131.01(s),130.01(s),
129.37 (s), 60.18 (d, J=21.6Hz), 59.91-59.79 (m), 58.06 (s), 47.40 (s), 42.34 (s), 21.00
(s), 18.54 (s), spectrogram is shown in Fig. 4.
Compound III 5.0g, 20~35 DEG C of addition ethyl alcohol 25ml are put into reaction flask, 20~35 DEG C of dissolved clarifications are added dropwise different pungent
Acid receives ethanol solution, there is solid precipitation, and 20~35 DEG C of heat preservation 2h are filtered, eluted with dehydrated alcohol, dries.Obtain compound IV
3.3g, yield 92%, content: 99%.
Embodiment 2:
Compound I 5g (18mmol) is put into reaction flask, acetone 50ml, palladium charcoal 0.5g are replaced at least 3 times with nitrogen, are used
At hydrogen is replaced 3 times, 25~35 DEG C, it is passed through hydrogen heat-insulation 3h, TLC detects fully reacting, is replaced 3 times with nitrogen, filters, with third
Ketone elutes filter cake, and filtrate cools to 0 DEG C, is added benzyl dimethylamine 9.7g (72mmol), is added dropwise sulfuric acid 3.5g (36mmol).Heat preservation
2h, fully reacting.Reaction solution be decompressed to it is dry, be added methylene chloride 50ml, pure water 30ml, split-phase, water phase 20ml methylene chloride
Primary, merging organic phase is extracted, dry, addition isopropyl ether 20ml is decompressed to, there is solid precipitation, suction filtration is eluted, 35 DEG C with isopropyl ether
Baking material obtains compound III 5.9g, yield 83%, content > 99%.
Reaction flask class puts into compound III 5.0g, 20~35 DEG C of addition ethyl alcohol 25ml, and 20~35 DEG C of dissolved clarifications are added dropwise different pungent
Acid receives ethanol solution, there is solid precipitation, and 20~35 DEG C of heat preservation 2h are filtered, eluted with dehydrated alcohol, dries.Obtain compound IV
3.4g, yield 95%, content: 99%.
Embodiment 3:
Compound I 5g (18mmol) is put into reaction flask, acetone 50ml, palladium charcoal 0.5g are replaced at least 3 times with nitrogen, are used
At hydrogen is replaced 3 times, 25~35 DEG C, it is passed through hydrogen heat-insulation 5h, TLC detects fully reacting, is replaced 3 times with nitrogen, filters, with third
Ketone elutes filter cake, and filtrate cools to 0 DEG C, is added benzyl dimethylamine 9.7g (72mmol), is added dropwise sulfuric acid 3.5g (36mmol).Heat preservation
2h, fully reacting.Reaction solution be decompressed to it is dry, be added methylene chloride 50ml, pure water 30ml, split-phase, water phase 20ml methylene chloride
It extracts primary, merges organic phase, be decompressed to dry, be added ethyl alcohol 25ml, 20~35 DEG C of dissolved clarifications are added dropwise isooctyl acid and receive ethanol solution,
There is solid precipitation, 20~35 DEG C of heat preservation 2h are filtered, eluted with dehydrated alcohol, are dried.Obtain compound IV 4.0g, yield
77%, content: 99%.
Embodiment 4:
Compound I 5g (18mmol) is put into reaction flask, tetrahydrofuran 50ml, palladium charcoal 0.5g, with nitrogen displacement at least 3
It is secondary, at being replaced 3 times, 25~35 DEG C with hydrogen, it is passed through hydrogen heat-insulation 4h, TLC detects fully reacting, is replaced 3 times with nitrogen, takes out
Filter elutes filter cake with tetrahydrofuran, and filtrate cools to 0 DEG C, is added 4- picoline 6.7g (72mmol), and chlorosulfonic acid is added dropwise
3.15g(27mmol).Keep the temperature 2h, fully reacting, reaction solution be decompressed to it is dry, be added methylene chloride 50ml, pure water 30ml, split-phase,
Water phase is extracted primary with 20ml methylene chloride, merges organic phase, is decompressed to dry, 20~35 DEG C of addition ethyl alcohol 25ml, and 20~35 DEG C
Dissolved clarification is added dropwise isooctyl acid and receives ethanol solution, there is solid precipitation, and 20~35 DEG C of heat preservation 2h are filtered, eluted with dehydrated alcohol, drying.
Obtain compound IV4.2g, yield 80.7%, content: 99%.
Embodiment 5:
Compound I 5g (18mmol) is put into reaction flask, acetone 50ml, palladium charcoal 0.5g are replaced at least 3 times with nitrogen, are used
At hydrogen is replaced 3 times, 25~35 DEG C, it is passed through hydrogen heat-insulation 3h, TLC detects fully reacting, is replaced 3 times with nitrogen, filters, with third
Ketone elutes filter cake, and filtrate cools to 0 DEG C, is added 4- picoline 6.7g (72mmol), is added dropwise chlorosulfonic acid 3.15g (27mmol).
Keep the temperature 2h, fully reacting, reaction solution be decompressed to it is dry, be added methylene chloride 50ml, pure water 30ml, split-phase, water phase 20ml dichloro
Methane extracts primary, merging organic phase, is decompressed to dry, 20~35 DEG C of addition ethyl alcohol 25ml, and isooctyl acid is added dropwise in 20~35 DEG C of dissolved clarifications
It receives ethanol solution, there is solid precipitation, 20~35 DEG C of heat preservation 2h are filtered, eluted with dehydrated alcohol, are dried.Obtain compound IV
4.1g, yield 78.8%, content: 99%.
Embodiment 6:
Compound I 5g (18mmol) is put into reaction flask, acetone 50ml, palladium charcoal 0.5g are replaced at least 3 times with nitrogen, are used
At hydrogen is replaced 3 times, 25~35 DEG C, it is passed through hydrogen heat-insulation 3h, TLC detects fully reacting, is replaced 3 times with nitrogen, filters, with third
Ketone elutes filter cake, and filtrate cools to 0 DEG C, is added triamylamine 16.4g (72mmol), is added dropwise chlorosulfonic acid 3.15g (27mmol).Heat preservation
2h, fully reacting, reaction solution be decompressed to it is dry, be added methylene chloride 50ml, pure water 30ml, split-phase, water phase 20ml methylene chloride
It extracts primary, merges organic phase, be decompressed to dry, 20~35 DEG C of additions ethyl alcohol 25ml, 20~35 DEG C of dissolved clarifications, dropwise addition isooctyl acid receives second
Alcoholic solution has solid precipitation, and 20~35 DEG C of heat preservation 2h are filtered, eluted with dehydrated alcohol, dries.Compound IV 4.0g is obtained,
Yield 77%, content: 99%.
Comparative example 1
According to the condition of embodiment 1, benzyl dimethylamine is replaced with to the ammonium hydrogen carbonate of equimolar amounts, according to identical rear place
Reason method, finally almost without obtaining any [(1R, 2S, 5R) -2- (amino carbonyl) -7- oxo -1,6- diazabicyclo
[3.2.1] octyl- 6- yl] ammonium sulfate, it may be possible to most chlorosulfonic acid is carbonated hydrogen ammonium and directly consumes into salt.
Comparative example 2
Embodiment 3,4 benzyl dimethylamine 9.7g (72mmol) of embodiment are replaced with to the dimethylformamide of 72mmol,
His condition after the reaction was completed, is being by the compound that detection discovery generates with sulfuric acid or chlorosulfonic acid with embodiment 3, embodiment 4
(1R, 2S, 5R) -6- sulfonic group -7- oxo -1,6- diazacyclo [3.2.1] octane -2- formamide.And ethyl alcohol is received with isooctyl acid
After solution reaction, final product compound IV is not obtained finally.This is also turned out, does sulfonation examination using chlorosulfonic acid, sulfuric acid etc.
When agent, obtained (1R, 2S, 5R) -6- sulfonic group -7- oxo -1,6- diazacyclo [3.2.1] octane -2- formamide can not
It directly receives and reacts with isooctyl acid.
Comparative example 3
Compound I 5g (18mmol) is put into reaction flask, tetrahydrofuran 50ml, palladium charcoal 0.5g, with nitrogen displacement at least 3
It is secondary, at being replaced 3 times, 25~35 DEG C with hydrogen, it is passed through hydrogen heat-insulation 4h, TLC detects fully reacting, is replaced 3 times with nitrogen, takes out
Filter elutes filter cake with tetrahydrofuran, and filtrate cools to 0 DEG C, is added dimethylformamide (72mmol), and chlorosulfonic acid 3.15g is added dropwise
(27mmol).2h is kept the temperature, system liquid is added in ammonium hydrogen carbonate (180mmol) aqueous solution (40ml) by fully reacting, keeps pH
Value is greater than 6, stirs 15min, and methylene chloride, layering is added, and water phase is washed with methylene chloride, merges organic phase, is then added four
Solution of the butyl ammonium hydrogen sulfate (27mmol) in methylene chloride (100ml) stirs 15min.Each layer is separated, methylene chloride is used
(50ml) aqueous layer extracted.Organic phase evaporated under reduced pressure, 20~35 DEG C of addition ethyl alcohol 25ml, 20~35 DEG C of dissolved clarifications are added dropwise isooctyl acid and receive
Ethanol solution has solid precipitation, and 20~35 DEG C of heat preservation 2h are filtered, eluted with dehydrated alcohol, dries.Compound IV2.8g is obtained,
Yield 55%.Significantly lower than yield of the invention.
Claims (10)
1. a kind of AVM hereinafter Batan intermediate, which is characterized in that including one of structure shown in following formula or a variety of:
A derives from trialkylamine, pyridine, alkyl pyridine, N- Alkylpiperidine, dialkyl aniline or dialkyl benzylamine, in which: described
Alkyl is C in trialkylamine5-8Alkyl, alkyl is C in alkyl pyridine1-4Alkyl, alkyl is C in N- Alkylpiperidine1-4Alkane
Base, alkyl is C in dialkyl aniline1-4Alkyl, alkyl is C in dialkyl benzylamine1-4Alkyl.
2. AVM hereinafter Batan intermediate according to claim 1, which is characterized in that the A derives from benzyl dimethylamine, 4- first
Yl pyridines, triamylamine.
3. a kind of preparation method of AVM hereinafter Batan intermediate described in claim 1, comprising: in the presence of alkaline agent, compound II
It reacts with sulfonated reagent, is then reacted again with alkaline agent, obtain the AVM hereinafter Batan intermediate；
The compound II structure is as follows:
The alkaline agent is trialkylamine, pyridine, alkyl pyridine, N- Alkylpiperidine, dialkyl aniline or dialkyl benzylamine, in which:
Alkyl is C in the trialkylamine5-8Alkyl, alkyl is C in alkyl pyridine1-4Alkyl, alkyl is C in N- Alkylpiperidine1-4
Alkyl, alkyl is C in dialkyl aniline1-4Alkyl, alkyl is C in dialkyl benzylamine1-4Alkyl.
4. the preparation method of AVM hereinafter Batan intermediate according to claim 3, which is characterized in that the sulfonated reagent is chlorine
One of sulfonic acid, sulfuric acid are a variety of.
5. the preparation method of AVM hereinafter Batan intermediate according to claim 3, which is characterized in that the alkaline agent is benzyl two
One of methylamine, 4- picoline, triamylamine are a variety of.
6. the preparation method of AVM hereinafter Batan intermediate according to claim 3, which is characterized in that the alkaline agent and describedization
The molar ratio for closing object II is (2~6): 1.
7. the preparation method of AVM hereinafter Batan intermediate according to claim 3, which is characterized in that the sulfonated reagent and institute
The molar ratio for stating compound II is (1~3): 1.
8. the preparation method of AVM hereinafter Batan intermediate according to claim 3, which is characterized in that reaction temperature be -10~
30℃。
9. a kind of method of the preparation AVM hereinafter Batan of AVM hereinafter Batan intermediate described in claim 1, which is characterized in that by the AVM hereinafter
Batan intermediate is handled to obtain AVM hereinafter Batan with sodium ion.
10. preparing the method for AVM hereinafter Batan according to claim 9, which is characterized in that the sodium ion derives from isooctyl acid
It receives.
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| CN112679498A (en) * | 2019-11-29 | 2021-04-20 | 北京耀诚惠仁科技有限公司 | Sulfonic acid quaternary ammonium salt compound and preparation method and application thereof |
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| CN1289500C (en) * | 2000-08-01 | 2006-12-13 | 艾文蒂斯药品公司 | Azabicyclic compounds, preparation thereof and use as medicines, in particular as antibacterial agents |
| CN102834395A (en) * | 2009-10-09 | 2012-12-19 | 诺维塞尔公司 | Polymorphic and pseudopolymorphic forms of a pharmaceutical compound |
| CN107417686A (en) * | 2017-09-19 | 2017-12-01 | 北京化工大学 | A kind of synthetic method of AVM hereinafter Batan sodium |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1289500C (en) * | 2000-08-01 | 2006-12-13 | 艾文蒂斯药品公司 | Azabicyclic compounds, preparation thereof and use as medicines, in particular as antibacterial agents |
| CN102834395A (en) * | 2009-10-09 | 2012-12-19 | 诺维塞尔公司 | Polymorphic and pseudopolymorphic forms of a pharmaceutical compound |
| CN107417686A (en) * | 2017-09-19 | 2017-12-01 | 北京化工大学 | A kind of synthetic method of AVM hereinafter Batan sodium |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112679498A (en) * | 2019-11-29 | 2021-04-20 | 北京耀诚惠仁科技有限公司 | Sulfonic acid quaternary ammonium salt compound and preparation method and application thereof |
| WO2021104483A1 (en) * | 2019-11-29 | 2021-06-03 | 北京耀诚惠仁科技有限公司 | Sulfonic acid quaternary ammonium salt compound, preparation method and application thereof |
| 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 |
| CN111732587B (en) * | 2020-06-05 | 2022-11-25 | 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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