CN110813384A - Method for treating catalyst carrier for meropenem synthesis and preparation method of catalyst - Google Patents
Method for treating catalyst carrier for meropenem synthesis and preparation method of catalyst Download PDFInfo
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- CN110813384A CN110813384A CN201910978684.5A CN201910978684A CN110813384A CN 110813384 A CN110813384 A CN 110813384A CN 201910978684 A CN201910978684 A CN 201910978684A CN 110813384 A CN110813384 A CN 110813384A
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- Prior art keywords
- palladium
- meropenem
- carbon
- aqueous solution
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- 239000003054 catalyst Substances 0.000 title claims abstract description 91
- 229960002260 meropenem Drugs 0.000 title claims abstract description 91
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 title claims abstract description 91
- 238000000034 method Methods 0.000 title claims abstract description 53
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title abstract description 21
- 238000001308 synthesis method Methods 0.000 title description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 72
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 70
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 52
- 239000007864 aqueous solution Substances 0.000 claims abstract description 47
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 36
- 238000010438 heat treatment Methods 0.000 claims abstract description 25
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 24
- 238000005406 washing Methods 0.000 claims abstract description 24
- 238000010992 reflux Methods 0.000 claims abstract description 23
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000001035 drying Methods 0.000 claims abstract description 10
- 239000000243 solution Substances 0.000 claims description 51
- 239000002002 slurry Substances 0.000 claims description 43
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 42
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- 239000012018 catalyst precursor Substances 0.000 claims description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 229910052763 palladium Inorganic materials 0.000 claims description 18
- 239000003638 chemical reducing agent Substances 0.000 claims description 14
- 239000012065 filter cake Substances 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- 238000004537 pulping Methods 0.000 claims description 14
- 230000000087 stabilizing effect Effects 0.000 claims description 14
- 239000002023 wood Substances 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 13
- KWSLGOVYXMQPPX-UHFFFAOYSA-N 5-[3-(trifluoromethyl)phenyl]-2h-tetrazole Chemical compound FC(F)(F)C1=CC=CC(C2=NNN=N2)=C1 KWSLGOVYXMQPPX-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- 229910001379 sodium hypophosphite Inorganic materials 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003610 charcoal Substances 0.000 claims description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 35
- 238000006243 chemical reaction Methods 0.000 abstract description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 8
- 239000000539 dimer Substances 0.000 abstract description 7
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 4
- 238000004381 surface treatment Methods 0.000 abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- 239000000084 colloidal system Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical group C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 5
- 238000007086 side reaction Methods 0.000 description 5
- 238000007142 ring opening reaction Methods 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000005470 impregnation Methods 0.000 description 2
- FWCHISPFSGCORQ-UHFFFAOYSA-N morpholine;hydrate Chemical compound O.C1COCCN1 FWCHISPFSGCORQ-UHFFFAOYSA-N 0.000 description 2
- PJGGEFUAFDAJJT-ALUDVLAQSA-N (4-nitrophenyl)methyl (4r,5s,6s)-3-[(3s,5s)-5-(dimethylcarbamoyl)-1-[(4-nitrophenyl)methoxycarbonyl]pyrrolidin-3-yl]sulfanyl-6-[(1r)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Chemical compound N1([C@@H](C[C@@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(=O)OCC=1C=CC(=CC=1)[N+]([O-])=O)=O)[C@H](O)C)C(=O)N(C)C)C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 PJGGEFUAFDAJJT-ALUDVLAQSA-N 0.000 description 1
- XKGABVKQWYZCQF-WWQIJRAWSA-N (4r,5s,6s)-3-[(3s,5s)-1-[(2s,3r)-2-[(2s,3r)-5-carboxy-4-[(3s,5s)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl-3-methyl-2,3-dihydro-1h-pyrrol-2-yl]-3-hydroxybutanoyl]-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl-6-[(1r)-1-hydroxyethyl]-4-methyl-7-oxo-1-a Chemical compound N([C@H]([C@H]1C)[C@@H]([C@H](O)C)C(=O)N2[C@@H](C[C@@H](C2)SC=2[C@@H]([C@H]3N(C([C@@H]3[C@@H](C)O)=O)C=2C(O)=O)C)C(=O)N(C)C)C(C(O)=O)=C1S[C@@H]1CN[C@H](C(=O)N(C)C)C1 XKGABVKQWYZCQF-WWQIJRAWSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WKDDRNSBRWANNC-ATRFCDNQSA-N Thienamycin Chemical compound C1C(SCCN)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 WKDDRNSBRWANNC-ATRFCDNQSA-N 0.000 description 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 125000001477 organic nitrogen group Chemical group 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- -1 p-nitrobenzyloxycarbonyl Chemical group 0.000 description 1
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0235—Nitrogen containing compounds
- B01J31/0244—Nitrogen containing compounds with nitrogen contained as ring member in aromatic compounds or moieties, e.g. pyridine
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
- B01J23/44—Palladium
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
- B01J31/28—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24 of the platinum group metals, iron group metals or copper
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
- C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
- C07D477/20—Sulfur atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
Abstract
The invention discloses a method for treating a palladium-carbon catalyst carrier for synthesizing meropenem, which comprises the following steps: under the microwave heating condition, performing reflux treatment on powdered activated carbon by using an aqueous solution of a nitrogen-containing organic reagent, washing until the pH value is 7.0-8.0, and drying to obtain the palladium-carbon catalyst carrier for meropenem synthesis. The invention also discloses a preparation method of the palladium-carbon catalyst. According to the invention, the powdery active carbon is subjected to reflux treatment under the microwave heating condition, the microwave heating is uniform, the uniformity of the reaction between the reagent and the surface of the active carbon in the surface treatment process of the active carbon is ensured, the microwave heating efficiency is high, and the carrier treatment efficiency can be ensured; the powdery active carbon is subjected to reflux treatment by adopting an aqueous solution containing a nitrogen organic reagent, an alkaline group is introduced on the surface of the active carbon, an alkaline environment is created, the prepared catalyst can effectively inhibit the generation of four-membered ring open loop and dimer in meropenem reaction, the meropenem synthesis operation is simplified, and the problem of organic reagent residue is avoided.
Description
Technical Field
The invention belongs to the technical field of precious metal catalyst preparation, and particularly relates to a method for treating a catalyst carrier for meropenem synthesis and preparing a catalyst.
Background
Meropenem is an important variety of carbapenem antibiotics, and has wide antibacterial spectrum and the most extensive application. In the last step of the chemical synthesis, palladium-carbon catalyst is used to simultaneously remove the protecting groups PNB (p-nitrobenzyl) and (p-nitrobenzyloxycarbonyl) PNZ, as shown in the following reaction formula (I). The reaction conditions are controlled, so that side reactions such as double bonds, carbonyl and side chain thienamycin can be avoided to the maximum extent, but development side reactions of a four-membered ring in a meropenem main ring cannot be avoided, as shown in a reaction formula (II), so that the contents of two impurities of a ring-opening product and a dimer formed by the ring-opening product in a meropenem crude product are very easy to exceed the standard, and the medication safety is influenced. The prior effective method is to add an organic nitrogen-containing reagent into the system to inhibit the side reaction, but has the defects of complicated operation and reagent residue.
Patent CN106861682B discloses a preparation method of palladium carbon catalyst for meropenem, the palladium carbon catalyst is obtained by dipping palladium hydroxide solution on activated carbon carrier and reducing by reducing agent, the preparation process of the method comprises: 1) preparing palladium hydroxide by using a palladium-containing compound; 2) preparing a palladium hydroxide solution; 3) putting activated carbon into a palladium hydroxide solution to prepare impregnation slurry; 4) the impregnation slurry is subjected to a chemical reduction reaction. The palladium-carbon catalyst is applied to meropenem in carbapenem antibiotics, and has the advantage of strong selection pertinence. The technical key point of the invention is to prepare a proper palladium hydroxide colloid and then to dip the colloid on the active carbon. However, two harsh conditions exist for palladium hydroxide colloid preparation: firstly, the temperature is controlled, and precipitates are easily formed at improper temperature; and secondly, the colloid palladium hydroxide can form colloid only when the concentration is very dilute, so that the preparation efficiency of the catalyst is very low, and industrial scale-up production is not easy. The method is also not suitable for mass production of high-content palladium-carbon catalysts.
Patent CN106179334B discloses a mesoporous carbon-supported palladium catalyst and application thereof, wherein the catalyst is composed of a carrier and an active component loaded on the carrier, the carrier is mesoporous carbon, and the mesoporous carbon-supported palladium catalyst obtained by the invention is applied to the process of removing a protecting group by catalytic hydrogenation synthesized by meropenem, and has the characteristics of high activity and high stability. The invention has the technical key points that the synthesized mesoporous carbon carrier has the advantages, and the proper pore size distribution of the mesoporous carbon provides an excellent catalytic reaction environment, thereby being very beneficial to the catalytic reaction of the participation of macromolecular substrates. However, the main limitation of the process of the present invention is that the cost of the mesoporous carbon is high, and the removal of the template agent in the synthesis process of the mesoporous carbon consumes a large amount of inorganic alkali and hydrofluoric acid, which is not beneficial to environmental protection and goes against the current trend of green industrial development.
In summary, no method or scheme for inhibiting the ring opening of the four-membered ring and the formation of the dimer in the meropenem reaction by activated carbon treatment and catalyst process control is found in the published patents and documents.
Disclosure of Invention
The technical problem to be solved by the present invention is to provide a method for treating a palladium-carbon catalyst carrier for meropenem synthesis, aiming at the defects of the prior art. The method ensures the uniformity of the reaction between the reagent and the surface of the activated carbon in the surface treatment process of the activated carbon by carrying out reflux treatment on the powdery activated carbon under the microwave heating condition, has high microwave heating efficiency and can ensure the efficiency of carrier treatment; the powdery active carbon is subjected to reflux treatment by adopting an aqueous solution containing a nitrogen organic reagent, an alkaline group is introduced on the surface of the active carbon, an alkaline environment is created, the prepared catalyst can effectively inhibit the generation of four-membered ring open loop and dimer in meropenem reaction, the meropenem synthesis operation is simplified, and the problem of organic reagent residue is avoided.
In order to solve the technical problems, the invention adopts the technical scheme that: a treatment method of a palladium-carbon catalyst carrier for meropenem synthesis is characterized by comprising the following steps: under the microwave heating condition, performing reflux treatment on powdered activated carbon by using an aqueous solution of a nitrogen-containing organic reagent, washing until the pH value is 7.0-8.0, and drying to obtain a palladium-carbon catalyst carrier for meropenem synthesis; the mass percentage of the nitrogenous organic reagent in the aqueous solution of the nitrogenous organic reagent is 1-10%.
The method for treating the palladium-carbon catalyst carrier for synthesizing meropenem is characterized in that the nitrogen-containing organic reagent is pyridine, morpholine, quinoline, pyrrole, triethylamine or diethylamine.
The treatment method of the palladium-carbon catalyst carrier for the meropenem synthesis is characterized in that the microwave heating temperature is 60-100 ℃, and the reflux treatment time is 2-3 h.
The method for treating the palladium-carbon catalyst carrier for synthesizing the meropenem is characterized in that the powdery active carbon has the granularity of 200-400 meshes and the specific surface area of 800m2/g～1000m2Wood charcoal per gram.
The method for treating the palladium-carbon catalyst carrier for synthesizing the meropenem is characterized in that the mass percentage of the nitrogen-containing organic reagent in the aqueous solution of the nitrogen-containing organic reagent is 1-5%.
In addition, the invention also discloses a method for preparing the palladium-carbon catalyst for synthesizing meropenem by adopting the carrier treated by the treatment method, which is characterized by comprising the following steps:
pulping a carrier by using pure water to obtain carbon pulp, adding a palladium chloride solution into the carbon pulp, stirring for 1-2 h, then adjusting the pH value of a system to 8.0 by using an inorganic alkali solution, and stabilizing for 2-4 h to obtain catalyst precursor slurry;
and step two, dropwise adding an aqueous solution of a reducing agent into the catalyst precursor slurry obtained in the step one, reducing for 2-4 h, filtering, and washing a filter cake to obtain the palladium-carbon catalyst for meropenem synthesis.
The method described above, wherein the carrier in the first step accounts for 10% by mass of pure water.
The method is characterized in that the reducing agent in the step two is sodium hypophosphite, hydrazine hydrate, glucose or sodium thiosulfate, the molar weight of the reducing agent is 5-10 times of that of palladium metal, and the concentration of the reducing agent aqueous solution is 5-10 wt%.
The method is characterized in that the inorganic base solution in the step one is KHCO3Aqueous solution, NaHCO3Aqueous solution, K2CO3Aqueous solution or Na2CO3An aqueous solution.
The method is characterized in that the molar weight of the reducing agent is 8-10 times of that of the palladium metal, and the concentration of the reducing agent aqueous solution is 8-10 wt%.
Compared with the prior art, the invention has the following advantages:
1. according to the invention, the powdery active carbon is subjected to reflux treatment under the microwave heating condition, the microwave heating is uniform, the uniformity of the reaction between the reagent and the surface of the active carbon in the surface treatment process of the active carbon is ensured, the microwave heating efficiency is high, and the carrier treatment efficiency can be ensured; the powdery active carbon is subjected to reflux treatment by adopting an aqueous solution containing a nitrogen organic reagent, an alkaline group is introduced on the surface of the active carbon, an alkaline environment is created, the prepared catalyst can effectively inhibit the generation of four-membered ring open loop and dimer in meropenem reaction, the meropenem synthesis operation is simplified, and the problem of organic reagent residue is avoided.
2. The catalyst of the invention has simple preparation process and no harsh control point, and is beneficial to batch production.
3. The catalyst prepared by the method can be applied to the production of other penem medicines, and has positive significance for improving the main reaction yield and inhibiting the occurrence of side reactions.
The technical solution of the present invention is further described in detail by the following examples.
Detailed Description
Example 1
The method for treating the palladium-carbon catalyst carrier for synthesizing meropenem of the embodiment comprises the following steps: under the condition of microwave heating and constant temperature of 95 ℃, the granularity is 200-400 meshes, and the specific surface area is 900m2And refluxing/g of wood carbon by using a pyridine aqueous solution with the mass concentration of 5% for 3 hours, washing until the pH value is 7.5, and drying to obtain the palladium-carbon catalyst carrier for synthesizing meropenem.
The preparation method of the 5.0% palladium-carbon catalyst for synthesizing meropenem of the embodiment comprises the following steps:
step one, pulping 9.5g of carrier by using pure water to obtain carbon pulp; dissolving palladium chloride containing 0.5g of palladium by using dilute hydrochloric acid to obtain a palladium chloride solution; adding palladium chloride solution into the carbon slurry, stirring for 1h, and then adding Na2CO3Adjusting the pH value of the system to 8.0 by using an aqueous solution, and stabilizing for 3 hours to obtain catalyst precursor slurry; the mass of the carrier is 10% of that of the pure water;
and step two, dripping 82g of 5 wt% aqueous sodium hypophosphite solution into the catalyst precursor slurry obtained in the step one, reducing for 3 hours, filtering, and washing a filter cake to obtain the palladium-carbon catalyst for meropenem synthesis.
Example 2
The method for treating the palladium-carbon catalyst carrier for synthesizing meropenem of the embodiment comprises the following steps: under the condition of microwave heating and constant temperature of 95 ℃, the granularity is 200-400 meshes, and the specific surface area is 900m2Refluxing/g of wood charcoal with 5% quinoline water solution for 3h,and washing until the pH value is 7.5, and drying to obtain the palladium-carbon catalyst carrier for synthesizing meropenem.
The preparation method of the 5.0% palladium-carbon catalyst for synthesizing meropenem of the embodiment comprises the following steps:
step one, pulping 9.5g of carrier by using pure water to obtain carbon pulp; dissolving palladium chloride containing 0.5g of palladium by using dilute hydrochloric acid to obtain a palladium chloride solution; adding palladium chloride solution into the carbon slurry, stirring for 1h, and then adding Na2CO3Adjusting the pH value of the system to 8.0 by using an aqueous solution, and stabilizing for 3 hours to obtain catalyst precursor slurry; the mass of the carrier is 10% of that of the pure water;
and step two, dripping 82g of 5 wt% aqueous sodium hypophosphite solution into the catalyst precursor slurry obtained in the step one, reducing for 3 hours, filtering, and washing a filter cake to obtain the palladium-carbon catalyst for meropenem synthesis.
Example 3
The method for treating the palladium-carbon catalyst carrier for synthesizing meropenem of the embodiment comprises the following steps: under the condition of microwave heating and constant temperature of 95 ℃, the granularity is 200-400 meshes, and the specific surface area is 900m2And refluxing/g of wood carbon by using a pyrrole aqueous solution with the mass concentration of 5% for 3 hours, washing until the pH value is 7.5, and drying to obtain the palladium-carbon catalyst carrier for synthesizing meropenem.
The preparation method of the 5.0% palladium-carbon catalyst for synthesizing meropenem of the embodiment comprises the following steps:
step one, pulping 9.5g of carrier by using pure water to obtain carbon pulp; dissolving palladium chloride containing 0.5g of palladium by using dilute hydrochloric acid to obtain a palladium chloride solution; adding palladium chloride solution into the carbon slurry, stirring for 1h, and then adding Na2CO3Adjusting the pH value of the system to 8.0 by using an aqueous solution, and stabilizing for 3 hours to obtain catalyst precursor slurry; the mass of the carrier is 10% of that of the pure water;
and step two, dripping 82g of 5 wt% aqueous sodium hypophosphite solution into the catalyst precursor slurry obtained in the step one, reducing for 3 hours, filtering, and washing a filter cake to obtain the palladium-carbon catalyst for meropenem synthesis.
Example 4
Treatment of palladium on carbon catalyst support for meropenem synthesis of this exampleThe method comprises the following steps: under the condition of microwave heating and constant temperature of 95 ℃, the granularity is 200-400 meshes, and the specific surface area is 900m2And/g wood carbon is treated by refluxing with morpholine water solution with the mass concentration of 5% for 3h, washed until the pH value is 7.5, and dried to obtain the palladium-carbon catalyst carrier for meropenem synthesis.
The preparation method of the 5.0% palladium-carbon catalyst for synthesizing meropenem of the embodiment comprises the following steps:
step one, pulping 9.5g of carrier by using pure water to obtain carbon pulp; dissolving palladium chloride containing 0.5g of palladium by using dilute hydrochloric acid to obtain a palladium chloride solution; adding palladium chloride solution into the carbon slurry, stirring for 1h, and then adding Na2CO3Adjusting the pH value of the system to 8.0 by using an aqueous solution, and stabilizing for 3 hours to obtain catalyst precursor slurry; the mass of the carrier is 10% of that of the pure water;
and step two, dripping 82g of 5 wt% aqueous sodium hypophosphite solution into the catalyst precursor slurry obtained in the step one, reducing for 3 hours, filtering, and washing a filter cake to obtain the palladium-carbon catalyst for meropenem synthesis.
Example 5
The method for treating the palladium-carbon catalyst carrier for synthesizing meropenem of the embodiment comprises the following steps: under the condition of microwave heating and constant temperature of 95 ℃, the granularity is 200-400 meshes, and the specific surface area is 900m2And/g wood carbon is subjected to reflux treatment for 3 hours by using a triethylamine aqueous solution with the mass concentration of 5%, and is dried after being washed until the pH value is 7.5, so that the palladium-carbon catalyst carrier for synthesizing meropenem is obtained.
The preparation method of the 5.0% palladium-carbon catalyst for synthesizing meropenem of the embodiment comprises the following steps:
step one, pulping 9.5g of carrier by using pure water to obtain carbon pulp; dissolving palladium chloride containing 0.5g of palladium by using dilute hydrochloric acid to obtain a palladium chloride solution; adding palladium chloride solution into the carbon slurry, stirring for 1h, and then adding Na2CO3Adjusting the pH value of the system to 8.0 by using an aqueous solution, and stabilizing for 3 hours to obtain catalyst precursor slurry; the mass of the carrier is 10% of that of the pure water;
and step two, dripping 82g of 5 wt% aqueous sodium hypophosphite solution into the catalyst precursor slurry obtained in the step one, reducing for 3 hours, filtering, and washing a filter cake to obtain the palladium-carbon catalyst for meropenem synthesis.
Example 6
The method for treating the palladium-carbon catalyst carrier for synthesizing meropenem of the embodiment comprises the following steps: under the condition of microwave heating and constant temperature of 95 ℃, the granularity is 200-400 meshes, and the specific surface area is 900m2And refluxing/g of wood carbon by using a diethylamine aqueous solution with the mass concentration of 5% for 3 hours, washing until the pH is 7.5, and drying to obtain the palladium-carbon catalyst carrier for synthesizing meropenem.
The preparation method of the 5.0% palladium-carbon catalyst for synthesizing meropenem of the embodiment comprises the following steps:
step one, pulping 9.5g of carrier by using pure water to obtain carbon pulp; dissolving palladium chloride containing 0.5g of palladium by using dilute hydrochloric acid to obtain a palladium chloride solution; adding palladium chloride solution into the carbon slurry, stirring for 1h, and then adding Na2CO3Adjusting the pH value of the system to 8.0 by using an aqueous solution, and stabilizing for 3 hours to obtain catalyst precursor slurry; the mass of the carrier is 10% of that of the pure water;
and step two, dripping 82g of 5 wt% aqueous sodium hypophosphite solution into the catalyst precursor slurry obtained in the step one, reducing for 3 hours, filtering, and washing a filter cake to obtain the palladium-carbon catalyst for meropenem synthesis.
Comparative example
Preparation of 5.0% palladium on carbon catalyst for meropenem synthesis:
step one, selecting the particle size of 200-400 meshes and the specific surface area of 900m2Heating wood charcoal/g with microwave, refluxing with water solution at constant temperature of 95 deg.C for 3 hr, washing with pure water until pH is 7.5, and oven drying to obtain carrier;
step two, pulping the carrier in the step one by using pure water to obtain carbon pulp; dissolving a metered amount of palladium chloride by using dilute hydrochloric acid to obtain a palladium chloride solution; adding palladium chloride solution into the carbon slurry, stirring for 1h, and then adding Na2CO3Adjusting the pH value of the system to 8.0 by using an aqueous solution, and stabilizing for 3 hours to obtain catalyst precursor slurry; the mass of the carrier is 10% of that of the pure water;
and step two, dripping 82g of 5 wt% aqueous sodium hypophosphite solution into the catalyst precursor slurry obtained in the step one, reducing for 3 hours, filtering, and washing a filter cake to obtain the palladium-carbon catalyst for meropenem synthesis.
Example 7
The method for treating the palladium-carbon catalyst carrier for synthesizing meropenem of the embodiment comprises the following steps: under the condition of microwave heating and constant temperature of 100 ℃, the granularity is 200-400 meshes, and the specific surface area is 800m2And refluxing/g of wood carbon by using a 1% diethylamine aqueous solution, washing for 3 hours until the pH is 7.5, and drying to obtain the palladium-carbon catalyst carrier for synthesizing meropenem.
The preparation method of the 5.0% palladium-carbon catalyst for synthesizing meropenem of the embodiment comprises the following steps:
step one, pulping 9.5g of carrier by using pure water to obtain carbon pulp; dissolving palladium chloride containing 0.5g of palladium by using dilute hydrochloric acid to obtain a palladium chloride solution; adding palladium chloride solution into the carbon slurry, stirring for 2h, and then adding KHCO3Adjusting the pH value of the system to 8.0 by using an aqueous solution, and stabilizing for 2 hours to obtain catalyst precursor slurry; the mass of the carrier is 10% of that of the pure water;
and step two, dripping 19g of 10 wt% hydrazine hydrate aqueous solution into the catalyst precursor slurry obtained in the step one, reducing for 2 hours, filtering, and washing a filter cake to obtain the palladium-carbon catalyst for meropenem synthesis.
Example 8
The method for treating the palladium-carbon catalyst carrier for synthesizing meropenem of the embodiment comprises the following steps: under the condition of microwave heating and constant temperature of 60 ℃, the granularity is 200-400 meshes, and the specific surface area is 1000m2And refluxing/g of wood carbon by using a pyridine aqueous solution with the mass concentration of 10% for 2 hours, washing until the pH value is 7.0, and drying to obtain the palladium-carbon catalyst carrier for synthesizing meropenem.
The preparation method of the 5.0% palladium-carbon catalyst for synthesizing meropenem of the embodiment comprises the following steps:
step one, pulping 9.5g of carrier by using pure water to obtain carbon pulp; dissolving palladium chloride containing 0.5g of palladium by using dilute hydrochloric acid to obtain a palladium chloride solution; adding palladium chloride solution into the carbon slurry, stirring for 2 hours, and then using K2CO3Adjusting the pH value of the system to 8.0 by using an aqueous solution, and stabilizing for 4 hours to obtain catalyst precursor slurry; the carrierThe mass of the body is 10 percent of the mass of the pure water;
and step two, 53g of glucose aqueous solution with the concentration of 8 wt% is dripped into the catalyst precursor slurry in the step one, the catalyst precursor slurry is reduced for 4 hours, then the filtration is carried out, and a filter cake is washed, so that the palladium-carbon catalyst for meropenem synthesis is obtained.
Example 9
The method for treating the palladium-carbon catalyst carrier for synthesizing meropenem of the embodiment comprises the following steps: under the condition of microwave heating and constant temperature of 80 ℃, the granularity is 200-400 meshes, and the specific surface area is 900m2And/g wood carbon is treated by refluxing with morpholine water solution with the mass concentration of 5% for 3h, washed until the pH value is 8.0, and dried to obtain the palladium-carbon catalyst carrier for meropenem synthesis.
The preparation method of the 5.0% palladium-carbon catalyst for synthesizing meropenem of the embodiment comprises the following steps:
step one, pulping 9.5g of carrier by using pure water to obtain carbon pulp; dissolving palladium chloride containing 0.5g of palladium by using dilute hydrochloric acid to obtain a palladium chloride solution; to the carbon slurry was added a palladium chloride solution, stirred for 1.5h, then with NaHCO3Adjusting the pH value of the system to 8.0 by using an aqueous solution, and stabilizing for 3 hours to obtain catalyst precursor slurry; the mass of the carrier is 10% of that of the pure water;
and step two, dropwise adding 134g of 5 wt% sodium thiosulfate aqueous solution into the catalyst precursor slurry obtained in the step one, reducing for 2 hours, filtering, and washing a filter cake to obtain the palladium-carbon catalyst for meropenem synthesis.
Example 10
The method for treating the palladium-carbon catalyst carrier for synthesizing meropenem of the embodiment comprises the following steps: under the condition of microwave heating and constant temperature of 70 ℃, the granularity is 200-400 meshes, and the specific surface area is 900m2And refluxing/g of wood carbon by using a 10% pyrrole aqueous solution, washing for 2 hours until the pH is 7.5, and drying to obtain the palladium-carbon catalyst carrier for synthesizing meropenem.
The preparation method of the 5.0% palladium-carbon catalyst for synthesizing meropenem of the embodiment comprises the following steps:
step one, pulping 9.5g of carrier by using pure water to obtain carbon pulp; dissolving palladium chloride containing 0.5g of palladium by using dilute hydrochloric acid to obtain a palladium chloride solution; to the direction ofAdding a palladium chloride solution into the carbon slurry, stirring for 1h, and then adding Na2CO3Adjusting the pH value of the system to 8.0 by using an aqueous solution, and stabilizing for 2 hours to obtain catalyst precursor slurry; the mass of the carrier is 10% of that of the pure water;
and step two, dropwise adding 70g of 9 wt% sodium thiosulfate aqueous solution into the catalyst precursor slurry obtained in the step one, reducing for 4 hours, filtering, and washing a filter cake to obtain the palladium-carbon catalyst for meropenem synthesis.
Example 11
The method for treating the palladium-carbon catalyst carrier for synthesizing meropenem of the embodiment comprises the following steps: under the condition of microwave heating and constant temperature of 90 ℃, the granularity is 200-400 meshes, and the specific surface area is 900m2And/g wood carbon is subjected to reflux treatment for 3 hours by using a quinoline water solution with the mass concentration of 3%, and is dried after being washed until the pH value is 7.5, so that the palladium-carbon catalyst carrier for synthesizing the meropenem is obtained.
The preparation method of the 5.0% palladium-carbon catalyst for synthesizing meropenem of the embodiment comprises the following steps:
step one, pulping 9.5g of carrier by using pure water to obtain carbon pulp; dissolving palladium chloride containing 0.5g of palladium by using dilute hydrochloric acid to obtain a palladium chloride solution; adding palladium chloride solution into the carbon slurry, stirring for 2 hours, and then using K2CO3Adjusting the pH value of the system to 8.0 by using an aqueous solution, and stabilizing for 4 hours to obtain catalyst precursor slurry; the mass of the carrier is 10% of that of the pure water;
and step two, dripping 20g of 10 wt% aqueous sodium hypophosphite solution into the catalyst precursor slurry obtained in the step one, reducing for 2 hours, filtering, and washing a filter cake to obtain the palladium-carbon catalyst for meropenem synthesis.
The performance evaluation of the catalysts prepared in examples 1 to 10 of the present invention and comparative examples was carried out by the following specific methods:
evaluation system: adding 5g of protected meropenem, 174mL of tetrahydrofuran, 250g of pure water and 0.5g of Pd/C catalyst into a 300mL stainless steel high-pressure reaction kettle in sequence; flushing the kettle with nitrogen and hydrogen sequentially for three times, keeping the hydrogen pressure at 1.8MPa, constant pressure, controlling the temperature at 38 ℃ and the reaction time at 1.5 h.
Yield: after the reaction is finished, the palladium-carbon is filtered, the filtrate is crystallized by acetone in an ice bath, crystals are filtered out, the product mass yield is calculated to be (constant weight mass ÷ 15.0) multiplied by 100 percent in a vacuum drying oven at 40 ℃ to constant weight. The results are shown in Table 1.
Impurities: meropenem impurity analysis was performed according to the chinese pharmacopoeia method using a C18 chromatographic column packed with octadecylsilane chemically bonded silica, 0.1% triethylamine solution (1.0 mL triethylamine, 900mL water, 10% phosphoric acid solution to adjust pH to 5.0 ± 0.1, water diluted to 1000mL) -acetonitrile ═ 93.5:6.5 as the mobile phase, and the detection wavelength was 220 nm. Dissolving 0.1g of crude meropenem product by using 0.1% triethylamine solution, injecting 10 mu L of the crude meropenem product into a liquid chromatograph, recording a chromatogram, wherein the appearance sequence is meropenem ring-opening product, meropenem and meropenem dimer, the retention time of the meropenem is about 7min, and the content of impurities in the meropenem is calculated by an area normalization method. The results are shown in Table 1.
TABLE 1 comparison example and Meropenem crude product yield and impurities comparison Table of examples 1-10
| Examples | Mass yield of meropenem% | Ring-opened article | Dimer | Total miscellaneous |
| Comparative example | 49.5 | 0.36 | 0.43 | 1.37 |
| Example 1 | 50.6 | 0.11 | 0.14 | 0.64 |
| Example 2 | 50.7 | 0.20 | 0.19 | 0.95 |
| Example 3 | 50.9 | 0.26 | 0.21 | 0.79 |
| Example 4 | 50.4 | 0.19 | 0.23 | 0.93 |
| Example 5 | 50.3 | 0.21 | 0.20 | 0.92 |
| Example 6 | 50.5 | 0.25 | 0.19 | 0.96 |
| Example 7 | 50.4 | 0.18 | 0.18 | 0.72 |
| Example 8 | 50.6 | 0.23 | 0.21 | 0.88 |
| Example 9 | 50.8 | 0.16 | 0.22 | 0.76 |
| Example 10 | 50.5 | 0.22 | 0.16 | 0.93 |
| Example 11 | 50.4 | 0.19 | 0.21 | 0.89 |
As can be seen from Table 1, the catalyst prepared by treating the carrier by the method of the invention can effectively inhibit the generation of four-membered ring open loop and dimer in the meropenem reaction, and has positive significance for improving the main reaction yield and inhibiting the occurrence of side reactions.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and all simple modifications, changes and equivalent structural changes made to the above embodiment according to the technical spirit of the present invention still fall within the protection scope of the technical solution of the present invention.
Claims (10)
1. A treatment method of a palladium-carbon catalyst carrier for meropenem synthesis is characterized by comprising the following steps: under the microwave heating condition, performing reflux treatment on powdered activated carbon by using an aqueous solution of a nitrogen-containing organic reagent, washing until the pH value is 7.0-8.0, and drying to obtain a palladium-carbon catalyst carrier for meropenem synthesis; the mass percentage of the nitrogenous organic reagent in the aqueous solution of the nitrogenous organic reagent is 1-10%.
2. The method for treating a palladium-carbon catalyst carrier for the synthesis of meropenem according to claim 1, wherein the nitrogen-containing organic reagent is pyridine, morpholine, quinoline, pyrrole, triethylamine or diethylamine.
3. The method for treating the palladium-carbon catalyst carrier for the synthesis of meropenem according to claim 1, wherein the microwave heating temperature is 60-100 ℃ and the reflux treatment time is 2-3 h.
4. The method for treating palladium-carbon catalyst carrier for meropenem synthesis according to claim 1, wherein the powdered activated carbon has a particle size of 200-400 mesh and a specific surface area of 800m2/g～1000m2Wood charcoal per gram.
5. The method for treating the palladium-carbon catalyst carrier for the synthesis of meropenem according to claim 1, wherein the mass percentage of the nitrogen-containing organic reagent in the aqueous solution of the nitrogen-containing organic reagent is 1-5%.
6. A method for preparing a palladium-carbon catalyst for meropenem synthesis by using the carrier treated by the treatment method of any one of claims 1 to 5, which comprises the following steps:
pulping a carrier by using pure water to obtain carbon pulp, adding a palladium chloride solution into the carbon pulp, stirring for 1-2 h, then adjusting the pH value of a system to 8.0 by using an inorganic alkali solution, and stabilizing for 2-4 h to obtain catalyst precursor slurry;
and step two, dropwise adding an aqueous solution of a reducing agent into the catalyst precursor slurry obtained in the step one, reducing for 2-4 h, filtering, and washing a filter cake to obtain the palladium-carbon catalyst for meropenem synthesis.
7. The method according to claim 6, wherein the carrier in step one has a mass of 10% of the mass of pure water.
8. The method of claim 6, wherein the inorganic base solution in step one is KHCO3Aqueous solution, NaHCO3Aqueous solution, K2CO3Aqueous solution or Na2CO3An aqueous solution.
9. The method according to claim 6, wherein the reducing agent in the second step is sodium hypophosphite, hydrazine hydrate, glucose or sodium thiosulfate, the molar amount of the reducing agent is 5-10 times of the molar amount of the palladium metal, and the concentration of the aqueous solution of the reducing agent is 5-10 wt%.
10. The method of claim 9, wherein the molar amount of the reducing agent is 8 to 10 times the molar amount of the palladium metal, and the concentration of the aqueous solution of the reducing agent is 8 to 10 wt%.
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