CN114163371A - Meropenem side chain optical isomer, preparation method and application thereof, and detection method of impurities in Meropenem side chain - Google Patents
Meropenem side chain optical isomer, preparation method and application thereof, and detection method of impurities in Meropenem side chain Download PDFInfo
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- CN114163371A CN114163371A CN202111573917.7A CN202111573917A CN114163371A CN 114163371 A CN114163371 A CN 114163371A CN 202111573917 A CN202111573917 A CN 202111573917A CN 114163371 A CN114163371 A CN 114163371A
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- VGLBNJWGUYQZHD-STQMWFEESA-N (4-nitrophenyl)methyl (2s,4s)-2-(dimethylcarbamoyl)-4-sulfanylpyrrolidine-1-carboxylate Chemical compound CN(C)C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 VGLBNJWGUYQZHD-STQMWFEESA-N 0.000 title claims abstract description 125
- 230000003287 optical effect Effects 0.000 title claims abstract description 88
- 238000001514 detection method Methods 0.000 title claims abstract description 31
- 239000012535 impurity Substances 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 239000000126 substance Substances 0.000 claims abstract description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 87
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 64
- 238000002156 mixing Methods 0.000 claims description 58
- 239000002904 solvent Substances 0.000 claims description 57
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 56
- 238000000034 method Methods 0.000 claims description 56
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 39
- MHSGOABISYIYKP-UHFFFAOYSA-N (4-nitrophenyl)methyl carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(COC(Cl)=O)C=C1 MHSGOABISYIYKP-UHFFFAOYSA-N 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- 238000007112 amidation reaction Methods 0.000 claims description 29
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 26
- 239000007788 liquid Substances 0.000 claims description 23
- 238000004811 liquid chromatography Methods 0.000 claims description 22
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 claims description 21
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 20
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 20
- 239000003513 alkali Substances 0.000 claims description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 18
- ULYZAYCEDJDHCC-UHFFFAOYSA-N isopropyl chloride Chemical compound CC(C)Cl ULYZAYCEDJDHCC-UHFFFAOYSA-N 0.000 claims description 17
- 238000005694 sulfonylation reaction Methods 0.000 claims description 15
- 238000005893 bromination reaction Methods 0.000 claims description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 230000003301 hydrolyzing effect Effects 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- 238000006467 substitution reaction Methods 0.000 claims description 11
- 238000005886 esterification reaction Methods 0.000 claims description 10
- 238000007280 thionation reaction Methods 0.000 claims description 9
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 claims description 8
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 claims description 8
- 238000010606 normalization Methods 0.000 claims description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 5
- 230000032050 esterification Effects 0.000 claims description 3
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 claims description 3
- 230000006103 sulfonylation Effects 0.000 claims description 3
- 238000007813 chromatographic assay Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 18
- 238000003786 synthesis reaction Methods 0.000 abstract description 18
- 239000003814 drug Substances 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 239000000543 intermediate Substances 0.000 description 211
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000000523 sample Substances 0.000 description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 29
- 239000012044 organic layer Substances 0.000 description 27
- 239000000463 material Substances 0.000 description 23
- 238000003756 stirring Methods 0.000 description 23
- 239000000243 solution Substances 0.000 description 20
- 238000005406 washing Methods 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- 238000001816 cooling Methods 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 12
- 239000003085 diluting agent Substances 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 230000007062 hydrolysis Effects 0.000 description 10
- 238000006460 hydrolysis reaction Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- -1 p-nitrobenzyloxycarbonyl Chemical group 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 239000012086 standard solution Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 238000004949 mass spectrometry Methods 0.000 description 5
- 229960002260 meropenem Drugs 0.000 description 5
- 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 description 5
- 239000003208 petroleum Substances 0.000 description 5
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- JMJMJDNHVXYAOC-MNOVXSKESA-N (2s,4r)-4-hydroxy-1-[(4-nitrophenyl)methoxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C1[C@H](O)C[C@@H](C(O)=O)N1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 JMJMJDNHVXYAOC-MNOVXSKESA-N 0.000 description 1
- SUQHNDGLACBBOE-HUUCEWRRSA-N (4-nitrophenyl)methyl (2r,4r)-4-acetylsulfanyl-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate Chemical compound CN(C)C(=O)[C@H]1C[C@@H](SC(C)=O)CN1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 SUQHNDGLACBBOE-HUUCEWRRSA-N 0.000 description 1
- SUQHNDGLACBBOE-LSDHHAIUSA-N (4-nitrophenyl)methyl (2r,4s)-4-acetylsulfanyl-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate Chemical compound CN(C)C(=O)[C@H]1C[C@H](SC(C)=O)CN1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 SUQHNDGLACBBOE-LSDHHAIUSA-N 0.000 description 1
- DOPMBTATMGPZGH-KGLIPLIRSA-N (4-nitrophenyl)methyl (2s,4r)-2-(dimethylcarbamoyl)-4-methylsulfonyloxypyrrolidine-1-carboxylate Chemical compound CN(C)C(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 DOPMBTATMGPZGH-KGLIPLIRSA-N 0.000 description 1
- SUQHNDGLACBBOE-CABCVRRESA-N (4-nitrophenyl)methyl (2s,4r)-4-acetylsulfanyl-2-(dimethylcarbamoyl)pyrrolidine-1-carboxylate Chemical compound CN(C)C(=O)[C@@H]1C[C@@H](SC(C)=O)CN1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 SUQHNDGLACBBOE-CABCVRRESA-N 0.000 description 1
- 241000304886 Bacilli Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- DHSUYTOATWAVLW-WFVMDLQDSA-N cilastatin Chemical compound CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O DHSUYTOATWAVLW-WFVMDLQDSA-N 0.000 description 1
- 229960004912 cilastatin Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
Abstract
The invention provides a meropenem side chain optical isomer, a preparation method and application thereof, and a detection method of meropenem side chain impurities, and belongs to the technical field of drug intermediate synthesis. The meropenem side chain optical isomer provided by the invention is a substance which influences the purity of a meropenem side chain product in the production process of the meropenem side chain, namely a generated impurity, and the meropenem side chain optical isomer can be used as a standard substance to realize effective detection of the impurity in the meropenem side chain, so that a foundation is laid for improving the quality of the meropenem side chain product.
Description
Technical Field
The invention relates to the technical field of drug intermediate synthesis, in particular to a meropenem side chain optical isomer, a preparation method and application thereof, and a detection method of meropenem side chain impurities.
Background
Meropenem (Meropenem) belongs to carbapenem antibiotics, has good antibacterial effect on anaerobic and aerobic gram-positive bacteria, negative bacteria and the like, and particularly has antibacterial activity on multi-drug resistant aerobic gram-negative bacilli. Because the chemical structure introduces methyl on the 4-position of the carbapenem mother ring, the stability of the carbapenem mother ring to human renal dehydropeptidase-1 (DHP-1) is obviously improved, so the DHP-1 inhibitor, such as cilastatin, does not need to be applied simultaneously, and can be used clinically independently. The Meropenem side chain (Meropenem side chain, 2S4S-M for short), namely (2S,4S) -2-dimethylcarbamoyl-4-mercapto-1- (p-nitrobenzyloxycarbonyl) -1-pyrrolidine (shown as the following formula 1), is a key intermediate for producing carbapenem antibiotic Meropenem, and the compound contains two chiral centers.
With the increasingly deep understanding of the harmfulness of medicine impurities in various countries in the world, the quality requirement on medicine intermediates is higher, the meropenem side chain is used as a key medicine intermediate, and the quality condition and the purity of the meropenem side chain directly influence the preparation and the safety of medicines. Because the chiral drug and the isomer thereof can generate different and even opposite pharmacological actions in a human body, the chiral drug and the isomer thereof have important significance for synthesizing the optical isomer of the meropenem side chain which is a key intermediate of the meropenem.
Disclosure of Invention
The invention aims to provide a meropenem side chain optical isomer, a preparation method and application thereof, and a detection method of meropenem side chain impurities.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a meropenem side chain optical isomer with a structural general formula shown in formula I,
the meropenem side chain optical isomer has a structural configuration shown in a formula II, a formula III or a formula IV:
the invention provides a preparation method of the meropenem side chain optical isomer, which comprises the following steps:
when the meropenem side chain optical isomer has the structural configuration shown in formula II, the preparation method of the meropenem side chain optical isomer comprises the following steps:
mixing cis-D-hydroxyproline, p-nitrobenzyl chloroformate, a first solvent, sodium hydroxide and water, and carrying out amidation reaction to obtain an intermediate 1;
mixing the intermediate 1, triethylamine, a second solvent, isopropyl chloride and dimethylamine, and performing amidation reaction to obtain an intermediate 2;
mixing the intermediate 2, triethylamine, a third solvent and methanesulfonyl chloride to perform a sulfonylation reaction to obtain an intermediate 3;
mixing the intermediate 3, potassium thioacetate and a fourth solvent, and carrying out a thionation reaction to obtain an intermediate 4;
mixing the intermediate 4 with alkali liquor, and hydrolyzing to obtain a meropenem side chain optical isomer with a structural configuration shown in formula II;
the intermediate 1 has a structure shown as a formula:
the intermediate 2 has a structure shown as a formula b:
the intermediate 3 has a structure shown as formula c:
the intermediate 4 has a structure shown in a formula d:
when the meropenem side chain optical isomer has the structural configuration shown in formula III, the preparation method of the meropenem side chain optical isomer comprises the following steps:
mixing the intermediate 3, sodium bromide, potassium iodide and a fifth solvent, and carrying out bromination reaction to obtain an intermediate 5;
mixing the intermediate 5 with potassium thioacetate for substitution reaction to obtain an intermediate 6;
mixing the intermediate 6 with alkali liquor, and hydrolyzing to obtain a meropenem side chain optical isomer with a structural configuration shown in formula III;
the intermediate 5 has a structure shown as a formula e:
the intermediate 6 has a structure represented by formula f:
when the meropenem side chain optical isomer has the structural configuration shown in formula IV, the preparation method of the meropenem side chain optical isomer comprises the following steps:
mixing trans-L-hydroxyproline, p-nitrobenzyl chloroformate, a sixth solvent, sodium hydroxide and water, and carrying out amidation reaction to obtain an intermediate 7;
mixing the intermediate 7, triethylamine, a seventh solvent and isopropyl chloride for esterification, mixing the obtained product with methanesulfonyl chloride for sulfonylation to obtain an intermediate 8;
mixing the intermediate 8 with dimethylamine, and carrying out amidation reaction to obtain an intermediate 9;
mixing the intermediate 9, sodium bromide, potassium iodide and an eighth solvent, and carrying out bromination reaction to obtain an intermediate 10;
mixing the intermediate 10 with potassium thioacetate for substitution reaction to obtain an intermediate 11;
mixing the intermediate 11 with alkali liquor, and hydrolyzing to obtain a meropenem side chain optical isomer with a structural configuration shown in formula IV;
the intermediate 7 has a structure shown in formula j:
the intermediate 8 has a structure represented by formula h:
the intermediate 9 has a structure represented by formula i:
the intermediate 10 has a structure represented by formula g:
the intermediate 11 has a structure represented by formula k:
preferably, when the meropenem side chain optical isomer with the structural configuration shown in formula II is prepared, the molar ratio of the cis-D-hydroxyproline to the p-nitrobenzyl chloroformate is (0.76: 0.86; when the intermediate 1 is prepared, the molar ratio of the cis-D-hydroxyproline to the p-nitrobenzyl chloroformate is (0.6-1.0): 0.8-1.2), the esterification reaction temperature is-5-10 ℃, and the esterification reaction time is 1-6 hours.
Preferably, when the intermediate 2 is prepared, the molar ratio of the intermediate 1, triethylamine, isopropyl chloride and dimethylamine is (0.10-0.15): (0.15-0.2): 0.12-0.18): (0.12-0.2); the temperature of the amidation reaction is-5-10 ℃, and the time is 1-6 h;
when the intermediate 3 is prepared, the molar ratio of the intermediate 2, triethylamine and methanesulfonyl chloride is (0.10-0.15): (0.13-0.25): (0.11-0.2); the temperature of the sulfonylation reaction is-5-10 ℃, and the time is 1-6 h.
Preferably, when the intermediate 4 is prepared, the molar ratio of the intermediate 3 to the potassium thioacetate is (0.010-0.015) to (0.022-0.028), the temperature of the thionation reaction is 40-60 ℃, and the time is 2-8 hours.
Preferably, when the intermediate 5 is prepared, the molar ratio of the intermediate 3 to the sodium bromide to the potassium iodide is (0.04-0.05): (0.20-0.03): 0.001-0.01); the temperature of the bromination reaction is 70-120 ℃, and the time is 1-5 h.
Preferably, when the intermediate 7 is prepared, the molar ratio of the trans-L-hydroxyproline to the p-nitrobenzyl chloroformate is (0.6-0.8): (0.8-1.0); the temperature of the amidation reaction is-5-10 ℃, and the time is 1-6 h;
when the intermediate 8 is prepared, the molar ratio of the intermediate 7 to the triethylamine to the isopropyl chloroformate to the methanesulfonyl chloride is (0.10-0.15) to (0.2-0.4) to (0.1-0.16): (0.11-0.2); the temperature of the esterification reaction is-5-10 ℃, and the time is 1-6 h;
when the intermediate 9 is prepared, the molar ratio of the intermediate 8 to dimethylamine is (0.1-0.2) to (0.1-0.3).
The invention provides an application of the meropenem side chain optical isomer in the technical scheme or the meropenem side chain optical isomer prepared by the preparation method in the technical scheme as a standard substance in detecting impurities in a meropenem side chain product.
The invention provides a detection method of meropenem side chain impurities, which comprises the following steps:
performing liquid chromatography detection by using a meropenem side chain optical isomer as an impurity standard substance by adopting a high performance liquid chromatography to obtain a standard liquid chromatography spectrogram; the meropenem side chain optical isomer is the meropenem side chain optical isomer in the technical scheme or the meropenem side chain optical isomer prepared by the preparation method in the technical scheme;
taking a meropenem side chain sample as a sample to be detected, and performing liquid chromatography detection to obtain a liquid chromatography spectrogram of the sample to be detected;
and comparing the liquid chromatogram of the sample to be detected with a standard liquid chromatogram, and calculating the content of impurities in the sample to be detected according to an area normalization method.
Preferably, the chromatographic conditions of the liquid chromatographic detection are as follows: a chromatographic column: chiralpak IC, 250 mm. times.4.6 mm, 5 μm; mobile phase: the mixture of n-hexane, ethanol, methanol and trifluoroacetic acid, wherein the volume ratio of the n-hexane, the ethanol, the methanol and the trifluoroacetic acid is (500-700): 200-400): 50-200): 1-10; flow rate: 1.0-1.5 mL/min; detection wavelength: 270 nm; sample introduction amount: 20-25 muL; column temperature: 30-60 ℃; collecting time: 20-50 min.
The meropenem side chain optical isomer provided by the invention is a substance which influences the purity of a meropenem side chain product in the production process of the meropenem side chain, namely a generated impurity, and can be used as a standard substance to realize effective detection of the impurity in the meropenem side chain, so that a foundation is laid for improving the quality of the meropenem side chain product.
Drawings
FIG. 1 is a nuclear magnetic spectrum of the product prepared in example 1;
FIG. 2 is a mass spectrum of the product prepared in example 1;
FIG. 3 is a nuclear magnetic spectrum of the product prepared in example 2;
FIG. 4 is a mass spectrum of the product prepared in example 2;
FIG. 5 is a nuclear magnetic spectrum of the product prepared in example 3;
FIG. 6 is a mass spectrum of the product prepared in example 3;
fig. 7 is a chiral liquid phase spectrum of the meropenem side chain;
FIG. 8 is a meropenem side chain optical isomer 2S4R-M chiral purity spectrum;
FIG. 9 is a meropenem side chain optical isomer 2R4S-M chiral purity spectrum;
FIG. 10 is a meropenem side chain optical isomer 2R4R-M chiral purity spectrum;
fig. 11 is a spectrum of a mixed sample of meropenem side chain and three isomers.
Detailed Description
The invention provides a meropenem side chain optical isomer with a structural general formula shown in formula I,
the meropenem side chain optical isomer has a structural configuration shown in a formula II, a formula III or a formula IV:
the invention provides a preparation method of the meropenem side chain optical isomer, which comprises the following steps:
when the meropenem side chain optical isomer has the structural configuration shown in formula II, the preparation method of the meropenem side chain optical isomer comprises the following steps:
mixing cis-D-hydroxyproline, p-nitrobenzyl chloroformate, a first solvent, sodium hydroxide and water, and carrying out amidation reaction to obtain an intermediate 1;
mixing the intermediate 1, triethylamine, a second solvent, isopropyl chloride and dimethylamine, and performing amidation reaction to obtain an intermediate 2;
mixing the intermediate 2, triethylamine, a third solvent and methanesulfonyl chloride to perform a sulfonylation reaction to obtain an intermediate 3;
mixing the intermediate 3, potassium thioacetate and a fourth solvent, and carrying out a thionation reaction to obtain an intermediate 4;
mixing the intermediate 4 with alkali liquor, and hydrolyzing to obtain a meropenem side chain optical isomer with a structural configuration shown in formula II;
the intermediate 1 has a structure shown as a formula:
the intermediate 2 has a structure shown as a formula b:
the intermediate 3 has a structure shown as formula c:
the intermediate 4 has a structure shown in a formula d:
when the meropenem side chain optical isomer has the structural configuration shown in formula III, the preparation method of the meropenem side chain optical isomer comprises the following steps:
mixing the intermediate 3, sodium bromide, potassium iodide and a fifth solvent, and carrying out bromination reaction to obtain an intermediate 5;
mixing the intermediate 5 with potassium thioacetate for substitution reaction to obtain an intermediate 6;
mixing the intermediate 6 with alkali liquor, and hydrolyzing to obtain a meropenem side chain optical isomer with a structural configuration shown in formula III;
the intermediate 5 has a structure shown as a formula e:
the intermediate 6 has a structure represented by formula f:
when the meropenem side chain optical isomer has the structural configuration shown in formula IV, the preparation method of the meropenem side chain optical isomer comprises the following steps:
mixing trans-L-hydroxyproline, p-nitrobenzyl chloroformate, a sixth solvent, sodium hydroxide and water, and carrying out amidation reaction to obtain an intermediate 7;
mixing the intermediate 7, triethylamine, a seventh solvent and isopropyl chloride for esterification, mixing the obtained product with methanesulfonyl chloride for sulfonylation to obtain an intermediate 8;
mixing the intermediate 8 with dimethylamine, and carrying out amidation reaction to obtain an intermediate 9;
mixing the intermediate 9, sodium bromide, potassium iodide and an eighth solvent, and carrying out bromination reaction to obtain an intermediate 10;
mixing the intermediate 10 with potassium thioacetate for substitution reaction to obtain an intermediate 11;
mixing the intermediate 11 with alkali liquor, and hydrolyzing to obtain a meropenem side chain optical isomer with a structural configuration shown in formula IV;
the intermediate 7 has a structure shown in formula j:
the intermediate 8 has a structure represented by formula h:
the intermediate 9 has a structure represented by formula i:
the intermediate 10 has a structure represented by formula g:
the intermediate 11 has a structure represented by formula k:
in the present invention, unless otherwise specified, all the starting materials required for the preparation are commercially available products well known to those skilled in the art.
In the present invention, when the meropenem side chain optical isomer has the structural configuration shown in formula II:
the method comprises the steps of mixing cis-D-hydroxyproline, p-nitrobenzyl chloroformate, a first solvent, sodium hydroxide and water, and carrying out amidation reaction to obtain an intermediate 1. In the invention, the molar ratio of the cis-D-hydroxyproline to the p-nitrobenzyl chloroformate is preferably (0.6-0.8): (0.8-1.0), and more preferably 0.76: 0.86. In the invention, the first solvent is preferably dichloromethane, the dichloromethane is used for dissolving p-nitrobenzyl chloroformate, and the mass concentration of the dichloromethane solution of the p-nitrobenzyl chloroformate is preferably 50%; the mass ratio of the sodium hydroxide to the water is preferably 66.9: 600; the molar ratio of sodium hydroxide to cis-D-hydroxyproline is preferably 1.68: 0.76.
In the invention, the process of mixing the cis-D-hydroxyproline, the p-nitrobenzyl chloroformate, the first solvent, the sodium hydroxide and the water is preferably to firstly dissolve the p-nitrobenzyl chloroformate in the first solvent to obtain a p-nitrobenzyl chloroformate solution, stir and dissolve the sodium hydroxide and the water, then add the cis-D-hydroxyproline, stir and completely dissolve the solution, reduce the temperature to 0 ℃, and drop the dichloromethane solution of the p-nitrobenzyl chloroformate (the temperature is controlled not to exceed 5 ℃). The stirring, dropping and cooling processes are not particularly limited in the present invention, and may be performed according to processes well known in the art.
In the invention, the temperature of the esterification reaction is preferably-5-10 ℃, more preferably 0-5 ℃, and the time is preferably 1-6 hours, more preferably 3 hours.
After the amidation reaction is completed, the obtained material is preferably subjected to post-treatment, the post-treatment process preferably comprises the steps of standing and layering the obtained material, extracting an obtained water phase by using dichloromethane, separating the water phase, adjusting the pH value to 2-3 by using hydrochloric acid with the mass fraction of 10%, extracting for three times by using ethyl acetate, combining organic phases, washing by using saturated saline, drying by using anhydrous sodium sulfate, filtering, concentrating until the solution is dried, and recrystallizing by using ethanol to obtain an intermediate 1. The present invention is not particularly limited to the specific operation method of the above-mentioned post-treatment process, and the post-treatment process may be performed according to a process known in the art.
In the present invention, the intermediate 1 has a structure represented by formula a:
after the intermediate 1 is obtained, the intermediate 1, triethylamine, a second solvent, isopropyl chloride and dimethylamine are mixed for amidation reaction to obtain an intermediate 2. In the invention, the molar ratio of the intermediate 1, triethylamine, isopropyl chloride and dimethylamine is preferably (0.10-0.15): (0.15-0.2): 0.12-0.18): (0.12 to 0.2), more preferably 0.13:0.19:0.15: 0.18; the second solvent is preferably dichloromethane; the amount of the second solvent is not particularly limited, and the smooth reaction can be ensured. In the present invention, the dimethylamine is preferably used in the form of an aqueous solution of dimethylamine, and the mass concentration of the aqueous solution of dimethylamine is preferably 40%.
In the invention, the intermediate 1, triethylamine, the second solvent, isopropyl chloride and dimethylamine are preferably mixed by stirring the intermediate 1, triethylamine and dichloromethane to be fully dissolved, cooling to-10 ℃, dropwise adding isopropyl chloride, stirring for 2h, and dropwise adding dimethylamine aqueous solution (the temperature is controlled not to exceed 0 ℃). The dropping rate is not particularly limited in the present invention, and may be dropping at a rate well known in the art.
In the invention, the amidation reaction is preferably carried out under the protection of nitrogen, the temperature of the amidation reaction is preferably-5-10 ℃, more preferably 0 ℃, and the time is preferably 1-6 h, more preferably 3 h.
After the amidation reaction is completed, preferably, water is added into the obtained material, the mixture is stirred for 5 minutes and then is kept stand for layering, the obtained organic phase is washed by dilute hydrochloric acid with the mass fraction of 2%, potassium carbonate aqueous solution with the mass fraction of 5%, water and saturated salt water in sequence, the obtained washing material is separated into an organic layer, the obtained organic layer material is dried by anhydrous sodium sulfate, filtered, concentrated to be dry and recrystallized by adopting methanol, and an intermediate 2 is obtained. The amount of the added water is not specially limited, and the water adding amount can be adjusted according to actual requirements.
In the present invention, the intermediate 2 has a structure represented by formula b:
after the intermediate 2 is obtained, the intermediate 2, triethylamine, a third solvent and methanesulfonyl chloride are mixed for sulfonylation reaction, and an intermediate 3 is obtained. In the invention, the molar ratio of the intermediate 2, triethylamine and methanesulfonyl chloride is preferably (0.10-0.15): (0.13-0.25): (0.11 to 0.2), more preferably 0.14:0.19: 0.15; the third solvent is preferably dichloromethane; the amount of the third solvent is not particularly limited, and the smooth reaction can be ensured.
In the invention, the intermediate 2, triethylamine, the third solvent and methanesulfonyl chloride are preferably mixed in the process of stirring the intermediate 2, triethylamine and dichloromethane to be fully dissolved, cooling to-10 ℃, and dropwise adding methanesulfonyl chloride (the temperature is controlled to be not more than 0 ℃).
In the invention, the sulfonylation reaction is preferably carried out under the protection of nitrogen, the temperature of the sulfonylation reaction is preferably-5-10 ℃, more preferably 0 ℃, and the time is preferably 1-6 h, more preferably 2 h.
After the sulfonylation reaction is completed, the invention preferably adds water into the obtained material, stirs for 10 minutes, stands for layering, uses dilute hydrochloric acid with the mass fraction of 2 percent to wash the obtained organic phase, uses potassium carbonate with the mass fraction of 5 percent to wash, washes and washes with saturated salt water in sequence, separates out the organic layer, uses anhydrous sodium sulfate to dry, filters, concentrates to dry, and uses methanol to recrystallize, and obtains the intermediate 3. The amount of the added water is not specially limited, and the water adding amount can be adjusted according to actual requirements.
In the present invention, the intermediate 3 has a structure represented by formula c:
after the intermediate 3 is obtained, the intermediate 3, potassium thioacetate and a fourth solvent are mixed for thionation reaction to obtain an intermediate 4. In the invention, the molar ratio of the intermediate 3 to the potassium thioacetate is preferably (0.010-0.015) to (0.022-0.028), and more preferably 0.013: 0.026; the fourth solvent is preferably N, N-dimethylformamide; the amount of the fourth solvent is not particularly limited, and the smooth reaction can be ensured.
The process of mixing the intermediate 3, the potassium thioacetate and the fourth solvent is not particularly limited in the present invention, and the materials can be sufficiently mixed according to a process well known in the art.
In the invention, the thionation reaction is preferably carried out under the protection of nitrogen, the temperature of the thionation reaction is preferably 40-60 ℃, more preferably 55 ℃, and the time is preferably 2-8 h, more preferably 3 h.
After the thionation reaction is completed, the obtained material is preferably cooled to room temperature, water is added, stirring is carried out for 10 minutes, then ethyl acetate is used for extraction for three times, organic layers are combined, washing is carried out for 3 times by adopting water and washing by adopting saturated salt for 3 times, the organic layer is separated, and the obtained organic layer material is dried by anhydrous sodium sulfate, filtered and concentrated to be dry, so as to obtain an intermediate 4. The dosage of the added water is not specially limited, and the dosage can be adjusted according to actual requirements.
In the present inventionThe intermediate 4 has a structure represented by formula d:
after the intermediate 4 is obtained, the intermediate 4 is mixed with alkali liquor for hydrolysis to obtain the meropenem side chain optical isomer with the structural configuration shown as a formula II, and the side chain optical isomer is marked as 2R 4S-M.
In the present invention, the molar ratio of the intermediate 4 to the alkali in the lye is preferably 0.013: 0.03; the alkali liquor is preferably an aqueous solution of potassium hydroxide, and the concentration of the alkali liquor is not particularly limited, so that the reaction can be carried out smoothly.
In the process of mixing the intermediate 4 with alkali liquor, dichloromethane is required to be added, and the invention has no special limitation on the dosage of the dichloromethane, and can ensure that the reaction is carried out smoothly.
In the invention, the process of mixing the intermediate 4 and the alkali liquor is preferably to dissolve the intermediate 4 in dichloromethane under the protection of nitrogen, reduce the temperature to 0-5 ℃, and dropwise add 25mL of alkali liquor (the temperature is not more than 10 ℃).
In the present invention, the hydrolysis is preferably carried out under nitrogen protection conditions; the hydrolysis temperature is preferably 0-10 ℃ and not 0 ℃, and the hydrolysis time is preferably 1.5 h.
After the hydrolysis is completed, the invention preferably adds water to the obtained material, reduces the temperature to 0 ℃, adjusts the pH to 7 (the temperature is not more than 5 ℃) by hydrochloric acid with the mass fraction of 10%, stands the obtained material for liquid separation, washes the obtained organic layer twice, then washes the organic layer by saturated salt water, separates the organic layer, dries by anhydrous sodium sulfate, filters, concentrates, and purifies by column chromatography (the eluent is preferably ethyl acetate and petroleum ether with the volume ratio of 2:1), and obtains 2R 4S-M. The dosage of the added water is not specially limited, and the dosage can be adjusted according to actual requirements.
In the present invention, the synthesis process of 2R4S-M is shown as the following formula:
in the present invention, when the meropenem side chain optical isomer has the structural configuration shown in formula III:
the intermediate 3, sodium bromide, potassium iodide and a fifth solvent are mixed for bromination reaction to obtain an intermediate 5. In the invention, the molar ratio of the intermediate 3, the sodium bromide and the potassium iodide is preferably (0.04-0.05): 0.20-0.03): 0.001-0.01, and more preferably 0.048:0.241: 0.001; the fifth solvent is preferably N, N-dimethylformamide; the dosage of the fifth solvent is not specially limited, and the smooth reaction can be ensured.
The process of mixing the intermediate 3, the sodium bromide, the potassium iodide and the fifth solvent is not particularly limited in the present invention, and the materials can be uniformly mixed according to a process well known in the art.
In the invention, the bromination reaction is preferably carried out under the protection of nitrogen, the temperature of the bromination reaction is preferably 70-120 ℃, more preferably 100 ℃, and the time is preferably 1-5 h, more preferably 2 h.
After the bromination reaction is finished, the obtained material is preferably cooled to room temperature, water is added, the mixture is stirred for 10 minutes, then ethyl acetate is used for extraction for three times, organic layers are combined, washing is sequentially carried out for 3 times by using water and washing by using saturated salt for 3 times, the organic layer is separated, anhydrous sodium sulfate is dried, filtered, concentrated to be dry, and purified by column chromatography, so that an intermediate 5 is obtained. In the invention, the eluent for the column chromatography is preferably a mixture of ethyl acetate and petroleum ether, and the volume ratio of the ethyl acetate to the petroleum ether is preferably 1: 1. The dosage of the added water is not specially limited, and the dosage can be adjusted according to actual requirements. The filtration and concentration process of the present invention is not particularly limited, and may be carried out according to a process well known in the art.
In the present invention, the intermediate 5 has a structure represented by formula e:
after the intermediate 5 is obtained, the intermediate 5 is mixed with potassium thioacetate for substitution reaction to obtain an intermediate 6. In the invention, the molar ratio of the intermediate 5 to the potassium thioacetate is preferably (0.010-0.015): (0.022-0.028), and more preferably 0.013: 0.026.
In the process of mixing the intermediate 5 with the potassium thioacetate, adding a solvent; the solvent is preferably N, N-dimethylformamide; the process of mixing the intermediate 5, the potassium thioacetate and the solvent is not particularly limited, and the materials can be fully mixed according to the process well known in the field; the invention has no special limitation on the dosage of the solvent, and ensures that the reaction is carried out smoothly.
In the invention, the substitution reaction is preferably carried out under the protection of nitrogen, and the temperature of the substitution reaction is preferably 40-60 ℃, and more preferably 55 ℃; the time is preferably 2-8 h, and more preferably 3 h;
after the substitution reaction is completed, the obtained material is preferably subjected to post-treatment, and the specific process is preferably that the obtained crude product liquid is cooled to room temperature, water is added and stirred for 10 minutes, then ethyl acetate is used for extraction for three times, organic layers are combined and washed by water and saturated salt water in sequence, an organic layer is separated, the obtained organic layer material is dried by anhydrous sodium sulfate, filtered and concentrated to be dry, and the intermediate 6 is obtained. The number of times of the water washing is preferably 3, and the number of times of the saturated brine washing is preferably 3. The drying, filtering and concentrating processes are not particularly limited in the present invention, and may be performed according to processes well known in the art.
In the present invention, the intermediate 6 has a structure represented by formula f:
after the intermediate 6 is obtained, the intermediate 6 is mixed with alkali liquor for hydrolysis to obtain the meropenem side chain optical isomer with the structural configuration shown as a formula IV, and the side chain optical isomer is marked as 2R 4R-M. In the present invention, the process of mixing the intermediate 6 with the alkali solution for hydrolysis is preferably identical to the process of hydrolyzing the intermediate 4, and is not described herein.
In the present invention, the synthesis process of 2R4R-M is shown as the following formula:
in the present invention, when the meropenem side chain optical isomer has the structural configuration shown in formula IV:
the method comprises the steps of mixing trans-L-hydroxyproline, p-nitrobenzyl chloroformate, a sixth solvent, sodium hydroxide and water, and carrying out amidation reaction to obtain an intermediate 7. In the invention, the molar ratio of the trans-L-hydroxyproline to the p-nitrobenzyl chloroformate is preferably (0.6-0.8): 0.8-1.0, and more preferably 0.76: 0.86; the sixth solvent is preferably dichloromethane, the dichloromethane is used for dissolving p-nitrobenzyl chloroformate, and the mass concentration of the dichloromethane solution of the p-nitrobenzyl chloroformate is preferably 50%; the mass ratio of the sodium hydroxide to the water is preferably 66.9: 600; the molar ratio of sodium hydroxide to trans-D-hydroxyproline is preferably 1.68: 0.76.
In the invention, the process of mixing the trans-D-hydroxyproline, the p-nitrobenzyl chloroformate, the sixth solvent, the sodium hydroxide and the water is preferably to dissolve the p-nitrobenzyl chloroformate in the sixth solvent to obtain a p-nitrobenzyl chloroformate solution, stir and dissolve the sodium hydroxide and the water, then add the cis-D-hydroxyproline, stir and completely dissolve the p-nitrobenzyl chloroformate, cool the solution to 0 ℃, and add the dichloromethane solution of the p-nitrobenzyl chloroformate (the temperature is controlled not to exceed 5 ℃). The stirring, dropping and cooling processes are not particularly limited in the present invention, and may be performed according to processes well known in the art.
In the invention, the temperature of the amidation reaction is preferably-5-10 ℃, more preferably 0-5 ℃, and the time is preferably 1-6 hours, more preferably 3 hours.
After the amidation reaction is completed, the obtained material is preferably subjected to post-treatment, the post-treatment process preferably comprises the steps of standing and layering the obtained material, extracting an obtained water phase by using dichloromethane, separating the water phase, adjusting the pH value to 2-3 by using hydrochloric acid with the mass fraction of 10%, extracting for three times by using ethyl acetate, combining organic phases, washing by using saturated saline, drying by using anhydrous sodium sulfate, filtering, concentrating until the solution is dried, and recrystallizing by using ethanol to obtain an intermediate 7. The present invention is not particularly limited to the specific operation method of the above-mentioned post-treatment process, and the post-treatment process may be performed according to a process known in the art.
In the present invention, the intermediate 7 has a structure represented by formula j:
after the intermediate 7 is obtained, the intermediate 7, triethylamine, a seventh solvent and isopropyl chloride are mixed for amidation reaction, the obtained product is mixed with methanesulfonyl chloride for sulfonylation reaction, and the intermediate 8 is obtained. In the invention, the molar ratio of the intermediate 7, triethylamine, isopropyl chloride and methanesulfonyl chloride is preferably (0.10-0.15): (0.2-0.4): (0.1-0.16): (0.11 to 0.2), more preferably 0.1:0.28:0.11: 0.13; the seventh solvent is preferably dichloromethane, and the amount of the seventh solvent is not particularly limited in the present invention, so that the reaction can be smoothly performed.
In the present invention, the intermediate 7, triethylamine, the seventh solvent and isopropyl chloride are preferably mixed, the temperature of the mixture is reduced to-10 ℃, and isopropyl chloride is added dropwise (the temperature is not higher than 0 ℃). In the invention, the esterification reaction is preferably carried out under the protection of nitrogen, the reaction temperature is preferably-5-10 ℃, more preferably 0 ℃, and the reaction time is preferably 1-6 h, more preferably 2 h.
In the invention, the process of mixing the obtained product with methanesulfonyl chloride is preferably to cool the material obtained by the reaction to-10 ℃, and dropwise add methanesulfonyl chloride (the temperature is not more than 0 ℃); the sulfonylation reaction is preferably carried out under the protection of nitrogen, the temperature of the sulfonylation reaction is preferably 0 ℃, and the time is preferably 2 hours.
In the present invention, the intermediate 8 has a structure represented by formula h:
after obtaining the intermediate 8, the present invention preferably does not perform any post-treatment, and dimethylamine is directly added dropwise to the obtained material to perform amidation reaction to obtain an intermediate 9. In the present invention, the dimethylamine is preferably used in the form of an aqueous solution of dimethylamine, preferably having a mass concentration of.40%; the molar ratio of the intermediate 8 to dimethylamine is preferably (0.1-0.2) to (0.1-0.3), and more preferably 0.1: 0.13. The dropping rate is not particularly limited in the invention, and the dropping can be carried out according to the rate well known in the field; during the dropwise addition, the temperature does not exceed 10 ℃. In the invention, the amidation reaction is preferably carried out under the protection of nitrogen, the reaction temperature is preferably 0-10 ℃ and is not 0, and the time is preferably 3 h.
After the amidation reaction is completed, preferably, the obtained material is washed by dilute hydrochloric acid with the mass fraction of 2%, potassium carbonate with the mass fraction of 5%, water and saturated salt water in sequence, the obtained washed material is separated into an organic layer, the obtained organic layer material is dried by anhydrous sodium sulfate, filtered, concentrated to be dry and recrystallized by methanol to obtain an intermediate 9.
In the present invention, the intermediate 9 has a structure represented by formula i:
after the intermediate 9 is obtained, the intermediate 9, sodium bromide, potassium iodide and an eighth solvent are mixed for bromination reaction to obtain an intermediate 10. In the present invention, the process for preparing the intermediate 10 from the intermediate 9 is preferably the same as the process for preparing the intermediate 5 from the intermediate 3 (including the ratio of the raw materials and the conditions), and will not be described herein again.
In the present invention, the intermediate 10 has a structure represented by formula g:
after the intermediate 10 is obtained, the intermediate 10 is mixed with potassium thioacetate for substitution reaction to obtain an intermediate 11. In the present invention, the process for preparing intermediate 11 from intermediate 10 is preferably the same as the process for preparing intermediate 6 from intermediate 5 (including the proportions and conditions of the raw materials), and will not be described in detail herein.
In the present invention, the intermediate 11 has a structure represented by formula k:
after the intermediate 11 is obtained, the intermediate 11 is mixed with alkali liquor and hydrolyzed to obtain the meropenem side chain optical isomer with the structural configuration shown as the formula IV, which is marked as 2S 4R-M. In the present invention, the process of hydrolyzing the intermediate 11 is the same as that of hydrolyzing the intermediate 6 (including raw material ratio and conditions), and is not described herein again.
In the present invention, the synthesis process of 2S4R-M is shown as the following formula:
the invention provides an application of the meropenem side chain optical isomer in the technical scheme or the meropenem side chain optical isomer prepared by the preparation method in the technical scheme as a standard substance in detecting impurities in a meropenem side chain product.
The invention provides a detection method of meropenem side chain impurities, which comprises the following steps:
performing liquid chromatography detection by using a meropenem side chain optical isomer as an impurity standard substance by adopting a high performance liquid chromatography to obtain a standard liquid chromatography spectrogram; the meropenem side chain optical isomer is the meropenem side chain optical isomer in the technical scheme or the meropenem side chain optical isomer prepared by the preparation method in the technical scheme;
taking a meropenem side chain sample as a sample to be detected, and performing liquid chromatography detection to obtain a liquid chromatography spectrogram of the sample to be detected;
and comparing the liquid chromatogram of the sample to be detected with a standard liquid chromatogram, and calculating the content of impurities in the sample to be detected according to an area normalization method.
The method adopts high performance liquid chromatography, takes meropenem side chain optical isomer as an impurity standard substance, and carries out liquid chromatography detection to obtain a standard liquid chromatography spectrogram. In the invention, the preparation method of the impurity standard solution used for liquid chromatography detection is preferably to mix the meropenem side chain optical isomer with a diluent to obtain the impurity standard solution. In the present invention, the diluent is preferably a mixed solution of n-hexane and ethanol, and the volume ratio of n-hexane to ethanol is preferably 1: 1.
The high performance liquid chromatograph used for the liquid chromatography detection is not specially limited, meets the requirements of the general rule of GB/T16631-2008 high performance liquid chromatography, and can be an instrument with an ultraviolet spectrophotometry detector, such as SHIMAZU LC-20 AT.
In the present invention, the chromatographic conditions for the liquid chromatography detection are preferably: a chromatographic column: chiralpak IC, 250 mm. times.4.6 mm, 5 μm; mobile phase: the volume ratio of the n-hexane to the ethanol to the methanol to the trifluoroacetic acid is preferably (500-700) to (200-400) to (50-200) to (1-10), and more preferably 600:300:100: 1; flow rate: 1.0-1.5 mL/min; detection wavelength: 270 nm; sample introduction amount: 20-25 muL; column temperature: 30-60 ℃, and more preferably 40 ℃; collecting time: 20-50 min, more preferably 35 min.
And (3) taking the meropenem side chain sample as a sample to be detected, and performing liquid chromatography detection to obtain a liquid chromatography spectrogram of the sample to be detected. In the present invention, the meropenem side chain sample is a commercially available meropenem side chain or a key intermediate meropenem side chain produced in the process of producing meropenem.
In the present invention, the preparation process of the sample solution to be tested for the liquid chromatography detection is preferably to mix the meropenem side chain sample with the diluent to obtain the sample solution to be tested. In the present invention, the diluent is the same as the diluent used for the impurity standard solution, and the details are not repeated herein.
In the present invention, the liquid chromatography detection conditions of the sample to be detected are preferably identical to the liquid chromatography detection conditions of the impurity standard substance, and are not described herein again.
After a standard liquid chromatogram and a liquid chromatogram of a sample to be detected are obtained, the liquid chromatogram of the sample to be detected is compared with the standard liquid chromatogram, and the content of impurities in the sample to be detected is calculated according to an area normalization method. In the invention, when the comparison is carried out, the separation degree between the meropenem side chain sample and the meropenem side chain optical isomer is more than or equal to 1.4.
The specific process for calculating the content of the impurities in the sample to be detected by adopting the area normalization method is not specially limited, and the process is carried out according to the process known in the field.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
1) Synthesis of (2R,4R) -4-hydroxy-1- (p-nitrobenzyloxycarbonyl) pyrrolidine-2-carboxylic acid (intermediate 1):
sodium hydroxide (66.9g,1.68mol) and 600g of water were added to a reaction flask, and after dissolving by stirring, cis-D-hydroxyproline (100g,0.76mol) was added. Cooling to 0 ℃ after stirring and complete dissolution, and dropwise adding 50% p-nitrobenzyl chloroformate solution (370g,0.86mol) in dichloromethane, wherein the temperature is not more than 5 ℃;after the dripping is finished, the mixture reacts for 3 hours at the temperature of 0-5 ℃, after the reaction is finished, the mixture is kept stand for demixing, and the aqueous phase is extracted by 100mL of dichloromethane. Separating out the water phase, adjusting the pH value to 2-3 by using 10% hydrochloric acid, extracting for three times by using ethyl acetate (200mL multiplied by 3), combining the organic phases, washing by using saturated salt water, drying by using anhydrous sodium sulfate, filtering, concentrating to dryness, and recrystallizing by using ethanol to obtain 221.0g of white solid (intermediate 1) with the yield of 93.4%; the nuclear magnetic data are:1H NMR(D2O，400MHz):δ2.03(m,1H),2.26(m,1H),3.39-3.53(m,2H), 4.28-4.38(m,2H),4.99-5.15(m,2H),7.37-7.44(m,2H),8.07(m,2H).
2) synthesis of (2R,4R) -2-dimethylcarbamoyl-4-hydroxy-1- (p-nitrobenzyloxycarbonyl) pyrrolidine (intermediate 2):
adding the intermediate 1(40g,0.13mol), triethylamine (19.6g, 0.19mol) and 300mL of dichloromethane into a reaction bottle under the protection of nitrogen, stirring to dissolve completely, cooling to-10 ℃, dropwise adding isopropyl chloride (19.0g, 0.15mol), stirring for 2h after adding, dropwise adding a dimethylamine aqueous solution (0.18 mol of dimethylamine), keeping the temperature not more than 0 ℃, and reacting at 0 ℃ for 3h after dropwise adding; after the reaction is finished, slowly adding 200mL of water, stirring for 5 minutes, standing for layering, washing the organic phase with 100mL of 2% dilute hydrochloric acid, 100mL of 5% potassium carbonate, washing with water and saturated salt water, separating an organic layer, drying with anhydrous sodium sulfate, filtering, concentrating to dryness, and recrystallizing with methanol to obtain 35.9g of light yellow solid powder (intermediate 2) with the yield of 82.6%; the nuclear magnetic data are:1H NMR(CDCl3，400MHz):δ2.04(s,1H),2.05-2.32(m,2H), 2.88-3.13(m,6H),3.59-4.15(m,2H),4.57(m,1H),4.86(m,1H),5.02-5.33(m, 2H),7.42-7.51(m,2H),8.19(m,2H).
3) synthesis of (2R,4R) -2-dimethylcarbamoyl-4-methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) pyrrolidine (intermediate 3):
under the protection of nitrogen, adding the intermediate 2(47g,0.14mol), triethylamine (18.8g, 0.19mol) and 200mL of dichloromethane into a four-mouth bottle, stirring to dissolve completely, cooling to-10 ℃, dropwise adding methanesulfonyl chloride (17.4g, 0.15mol) at the temperature of not more than 0 ℃, and reacting for 2 hours at 0 ℃ after dropwise adding; after the reaction is finished, slowly adding 200mL of water, stirring for 10 minutes, standing for layering, washing the organic phase with 100mL of 2% diluted hydrochloric acid and 100mL of 5% potassium carbonate,washing with water and saturated salt solution to separate organic layer, drying with anhydrous sodium sulfate, filtering, concentrating to dryness, and recrystallizing with methanol to obtain yellow solid powder 55.3g (intermediate 3) with yield of 95.5%; the nuclear magnetic data are:1H NMR(CDCl3，400MHz):δ2.27-2.37(m,1H), 2.51-2.71(m,1H),2.91-3.16(m,9H),3.87-3.97(m,2H),4.84-4.93(m,1H), 5.05-5.337(m,3H),7.442-7.52(m,2H),8.22(m,2H).
4) synthesis of (2R,4S) -2-dimethylcarbamoyl-4-acetylmercapto-1- (p-nitrobenzyloxycarbonyl) pyrrolidine (intermediate 4):
under the protection of nitrogen, adding the intermediate 3(5.5g,0.013mol), potassium thioacetate (3g,0.026mol) and 50mL of N, N-dimethylformamide into a reaction flask, and heating to 55 ℃ for reaction for 3 h. After the reaction is finished, cooling to room temperature, adding 200mL of water, stirring for 10 minutes, extracting with ethyl acetate for three times (50mL multiplied by 3), combining organic layers, washing with water for 3 times, washing with saturated salt for 3 times, separating the organic layer, drying with anhydrous sodium sulfate, filtering, and concentrating to dryness to obtain 5.0g of yellow oily matter (intermediate 4), wherein the yield is 96%, and the yellow oily matter is directly used in the next step without purification;
5) synthesis of 2R 4S-M:
adding the intermediate 4(5g,0.013mol) and 50mL of dichloromethane into a reaction bottle under the protection of nitrogen, cooling to 0-5 ℃, dropwise adding 25mL of a methanol solution of potassium hydroxide (1.7g,0.03mol), keeping the temperature not higher than 10 ℃, keeping the temperature for reacting for 1.5h after dropwise adding, after the reaction is finished, adding 70mL of water, cooling to 0 ℃, adjusting the pH to 7 with 10% hydrochloric acid, keeping the temperature not higher than 5 ℃, standing for liquid separation, washing an organic layer twice (50mL multiplied by 3) with water, then washing with saturated salt water, separating an organic layer, drying with anhydrous sodium sulfate, filtering, concentrating to obtain yellow oily substances, and purifying by column chromatography (ethyl acetate: petroleum ether is 2:1 in volume ratio) to obtain 3.6g of a light yellow solid, namely 2R4S-M, wherein the yield is 80.6%.
The end product prepared in example 1 was characterized by nuclear magnetic and mass spectrometry, and the results are shown in fig. 1 and fig. 2; the nuclear magnetic data obtained were:1H NMR(CDCl3400MHz Δ 1.72(m,1H),2.14(m,1H),2.28(m, 1H),2.90-3.09(m,6H),3.39(m,1H),3.65(m,1H),4.08(m,1H),4.83(m,1H), 5.06-5.33(m,2H),7.40-7.50(m,2H),8.19(m,2H). Mass Spectrometry data are: LCMS, m/z Calcd for (M + H) +, 354.4; found, 354.1. The above data indicate that the chemical structure of 2R4S-M is correct.
Example 2
1) Synthesis of (2R,4S) -2-dimethylcarbamoyl-4-bromo-1- (p-nitrobenzyloxycarbonyl) pyrrolidine (intermediate 5):
under the protection of nitrogen, the intermediate 3(20g,0.048mol) prepared in example 1, sodium bromide (24.8g,0.241mol), potassium iodide (0.2g,0.001mol) and 100mL of N, N-dimethylformamide were added to a reaction flask, the temperature was raised to 100 ℃ to react for 2 hours, after the reaction was completed, the temperature was lowered to room temperature, 500mL of water was added, stirring was performed for 10 minutes, then, the mixture was extracted three times with ethyl acetate (100mL × 3), the organic layers were combined, washed with water for 3 times, washed with saturated common salt water for 3 times, the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain a brown oily substance, and column chromatography (ethyl acetate: petroleum ether: 1) was performed to obtain 12g of a yellow oily substance (intermediate 5), yield was 62.3%, and data was that nuclear magnetic resonance was recorded as data1H NMR(CDCl3，400MHz):δ 2.10-2.29(m,1H),2.75-2.90(m,1H),2.92-3.07(m,6H),3.58-3.74(m,1H), 4.10-4.29(m,2H),4.60-4.73(m,1H),5.01-5.31(m,2H),7.420-7.50(m,2H), 8.18(m,2H).
6) Synthesis of (2R,4R) -2-dimethylcarbamoyl-4-acetylmercapto-1- (p-nitrobenzyloxycarbonyl) pyrrolidine (intermediate 6):
adding the intermediate 5(5.5g,0.013mol), potassium thioacetate (3g,0.026mol) and 50mL of N, N-dimethylformamide into a reaction bottle, heating to 55 ℃ and reacting for 3 h; after the reaction is finished, cooling to room temperature, adding 200mL of water, stirring for 10 minutes, extracting with ethyl acetate for three times (50mL multiplied by 3), combining organic layers, washing with water for 3 times, washing with saturated salt water for 3 times, separating the organic layer, drying with anhydrous sodium sulfate, filtering, and concentrating to dryness to obtain 5.26g of yellow oily matter (intermediate 6), wherein the yield is 96.8%, and the yellow oily matter is directly used in the next step without purification;
7) synthesis of 2R 4R-M:
the same procedure as for the hydrolysis of intermediate 4 in example 1 was followed, except that: hydrolysis was carried out starting from intermediate 6(2.2g, 0.006mol) to give 1.7g (i.e. 2R4R-M) as a pale yellow solid in 77.3% yield.
To the embodiments2 nuclear magnetic and mass spectrometry characterization of the prepared final product, the results are shown in fig. 3 and fig. 4; the nuclear magnetic data obtained were:1H NMR(CDCl3400MHz δ 1.88(m,2H),2.74(m,1H), 2.91-3.08(m,6H),3.26(m,1H),3.44(m,1H),4.07(m,1H),4.68(m,1H), 5.01-5.31(m,2H),7.40-7.50(m,2H),8.19(m,2H). Mass Spectrometry data are: LCMS, M/z Calcd for (M + H) +, 354.4; found, 354.1. The above data indicate that the chemical structure of 2R4R-M is correct.
Example 3
1) Synthesis of (2S,4R) -4-hydroxy-1- (p-nitrobenzyloxycarbonyl) pyrrolidine-2-carboxylic acid (intermediate 7):
adding sodium hydroxide (66.9g,1.68mol) and water 600g into a reaction bottle, stirring to dissolve, then adding trans-L-hydroxyproline (100g,0.76mol), stirring to dissolve completely, cooling to 0 ℃, and dropwise adding a 50% p-nitrobenzyl chloroformate dichloromethane solution (370g,0.86mol) at the temperature of not more than 5 ℃; after the dripping is finished, reacting for 3 hours at 0-5 ℃, standing and layering after the reaction is finished, and extracting impurities from a water phase by using 100mL of dichloromethane; the aqueous phase was separated, the pH was adjusted to 2-3 with 10% hydrochloric acid, then extracted three times with ethyl acetate (200mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and recrystallized with ethanol to give 219.2g of a white solid (intermediate 7) with a yield of 92.6%.1HNMR(D2O，400MHz): δ2.02(m,1H),2.25(m,1H),3.44(m,1H),3.52(m,1H),4.28-4.38(m,2H), 5.00-5.16(m,2H),7.37-7.44(m,2H),8.08(m,2H).
2) Synthesis of (2S,4R) -2-dimethylcarbamoyl-4-methanesulfonyloxy-1- (p-nitrobenzyloxycarbonyl) pyrrolidine (intermediate 9):
adding the intermediate 7(30g,0.10mol), triethylamine (27.9g, 0.28mol) and 500mL of dichloromethane into a reaction bottle under the protection of nitrogen, cooling to-10 ℃, dropwise adding isopropyl chloride (13.1g, 0.11mol) at the temperature of not more than 0 ℃, reacting at 0 ℃ for 2 hours after dropwise adding, cooling to-10 ℃, dropwise adding methanesulfonyl chloride (15.0g,0.13mol) at the temperature of not more than 0 ℃, reacting at 0 ℃ for 2 hours after dropwise adding to obtain a product containing the intermediate 8, dropwise adding a dimethylamine aqueous solution (14.2g, 0.13mol) with the mass concentration of 40% into the product containing the intermediate 8, keeping the temperature and reacting for 3 hours after dropwise adding,after the reaction, the reaction mixture was washed with 300mL of 2% dilute hydrochloric acid, 300mL of 5% potassium carbonate, washed with water and saturated brine in this order, and the organic layer was separated, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and recrystallized from methanol to give 29.8g of a yellow solid powder (intermediate 9) with a yield of 74.2%.1H NMR(CDCl3， 400MHz):δ2.34(m,1H),2.51-2.70(m,1H),2.91-3.16(m,9H),3.94(m,2H), 4.84-4.93(m,1H),5.05-5.37(m,3H),7.44-7.52(m,2H),8.22(m,2H).
3) Synthesis of (2S,4S) -2-dimethylcarbamoyl-4-bromo-1- (p-nitrobenzyloxycarbonyl) pyrrolidine (intermediate 10):
the same procedure was followed as for the preparation of intermediate 5 using intermediate 3 in example 2, except that: intermediate 9(15g,0.036mol) was used as the starting material to prepare 9.8g (intermediate 10) as a yellow oil in 67.8% yield; the nuclear magnetic data are:1H NMR(CDCl3，400MHz):δ2.43-2.57(m,2H), 2.89-3.14(m,6H),3.93-4.11(m,2H),4.60(m,1H),4.96(m,1H),5.05-5.35(m,2H) 7.42-7.49(m,2H),8.19(m,2H).
4) synthesis of (2S,4R) -2-dimethylcarbamoyl-4-acetylmercapto-1- (p-nitrobenzyloxycarbonyl) pyrrolidine (intermediate 11):
the same procedure was followed as for intermediate 3 to prepare intermediate 4 in example 1, except that: starting from intermediate 10(11.9g,0.03mol), 10.3g of a yellow oil (intermediate 11) was prepared in 87.6% yield and used in the next step without purification;
5) synthesis of 2S 4R-M:
the same procedure as for the hydrolysis of intermediate 4 in example 1 was followed, except that: starting from intermediate 11(5.4g, 0.014mol), 3.7g of a pale yellow solid was prepared in 76.7% yield.
The end product prepared in example 3 was characterized by nuclear magnetic and mass spectrometry, and the results are shown in fig. 5 and 6; the nuclear magnetic data obtained were:1HNMR(CDCl 3400 MHz). delta.1.73 (m,1H),2.14(m,1H),2.28(m, 1H),2.91-3.09(m,6H),3.39(m,1H),3.64(m,1H),4.08(m,1H),4.83(m,1H), 5.05-5.32(m,2H),7.40-7.50(m,2H),8.19(m, 2H); the mass spectrum data is: LCMS, M/z Calcd for (M + H) +, 354.4; found, 354.1. The above data indicate that the chemical structure of 2S4R-M is correct.
Application example
The diluent used in the application is n-hexane, ethanol 1:1 (V/V); the high performance liquid chromatograph: SHIIMAZU LC-20 AT;
preparing a standard solution: accurately weighing 25mg of meropenem side chain sample in a 50mL volumetric flask, adding 15mL of diluent for dissolution, and then adding the diluent for dilution to the scale.
Preparing a solution of a to-be-detected product: accurately weighing 25mg of three optical isomers of the meropenem side chain in a 50mL volumetric flask, adding a diluent to dissolve and dilute the three optical isomers to a scale, and preparing three solutions to be detected.
Preparing a sample solution to be tested: accurately weighing 25mg of a mixed sample of the meropenem side chain and the three optical isomers in a 50mL volumetric flask, adding a diluent to dissolve and dilute to a scale mark.
Operating a blank solution (diluent) according to chromatographic conditions, recording a chromatogram, injecting the standard solution into a high performance liquid chromatograph under the premise of no interference peak, performing liquid chromatographic analysis, and recording the chromatogram and the peak area of a sample;
chromatographic conditions are as follows:
a chromatographic column: chiralpak IC, 250 mm. times.4.6 mm, 5 μm;
mobile phase: n-hexane, ethanol, methanol, trifluoroacetic acid, 600:300:100:1 (v/v/v/v);
flow rate: 1.0 mL/min;
detection wavelength: 270 nm;
sample introduction amount: 20 mu L of the solution;
column temperature: 40 ℃;
collecting time: 35 min;
respectively injecting the standard solution and the solution of the three optical isomers of the meropenem side chain to be measured into a liquid chromatograph, performing liquid chromatographic analysis according to the chromatographic conditions, and recording a chromatogram and a sample peak area;
calculating the content of the meropenem side chain isomer in the meropenem side chain sample according to an area normalization method, wherein the separation degree between the meropenem side chain sample and the meropenem side chain isomer is not less than 1.4, and the obtained spectrograms are respectively shown in figures 7-10; the retention times of the meropenem side chain and its three optical isomers under this detection method are shown in table 1.
TABLE 1 liquid phase Retention time of Meropenem side chain and its three optical isomers
As can be seen from FIGS. 7-10 and Table 1, the chiral purity of all three optical isomers of the meropenem side chain can reach more than 99%, and the meropenem side chain is expected to be used as a standard sample.
According to the process, the sample solution to be detected is injected into a liquid chromatograph, liquid chromatographic analysis is carried out according to the chromatographic conditions, a chromatogram and a sample peak area are recorded, the obtained chromatogram is shown in a figure 11, and the obtained retention time is shown in a table 2.
TABLE 2 liquid phase retention time of meropenem side chain and three optical isomer mixture
As can be seen from fig. 11 and table 2, the retention time of the mixture appeared slightly shifted from that of the pure substance, indicating that the detection method can effectively separate and identify the meropenem side chain and three optical isomers.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A meropenem side chain optical isomer with a structural general formula shown in formula I,
the meropenem side chain optical isomer is characterized by having a structural configuration shown in a formula II, a formula III or a formula IV:
2. the process for producing meropenem side-chain optical isomer of claim 1, which comprises the steps of:
when the meropenem side chain optical isomer has the structural configuration shown in formula II, the preparation method of the meropenem side chain optical isomer comprises the following steps:
mixing cis-D-hydroxyproline, p-nitrobenzyl chloroformate, a first solvent, sodium hydroxide and water, and carrying out amidation reaction to obtain an intermediate 1;
mixing the intermediate 1, triethylamine, a second solvent, isopropyl chloride and dimethylamine, and performing amidation reaction to obtain an intermediate 2;
mixing the intermediate 2, triethylamine, a third solvent and methanesulfonyl chloride to perform a sulfonylation reaction to obtain an intermediate 3;
mixing the intermediate 3, potassium thioacetate and a fourth solvent, and carrying out a thionation reaction to obtain an intermediate 4;
mixing the intermediate 4 with alkali liquor, and hydrolyzing to obtain a meropenem side chain optical isomer with a structural configuration shown in formula II;
the intermediate 1 has a structure shown as a formula:
the intermediate 2 has a structure shown as a formula b:
the intermediate 3 has a structure shown as formula c:
the intermediate 4 has a structure shown in a formula d:
when the meropenem side chain optical isomer has the structural configuration shown in formula III, the preparation method of the meropenem side chain optical isomer comprises the following steps:
mixing the intermediate 3, sodium bromide, potassium iodide and a fifth solvent, and carrying out bromination reaction to obtain an intermediate 5;
mixing the intermediate 5 with potassium thioacetate for substitution reaction to obtain an intermediate 6;
mixing the intermediate 6 with alkali liquor, and hydrolyzing to obtain a meropenem side chain optical isomer with a structural configuration shown in formula III;
the intermediate 5 has a structure shown as a formula e:
the intermediate 6 has a structure represented by formula f:
when the meropenem side chain optical isomer has the structural configuration shown in formula IV, the preparation method of the meropenem side chain optical isomer comprises the following steps:
mixing trans-L-hydroxyproline, p-nitrobenzyl chloroformate, a sixth solvent, sodium hydroxide and water, and carrying out amidation reaction to obtain an intermediate 7;
mixing the intermediate 7, triethylamine, a seventh solvent and isopropyl chloride for esterification, mixing the obtained product with methanesulfonyl chloride for sulfonylation to obtain an intermediate 8;
mixing the intermediate 8 with dimethylamine, and carrying out amidation reaction to obtain an intermediate 9;
mixing the intermediate 9, sodium bromide, potassium iodide and an eighth solvent, and carrying out bromination reaction to obtain an intermediate 10;
mixing the intermediate 10 with potassium thioacetate for substitution reaction to obtain an intermediate 11;
mixing the intermediate 11 with alkali liquor, and hydrolyzing to obtain a meropenem side chain optical isomer with a structural configuration shown in formula IV;
the intermediate 7 has a structure shown in formula j:
the intermediate 8 has a structure represented by formula h:
the intermediate 9 has a structure represented by formula i:
the intermediate 10 has a structure represented by formula g:
the intermediate 11 has a structure represented by formula k:
3. the method according to claim 2, wherein the molar ratio of cis-D-hydroxyproline to p-nitrobenzyl chloroformate is (0.6-1.0): (0.8-1.2) when preparing the meropenem side chain optical isomer having the structural configuration represented by formula II; when the intermediate 1 is prepared, the esterification reaction is carried out at the temperature of-5-10 ℃ for 1-6 h.
4. The method according to claim 2, wherein the intermediate 2 is prepared in such a manner that the molar ratio of the intermediate 1, triethylamine, isopropyl chloroformate and dimethylamine is (0.10-0.15), (0.15-0.2), (0.12-0.18): (0.12-0.2); the temperature of the amidation reaction is-5-10 ℃, and the time is 1-6 h;
when the intermediate 3 is prepared, the molar ratio of the intermediate 2, triethylamine and methanesulfonyl chloride is (0.10-0.15): (0.13-0.25): (0.11-0.2); the temperature of the sulfonylation reaction is-5-10 ℃, and the time is 1-6 h.
5. The preparation method according to claim 2, wherein the intermediate 4 is prepared by mixing the intermediate 3 and the potassium thioacetate at a molar ratio of (0.010-0.015) to (0.022-0.028), wherein the temperature of the thionation reaction is 40-60 ℃ and the time is 2-8 h.
6. The method according to claim 2, wherein the intermediate 5 is prepared in such a manner that the molar ratio of the intermediate 3 to sodium bromide to potassium iodide is (0.04-0.05): (0.20-0.03): 0.001-0.01); the temperature of the bromination reaction is 70-120 ℃, and the time is 1-5 h.
7. The method according to claim 2, wherein the intermediate 7 is prepared in such a manner that the molar ratio of trans-L-hydroxyproline to p-nitrobenzyl chloroformate is (0.6-0.8): (0.8-1.0); the temperature of the amidation reaction is-5-10 ℃, and the time is 1-6 h;
when the intermediate 8 is prepared, the molar ratio of the intermediate 7 to the triethylamine to the isopropyl chloroformate to the methanesulfonyl chloride is (0.10-0.15) to (0.2-0.4) to (0.1-0.16): (0.11-0.2); the temperature of the esterification reaction is-5-10 ℃, and the time is 1-6 h;
when the intermediate 9 is prepared, the molar ratio of the intermediate 8 to dimethylamine is (0.1-0.2) to (0.1-0.3).
8. The meropenem side chain optical isomer in claim 1 or the meropenem side chain optical isomer prepared by the preparation method in any one of claims 2 to 7 is used as a standard substance in detecting impurities in a meropenem side chain product.
9. A detection method of meropenem side chain impurities comprises the following steps:
performing liquid chromatography detection by using a meropenem side chain optical isomer as an impurity standard substance by adopting a high performance liquid chromatography to obtain a standard liquid chromatography spectrogram; the meropenem side chain optical isomer is the meropenem side chain optical isomer in claim 1 or the meropenem side chain optical isomer prepared by the preparation method in any one of claims 2 to 7;
taking a meropenem side chain sample as a sample to be detected, and performing liquid chromatography detection to obtain a liquid chromatography spectrogram of the sample to be detected;
and comparing the liquid chromatogram of the sample to be detected with a standard liquid chromatogram, and calculating the content of impurities in the sample to be detected according to an area normalization method.
10. The method according to claim 9, wherein the chromatographic conditions of the liquid chromatographic assay are: a chromatographic column: chiralpak IC, 250 mm. times.4.6 mm, 5 μm; mobile phase: the mixture of n-hexane, ethanol, methanol and trifluoroacetic acid, wherein the volume ratio of the n-hexane, the ethanol, the methanol and the trifluoroacetic acid is (500-700): 200-400): 50-200): 1-10; flow rate: 1.0-1.5 mL/min; detection wavelength: 270 nm; sample introduction amount: 20-25 muL; column temperature: 30-60 ℃; collecting time: 20-50 min.
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| US4933333A (en) * | 1983-05-09 | 1990-06-12 | Sumitomo Pharmaceuticals Co., Ltd. | β-lactam compounds |
| CN101041632A (en) * | 2007-04-28 | 2007-09-26 | 浙江耐司康药业有限公司 | Preparation method of penem drug branched chain intermediate-mercaptan derivative |
| CN101225069A (en) * | 2007-02-13 | 2008-07-23 | 天津市敬业精细化工有限公司 | Method for synthesizing meropenem intermediate |
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| US4933333A (en) * | 1983-05-09 | 1990-06-12 | Sumitomo Pharmaceuticals Co., Ltd. | β-lactam compounds |
| CN101225069A (en) * | 2007-02-13 | 2008-07-23 | 天津市敬业精细化工有限公司 | Method for synthesizing meropenem intermediate |
| CN101041632A (en) * | 2007-04-28 | 2007-09-26 | 浙江耐司康药业有限公司 | Preparation method of penem drug branched chain intermediate-mercaptan derivative |
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