CN114163371B - Meropenem side chain optical isomer, preparation method and application thereof, and meropenem side chain impurity detection method - Google Patents
Meropenem side chain optical isomer, preparation method and application thereof, and meropenem side chain impurity detection method Download PDFInfo
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- CN114163371B CN114163371B CN202111573917.7A CN202111573917A CN114163371B CN 114163371 B CN114163371 B CN 114163371B CN 202111573917 A CN202111573917 A CN 202111573917A CN 114163371 B CN114163371 B CN 114163371B
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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 104
- 230000003287 optical effect Effects 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 239000012535 impurity Substances 0.000 title abstract description 26
- 238000001514 detection method Methods 0.000 title abstract description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 96
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 64
- 238000002156 mixing Methods 0.000 claims description 59
- 239000002904 solvent Substances 0.000 claims description 56
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 51
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 48
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 39
- 238000007112 amidation reaction Methods 0.000 claims description 29
- 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 28
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 26
- 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
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 claims description 20
- 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 19
- 239000003513 alkali Substances 0.000 claims description 19
- 238000005694 sulfonylation reaction Methods 0.000 claims description 14
- 238000005893 bromination reaction Methods 0.000 claims description 13
- 238000006467 substitution reaction Methods 0.000 claims description 11
- 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
- 238000005886 esterification reaction Methods 0.000 claims description 8
- 230000003301 hydrolyzing effect Effects 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 18
- 238000003786 synthesis reaction Methods 0.000 abstract description 18
- -1 generated impurities Chemical compound 0.000 abstract description 11
- 239000000126 substance Substances 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 239000012450 pharmaceutical intermediate Substances 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 213
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000000523 sample Substances 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 32
- 239000012044 organic layer Substances 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- 239000000463 material Substances 0.000 description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 23
- 238000004811 liquid chromatography Methods 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- 238000003756 stirring Methods 0.000 description 19
- 238000005406 washing Methods 0.000 description 19
- 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
- 239000007788 liquid Substances 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 13
- 238000001816 cooling Methods 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000003085 diluting agent Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 229910052757 nitrogen Inorganic materials 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
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 230000007062 hydrolysis Effects 0.000 description 9
- 238000006460 hydrolysis reaction Methods 0.000 description 9
- 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 9
- 239000012071 phase Substances 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 235000002639 sodium chloride Nutrition 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 6
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 229960002260 meropenem Drugs 0.000 description 5
- 238000010606 normalization Methods 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- 239000012086 standard solution Substances 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 230000005311 nuclear magnetism Effects 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 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
- 241000192125 Firmicutes Species 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis 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
- 239000012043 crude product Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000010438 heat treatment Methods 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
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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, belonging to the technical field of synthesis of pharmaceutical intermediates. 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 generated impurities, and can be used as a standard to effectively detect the impurities 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 synthesis of pharmaceutical intermediates, 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, gram-negative bacteria and the like, and particularly has antibacterial activity on multi-drug resistant aerobic gram-negative bacteria. Because the chemical structure introduces methyl at the 4-position of the carbapenem parent ring, the stability of the carbapenem parent ring to human renal dehydropeptidase-1 (DHP-1) is obviously improved, so that a DHP-1 inhibitor such as cilastatin does not need to be applied simultaneously, and the carbapenem parent ring can be used singly in clinic. The meropenem side chain (Meropenem SIDE CHAIN, abbreviated as 2S 4S-M), i.e. (2S, 4S) -2-dimethylcarbamoyl-4-mercapto-1- (p-nitrobenzyloxycarbonyl) -1-pyrrolidine (shown in formula 1 below), is a key intermediate for the production of the carbapenem antibiotic meropenem, which contains two chiral centers.
Along with the deeper and deeper understanding of the harmfulness of medicine impurities in various countries in the world, the quality requirement on the medicine intermediate is also higher and higher, and the quality condition and purity of the meropenem side chain serving as a key medicine intermediate directly influence the preparation and the safety of medicines. The chiral medicine and the isomer thereof can generate different or even opposite pharmacological actions in human bodies, so the chiral medicine and the isomer thereof have important significance for synthesizing the optical isomer of the meropenem side chain which is a key intermediate for synthesizing meropenem.
Disclosure of Invention
The invention aims to provide a meropenem side chain optical isomer, a preparation method and application thereof, and a meropenem side chain impurity detection method.
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 a 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 a structural configuration shown in a 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 chloroformate and dimethylamine, and carrying out amidation reaction to obtain an intermediate 2;
Mixing the intermediate 2, triethylamine, a third solvent and methanesulfonyl chloride, and carrying out sulfonylation reaction to obtain an intermediate 3;
Mixing the intermediate 3, potassium thioacetate and a fourth solvent, and performing a thio 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 a formula II;
the intermediate 1 has a structure represented by formula a:
The intermediate 2 has a structure represented by formula b:
the intermediate 3 has a structure represented by formula c:
The intermediate 4 has a structure represented by formula d:
When the meropenem side chain optical isomer has a structural configuration shown in a 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, and carrying out 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 a formula III;
the intermediate 5 has a structure represented by formula e:
the intermediate 6 has a structure represented by formula f:
when the meropenem side chain optical isomer has a structural configuration shown in a 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 chloroformate, carrying out esterification reaction, mixing the obtained product with methanesulfonyl chloride, and carrying out sulfonylation reaction 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, and carrying out 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 a formula IV;
The intermediate 7 has a structure represented by 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 preparing the meropenem side chain optical isomer with the structural configuration shown in the formula II, the mol ratio of the cis-D-hydroxyproline to the p-nitrobenzyl chloroformate is (0.76:0.86), the ratio of the cis-D-hydroxyproline to the p-nitrobenzyl chloroformate is (0.6-1.0) to the p-nitrobenzyl chloroformate is (0.8-1.2) when preparing the intermediate 1, and the temperature of the esterification reaction is-5-10 ℃ for 1-6 h.
Preferably, in preparing intermediate 2, the molar ratio of 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 mol ratio of the intermediate 2 to triethylamine to 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 preparing the intermediate 4, the molar ratio of the intermediate 3 to the potassium thioacetate is (0.010-0.015): (0.022-0.028), the temperature of the thioation reaction is 40-60 ℃ and the time is 2-8 h.
Preferably, when preparing the intermediate 5, 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 bromination reaction temperature is 70-120 ℃ and the time is 1-5 h.
Preferably, in the preparation of the intermediate 7, the mol 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;
In the preparation of the intermediate 8, the molar ratio of the intermediate 7 to the triethylamine to the isopropyl chloroformate to the methanesulfonyl chloride is (0.10-0.15): 0.2-0.4): 0.1-0.16: (0.11-0.2); the temperature of the esterification reaction is-5-10 ℃ and the time is 1-6 h;
in the preparation of the intermediate 9, the molar ratio of the intermediate 8 to dimethylamine is (0.1-0.2): 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 product in detecting impurities of meropenem side chain products.
The invention provides a method for detecting meropenem side chain impurities, which comprises the following steps:
adopting a high performance liquid chromatography, and taking a meropenem side chain optical isomer as an impurity standard substance to perform liquid chromatography detection 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 the standard liquid chromatogram, and calculating the impurity content in the sample to be detected according to an area normalization method.
Preferably, the chromatographic conditions of the liquid chromatography detection are: chromatographic column: CHIRALPAK IC,250 mm X4.6 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: 270nm; sample injection amount: 20-25 mu L; column temperature: 30-60 ℃; acquisition time: 20-50 min.
The invention provides a meropenem side chain optical isomer, which is a substance affecting the purity of a meropenem side chain product in the production process of the meropenem side chain, namely generated impurities, and can be used as a standard to effectively detect the impurities in the meropenem side chain, thereby laying a foundation for improving the quality of the meropenem side chain product.
Drawings
FIG. 1 is a nuclear magnetic resonance 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 resonance 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 resonance 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 diagram of chiral purity of meropenem side-chain optical isomer 2S 4R-M;
FIG. 9 is a diagram of chiral purity of meropenem side-chain optical isomer 2R 4S-M;
FIG. 10 is a chart of chiral purity of meropenem side-chain optical isomer 2R 4R-M;
FIG. 11 is a spectrum of a sample mixture of meropenem side chains and three isomers.
Detailed Description
The invention provides a meropenem side chain optical isomer with a structural general formula shown in a 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 a structural configuration shown in a 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 chloroformate and dimethylamine, and carrying out amidation reaction to obtain an intermediate 2;
Mixing the intermediate 2, triethylamine, a third solvent and methanesulfonyl chloride, and carrying out sulfonylation reaction to obtain an intermediate 3;
Mixing the intermediate 3, potassium thioacetate and a fourth solvent, and performing a thio 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 a formula II;
the intermediate 1 has a structure represented by formula a:
The intermediate 2 has a structure represented by formula b:
the intermediate 3 has a structure represented by formula c:
The intermediate 4 has a structure represented by formula d:
When the meropenem side chain optical isomer has a structural configuration shown in a 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, and carrying out 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 a formula III;
the intermediate 5 has a structure represented by formula e:
the intermediate 6 has a structure represented by formula f:
when the meropenem side chain optical isomer has a structural configuration shown in a 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 chloroformate, carrying out esterification reaction, mixing the obtained product with methanesulfonyl chloride, and carrying out sulfonylation reaction 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, and carrying out 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 a formula IV;
The intermediate 7 has a structure represented by 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, the preparation materials are commercially available as known to those skilled in the art unless otherwise specified.
In the present invention, when the meropenem side chain optical isomer has the structural configuration shown in formula II:
The invention mixes cis-D-hydroxyproline, p-nitrobenzyl chloroformate, a first solvent, sodium hydroxide and water for amidation reaction to obtain an intermediate 1. In the present invention, the molar ratio of cis-D-hydroxyproline to p-nitrobenzyl chloroformate is preferably (0.6 to 0.8): 0.8 to 1.0, more preferably 0.76:0.86. In the present 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 mixing process of cis-D-hydroxyproline, p-nitrobenzyl chloroformate, a first solvent, sodium hydroxide and water is preferably to dissolve the p-nitrobenzyl chloroformate in the first solvent to obtain p-nitrobenzyl chloroformate solution, stirring and dissolving sodium hydroxide and water, then adding cis-D-hydroxyproline, stirring and dissolving completely, cooling to 0 ℃, and dripping methylene dichloride solution of p-nitrobenzyl chloroformate (the control temperature is not more than 5 ℃). The stirring, dropping and cooling processes are not particularly limited, and can be performed according to processes well known in the art.
In the present invention, the temperature of the esterification reaction is preferably-5 to 10 ℃, more preferably 0 to 5 ℃, and the time is preferably 1 to 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 standing and layering the obtained material, extracting the obtained water phase with dichloromethane, separating the water phase, adjusting the pH value to 2-3 with 10% hydrochloric acid by mass fraction, extracting with ethyl acetate three times, merging the organic phases, sequentially using saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating to dryness and recrystallizing with ethanol to obtain the intermediate 1. The specific method of operation of the above post-treatment process is not particularly limited and may be carried out according to a process well 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 chloroformate and dimethylamine are mixed for amidation reaction to obtain the intermediate 2. In the invention, the molar ratio of the intermediate 1, the triethylamine, the isopropyl chloroformate and the 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 reaction can be ensured to be carried out smoothly. 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 process of mixing the intermediate 1, the triethylamine, the second solvent, the isopropyl chloroformate and the dimethylamine is preferably to stir the intermediate 1, the triethylamine and the dichloromethane until the intermediate 1, the triethylamine and the dichloromethane are fully dissolved, the temperature is reduced to minus 10 ℃, the isopropyl chloroformate is dropwise added, the stirring is carried out for 2 hours, and the dimethylamine aqueous solution is dropwise added (the control temperature is not more than 0 ℃). The rate of the dropping is not particularly limited in the present invention, and the dropping may be performed at a rate well known in the art.
In the present invention, the amidation reaction is preferably performed under a nitrogen atmosphere, and the temperature of the amidation reaction is preferably-5 to 10 ℃, more preferably 0 ℃, and the time is preferably 1 to 6 hours, more preferably 3 hours.
After the amidation reaction is completed, water is preferably added into the obtained material, the obtained material is stirred for 5 minutes and then is stood for layering, the obtained organic phase is sequentially washed by dilute hydrochloric acid with the mass fraction of 2 percent, potassium carbonate aqueous solution with the mass fraction of 5 percent, water and saturated salt water, the obtained washed material is separated into an organic layer, the obtained organic layer material is dried by anhydrous sodium sulfate, filtered and concentrated to dryness, and methanol is adopted for recrystallization, so that the intermediate 2 is obtained. The invention has no special limitation on the amount of water added, and the water 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 to obtain an intermediate 3. In the invention, the molar ratio of the intermediate 2, the triethylamine and the 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 reaction can be ensured to be carried out smoothly.
In the invention, the process of mixing the intermediate 2, the triethylamine and the third solvent with the methanesulfonyl chloride is preferably to stir the intermediate 2, the triethylamine and the dichloromethane until the intermediate 2, the triethylamine and the dichloromethane are fully dissolved, the temperature is reduced to-10 ℃, and the methanesulfonyl chloride is dropwise added (the temperature is controlled to be not more than 0 ℃).
In the present invention, the sulfonylation reaction is preferably carried out under a nitrogen atmosphere, and the sulfonylation reaction is preferably carried out at a temperature of-5 to 10 ℃, more preferably 0 ℃, for a time of preferably 1 to 6 hours, more preferably 2 hours.
After the sulfonylation reaction is completed, water is preferably added into the obtained material, the obtained material is stirred for 10 minutes and then is stood for layering, the obtained organic phase is sequentially washed with dilute hydrochloric acid with the mass fraction of 2%, potassium carbonate with the mass fraction of 5%, water and saturated salt water, an organic layer is separated, dried by anhydrous sodium sulfate, filtered, concentrated to dryness and recrystallized by methanol, and the intermediate 3 is obtained. The invention has no special limitation on the amount of water added, and the water 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, the potassium thioacetate and the fourth solvent are mixed for carrying out a thio 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): (0.022-0.028), 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 reaction can be ensured to be carried out smoothly.
The process of mixing the intermediate 3, potassium thioacetate and the fourth solvent is not particularly limited in the present invention, and the materials may be sufficiently mixed according to the processes well known in the art.
In the present invention, the thio reaction is preferably carried out under nitrogen protection, and the temperature of the thio reaction is preferably 40 to 60 ℃, more preferably 55 ℃, and the time is preferably 2 to 8 hours, more preferably 3 hours.
After the completion of the thio reaction, the obtained material is cooled to room temperature, water is added, stirring is carried out for 10 minutes, then ethyl acetate is used for three times of extraction, the organic layers are combined, water washing is carried out for 3 times and saturated salt water washing is carried out for 3 times in sequence, the organic layers are separated, and the obtained organic layer material is dried by anhydrous sodium sulfate, filtered and concentrated to dryness in sequence, thus obtaining an intermediate 4. The amount of the water to be added is not particularly limited, and the water to be added can be adjusted according to actual requirements.
In the present invention, the intermediate 4 has a structure represented by formula d:
After obtaining the intermediate 4, the intermediate 4 is mixed with alkali liquor and hydrolyzed to obtain the meropenem side chain optical isomer with the structural configuration shown in the formula II, which is marked as 2R4S-M.
In the invention, the molar ratio of the intermediate 4 to the alkali in the alkali liquor is preferably 0.013:0.03; the alkali liquor is preferably an aqueous solution of potassium hydroxide, the concentration of the alkali liquor is not particularly limited, and the smooth reaction can be ensured.
In the process of mixing the intermediate 4 with the alkali liquor, dichloromethane is also required to be added, and the dosage of the dichloromethane is not particularly limited, so that the smooth reaction can be ensured.
In the invention, the process of mixing the intermediate 4 with the alkali liquor is preferably to dissolve the intermediate 4 in methylene dichloride under the protection of nitrogen, cool to 0-5 ℃ and drop 25mL (the temperature is not more than 10 ℃) of the alkali liquor.
In the present invention, the hydrolysis is preferably performed under nitrogen protection; the temperature of the hydrolysis is preferably 0 to 10 ℃ and not 0 ℃, and the time is preferably 1.5h.
After the hydrolysis is completed, water is preferably added into the obtained material, the temperature is reduced to 0 ℃, the pH is regulated to 7 by hydrochloric acid with the mass fraction of 10 percent (the temperature is not more than 5 ℃), the obtained material is kept stand for liquid separation, the obtained organic layer is washed twice and then is washed by saturated common salt, the organic layer is separated, dried by anhydrous sodium sulfate, filtered and concentrated, and column chromatography purification (the eluent is preferably ethyl acetate and petroleum ether with the volume ratio of 2:1) is carried out, so that 2R4S-M is obtained. The amount of the water to be added is not particularly limited, and the water to be added can be adjusted according to actual requirements.
In the invention, the synthesis process of the 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 present invention, the molar ratio of the intermediate 3, sodium bromide and potassium iodide is preferably (0.04-0.05): (0.20-0.03): (0.001-0.01), more preferably 0.048:0.241:0.001; the fifth solvent is preferably N, N-dimethylformamide; the amount of the fifth solvent is not particularly limited, and the reaction can be ensured to be carried out smoothly.
The process of mixing the intermediate 3, sodium bromide, potassium iodide and the fifth solvent is not particularly limited in the present invention, and the materials may be uniformly mixed according to a process well known in the art.
In the present invention, the bromination reaction is preferably performed under a nitrogen gas atmosphere, and the temperature of the bromination reaction is preferably 70 to 120 ℃, more preferably 100 ℃, and the time is preferably 1 to 5 hours, more preferably 2 hours.
After the bromination reaction is completed, the obtained material is cooled to room temperature, water is added, stirring is carried out for 10 minutes, then ethyl acetate is used for three times of extraction, the organic layers are combined, water washing is carried out for 3 times and saturated salt water washing is carried out for 3 times in sequence, the organic layers are separated, anhydrous sodium sulfate is dried, filtration and concentration are carried out until the dry, and column chromatography purification is carried out, thus obtaining the intermediate 5. In the present invention, the eluent used in 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 amount of the water to be added is not particularly limited, and the water to be added can be adjusted according to actual requirements. The filtration and concentration process is not particularly limited in the present invention, and may be performed according to a process well known in the art.
In the present invention, the intermediate 5 has a structure represented by formula e:
after obtaining intermediate 5, the invention mixes intermediate 5 with potassium thioacetate to carry out substitution reaction to obtain intermediate 6. In the present invention, the molar ratio of the intermediate 5 to potassium thioacetate is preferably (0.010 to 0.015): (0.022 to 0.028), more preferably 0.013:0.026.
During the mixing process of the intermediate 5 and 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 art; the invention has no special limit to the dosage of the solvent, and ensures that the reaction is carried out smoothly.
In the present invention, the substitution reaction is preferably performed under a nitrogen protection condition, and the temperature of the substitution reaction is preferably 40 to 60 ℃, more preferably 55 ℃; the time is preferably 2 to 8 hours, more preferably 3 hours;
After the substitution reaction is completed, the obtained material is preferably subjected to post-treatment, the specific process is preferably that the obtained crude product liquid is cooled to room temperature, water is added, stirring is carried out for 10 minutes, then ethyl acetate is used for three times of extraction, the organic layers are combined, water washing and saturated saline water washing are sequentially carried out, the organic layers are separated, the obtained organic layer material is dried by anhydrous sodium sulfate, and after filtration, the obtained organic layer material is concentrated to dryness, thus obtaining an intermediate 6. The number of times of water washing is preferably 3, and the number of times of 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 obtaining the intermediate 6, the intermediate 6 is mixed with alkali liquor and hydrolyzed to obtain the meropenem side chain optical isomer with the structural configuration shown in the formula IV, which is marked as 2R4R-M. In the present invention, the hydrolysis process of intermediate 6 by mixing with alkali solution is preferably identical to the hydrolysis process of intermediate 4, and will not be described in detail herein.
In the invention, the synthesis process of the 2R4R-M is shown as the following formula:
In the present invention, when the meropenem side chain optical isomer has a structural configuration represented by formula IV:
The invention mixes trans-L-hydroxyproline, p-nitrobenzyl chloroformate, a sixth solvent, sodium hydroxide and water for amidation reaction to obtain an intermediate 7. In the invention, the mol ratio of the trans-L-hydroxyproline to the p-nitrobenzyl chloroformate is preferably (0.6-0.8): 0.8-1.0, 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 mixing process of trans-D-hydroxyproline, p-nitrobenzyl chloroformate, a sixth solvent, sodium hydroxide and water is preferably that the p-nitrobenzyl chloroformate is dissolved in the sixth solvent to obtain p-nitrobenzyl chloroformate solution, the sodium hydroxide and the water are stirred and dissolved, then cis-D-hydroxyproline is added, the temperature is reduced to 0 ℃ after stirring and complete dissolution, and methylene dichloride solution of p-nitrobenzyl chloroformate is dropwise added (the control temperature is not more than 5 ℃). The stirring, dropping and cooling processes are not particularly limited, and can be performed according to processes well known in the art.
In the present invention, the temperature of the amidation reaction is preferably from-5 to 10 ℃, more preferably from 0 to 5 ℃, and the time is preferably from 1 to 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 standing and layering the obtained material, extracting the obtained water phase with dichloromethane, separating the water phase, adjusting the pH value to 2-3 with 10% hydrochloric acid by mass fraction, extracting with ethyl acetate three times, merging the organic phases, sequentially using saturated brine, drying with anhydrous sodium sulfate, filtering, concentrating to dryness and recrystallizing with ethanol to obtain an intermediate 7. The specific method of operation of the above post-treatment process is not particularly limited and may be carried out according to a process well 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 chloroformate are mixed for amidation reaction, and the obtained product is mixed with methanesulfonyl chloride for sulfonylation reaction to obtain an intermediate 8. In the invention, the mole ratio of the intermediate 7, triethylamine, isopropyl chloroformate 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 process of mixing the intermediate 7, triethylamine, seventh solvent and isopropyl chloroformate is preferably to mix the intermediate 7, triethylamine and methylene chloride, cool to-10 ℃, and drop isopropyl chloroformate (temperature not more than 0 ℃). In the present invention, the esterification reaction is preferably carried out under nitrogen protection, the reaction temperature is preferably-5 to 10 ℃, more preferably 0 ℃, and the time is preferably 1 to 6 hours, more preferably 2 hours.
In the invention, the process of mixing the obtained product with methanesulfonyl chloride is preferably to cool the reaction product 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 2h.
In the present invention, the intermediate 8 has a structure represented by formula h:
After intermediate 8 is obtained, dimethylamine is preferably directly added dropwise into the obtained material without any post-treatment, and amidation reaction is carried out to obtain intermediate 9. In the present invention, the dimethylamine is preferably used in the form of an aqueous solution of dimethylamine, the mass concentration of which is preferably.40%; the molar ratio of the intermediate 8 to dimethylamine is preferably (0.1 to 0.2): (0.1 to 0.3), more preferably 0.1:0.13. The dropping rate is not particularly limited, and the dropping is performed according to the rate well known in the art; in the dropping process, the temperature is not more than 10 ℃. In the present invention, the amidation reaction is preferably performed under a nitrogen atmosphere, the reaction temperature is preferably 0 to 10 ℃ and not 0, and the time is preferably 3 hours.
After the amidation reaction is completed, the obtained material is preferably washed with dilute hydrochloric acid with a mass fraction of 2%, potassium carbonate with a mass fraction of 5%, water and saturated brine in order, the obtained washed material is separated into an organic layer, the obtained organic layer material is dried with anhydrous sodium sulfate, filtered, concentrated to dryness, and recrystallized with methanol to obtain 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 intermediate 10 from intermediate 9 is preferably the same as the process for preparing intermediate 5 from intermediate 3 (including the ratio of raw materials and conditions), and will not be described in detail herein.
In the present invention, the intermediate 10 has a structure represented by formula g:
after intermediate 10 is obtained, intermediate 10 is mixed with potassium thioacetate to perform substitution reaction to obtain 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 ratio of the raw materials and the conditions), and will not be described in detail herein.
In the present invention, the intermediate 11 has a structure represented by formula k:
After obtaining intermediate 11, the intermediate 11 is mixed with alkali liquor and hydrolyzed to obtain the meropenem side chain optical isomer with the structural configuration shown in the formula IV, which is marked as 2S4R-M. In the present invention, the hydrolysis process of intermediate 11 is the same as that of intermediate 6 (including the ratio of raw materials and conditions), and will not be described in detail herein.
In the invention, the synthesis process of the 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 product in detecting impurities of meropenem side chain products.
The invention provides a method for detecting meropenem side chain impurities, which comprises the following steps:
adopting a high performance liquid chromatography, and taking a meropenem side chain optical isomer as an impurity standard substance to perform liquid chromatography detection 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 the standard liquid chromatogram, and calculating the impurity content in the sample to be detected according to an area normalization method.
The invention adopts high performance liquid chromatography, uses meropenem side chain optical isomer as impurity standard substance, and carries out liquid chromatography detection to obtain standard liquid chromatography spectrogram. In the invention, the preparation method of the impurity standard solution for liquid chromatography detection preferably comprises the step of mixing the meropenem side chain optical isomer with a diluent to obtain the impurity standard solution. In the 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 particularly limited, meets the requirements of GB/T16631-2008 high performance liquid chromatography rule, and can be provided with an ultraviolet spectrophotometry detector, such as SHIMAZU LC-20AT.
In the present invention, the chromatographic conditions for the liquid chromatography detection are preferably: chromatographic column: CHIRALPAK IC,250 mm. Times.4.6 mm,5 μm; mobile phase: a 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 preferably (500-700): (200-400): (50-200): (1-10), more preferably 600:300:100:1; flow rate: 1.0 to 1.5 mL/min; detection wavelength: 270nm; sample injection amount: 20-25 mu L; column temperature: 30-60 ℃, more preferably 40 ℃; acquisition time: 20 to 50 minutes, more preferably 35 minutes.
And 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 invention, the meropenem side chain sample is a commercial meropenem side chain or a key intermediate meropenem side chain generated in the meropenem production process.
In the invention, the preparation process of the sample solution to be detected for liquid chromatography detection is preferably to mix the meropenem side chain sample with a diluent to obtain the sample solution to be detected. In the present invention, the diluent is the same as the diluent used for the impurity standard solution, and will not be described here.
In the present invention, the conditions for detecting the liquid chromatography of the sample to be detected are preferably identical to those of the impurity standard, and are not described herein.
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 impurity content of 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 of calculating the impurity content in the sample to be measured by adopting the area normalization method is not particularly limited, and the method can be carried out according to the process known in the art.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
1) Synthesis of (2R, 4R) -4-hydroxy-1- (p-nitrobenzyloxycarbonyl) pyrrolidine-2-carboxylic acid (intermediate 1):
To the reaction flask were added sodium hydroxide (66.9 g,1.68 mol) and water (600 g), and after stirring to dissolve, cis-D-hydroxyproline (100 g,0.76 mol) was added. Stirring and fully dissolving, cooling to 0 ℃, and dropwise adding 50% of p-nitrobenzyl chloroformate dichloromethane solution (370 g,0.86 mol) at a temperature not exceeding 5 ℃; after the completion of the dropping, the mixture was reacted at 0 to 5℃for 3 hours, and after the completion of the reaction, the mixture was allowed to stand and delaminate, and the aqueous phase was purified by 100mL of methylene chloride. Separating out water phase, adjusting pH to 2-3 with 10% hydrochloric acid, extracting with ethyl acetate (200 mL×3) for three times, mixing organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, concentrating to dryness, recrystallizing with ethanol to obtain white solid 221.0g (intermediate 1), and obtaining 93.4% yield; nuclear magnetic data of ：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):
Under the protection of nitrogen, adding an intermediate 1 (40 g,0.13 mol), triethylamine (19.6 g, 0.19 mol) and 300mL of dichloromethane into a reaction bottle, stirring for complete dissolution, cooling to-10 ℃, dropwise adding isopropyl chloroformate (19.0 g,0.15 mol), stirring for 2 hours after the addition, dropwise adding a dimethylamine aqueous solution (dimethylamine 0.18 mol) at a temperature of not more than 0 ℃, and reacting for 3 hours at 0 ℃ after the addition; after the reaction is finished, 200mL of water is slowly added, stirred for 5 minutes, then the mixture is stood for layering, the organic phase is sequentially washed by 100mL of 2% dilute hydrochloric acid, 100mL of 5% potassium carbonate, washed by water and saturated saline, an organic layer is separated, dried by anhydrous sodium sulfate, filtered and concentrated to dryness, 35.9g (intermediate 2) of pale yellow solid powder is obtained by recrystallisation by methanol, and the yield is 82.6%; nuclear magnetic data of ：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 an intermediate 2 (47 g,0.14 mol), triethylamine (18.8 g, 0.19 mol) and 200mL of dichloromethane into a four-mouth bottle, stirring and fully dissolving, cooling to-10 ℃, dropwise adding methanesulfonyl chloride (17.4 g,0.15 mol) at a temperature not exceeding 0 ℃, and reacting for 2 hours at the temperature of 0 ℃ after the completion of dropwise adding; after the reaction is finished, 200mL of water is slowly added, stirred for 10 minutes, then the mixture is stood for layering, the organic phase is sequentially washed by 100mL of 2% dilute hydrochloric acid, 100mL of 5% potassium carbonate and saturated saline, the organic layer is separated by water washing and saturated saline water washing, dried by anhydrous sodium sulfate, filtered and concentrated to dryness, 55.3g (intermediate 3) of yellow solid powder is obtained by recrystallisation by methanol, and the yield is 95.5%; nuclear magnetic data of ：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):
To the flask was added intermediate 3 (5.5 g,0.013 mol), potassium thioacetate (3 g,0.026 mol) and 50mL of N, N-dimethylformamide under nitrogen atmosphere, and the mixture was heated to 55℃to react for 3 hours. After the reaction was completed, the temperature was lowered to room temperature, 200mL of water was added, stirred for 10 minutes, then extracted three times with ethyl acetate (50 ml×3), the organic layers were combined, washed 3 times with water, 3 times with saturated brine, the organic layers were separated, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 5.0g of yellow oil (intermediate 4) in 96% yield, which was used in the next step without purification;
5) Synthesis of 2R 4S-M:
Under the protection of nitrogen, adding intermediate 4 (5 g,0.013 mol) and 50mL of dichloromethane into a reaction bottle, cooling to 0-5 ℃, dropwise adding 25mL of methanol solution of potassium hydroxide (1.7 g,0.03 mol) at the temperature of not more than 10 ℃, carrying out heat preservation reaction for 1.5h after the completion of the dropwise adding, adding 70mL of water, cooling to 0 ℃, regulating the pH to 7 by using 10% hydrochloric acid at the temperature of not more than 5 ℃, standing for liquid separation, washing an organic layer twice (50 mL multiplied by 3) by using water, washing the organic layer by using saturated salt, separating the organic layer, drying by using anhydrous sodium sulfate, filtering, concentrating to obtain yellow oily matter, and purifying by column chromatography (ethyl acetate: petroleum ether=volume ratio of 2:1) to obtain light yellow solid of 3.6g, namely 2R4S-M, wherein the yield is 80.6%.
The final product prepared in example 1 was subjected to nuclear magnetism and mass spectrometry characterization, and the results are shown in fig. 1 and 2; the obtained nuclear magnetic data is ：1H NMR(CDCl3,400MHz):δ1.72(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 spectrum data: 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, adding intermediate 3 (20 g,0.048 mol), sodium bromide (24.8 g,0.241 mol), potassium iodide (0.2 g,0.001 mol) and N, N-dimethylformamide 100mL prepared in example 1 into a reaction bottle, heating to 100 ℃ for 2 hours, cooling to room temperature after the reaction is finished, adding 500mL of water, stirring for 10 minutes, extracting three times (100 mL multiplied by 3) with ethyl acetate, combining organic layers, washing 3 times with water, washing 3 times with saturated salt water, separating an organic layer, drying with anhydrous sodium sulfate, filtering, concentrating to dryness to obtain brown oily matter, purifying by column chromatography (ethyl acetate: petroleum ether=1:1) to obtain yellow oily matter 12g (intermediate 5), and obtaining 62.3% yield, wherein nuclear magnetic data are 1H 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):
To the reaction flask were added intermediate 5 (5.5 g,0.013 mol), potassium thioacetate (3 g,0.026 mol) and 50mL of N, N-dimethylformamide, and the mixture was heated to 55 ℃ to react for 3 hours; after the reaction was completed, the temperature was lowered to room temperature, 200mL of water was added, stirred for 10 minutes, then extracted three times with ethyl acetate (50 ml×3), the organic layers were combined, washed 3 times with water, 3 times with saturated brine, the organic layers were separated, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 5.26g of yellow oil (intermediate 6) in 96.8% yield, which was used directly in the next step without purification;
7) Synthesis of 2R 4R-M:
The same hydrolysis process as in intermediate 4 of example 1, except that: hydrolysis of intermediate 6 (2.2 g, 0.006 mol) was used as starting material to give 1.7g (i.e., 2R 4R-M) as a pale yellow solid in 77.3% yield.
The final product prepared in example 2 was subjected to nuclear magnetism and mass spectrometry characterization, and the results are shown in fig. 3 and 4; the obtained nuclear magnetic data is ：1H NMR(CDCl3,400MHz):δ1.88(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 spectrum data: 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 (66.9 g,1.68 mol) and 600g of water into a reaction bottle, stirring and dissolving, then adding trans-L-hydroxyproline (100 g,0.76 mol), stirring and fully dissolving, cooling to 0 ℃, and dropwise adding 50% of p-nitrobenzyl chloroformate dichloromethane solution (370 g,0.86 mol) at a temperature not exceeding 5 ℃; after the dripping is finished, reacting for 3 hours at the temperature of 0-5 ℃, standing for layering after the reaction is finished, and extracting impurities from the water phase by using 100mL of dichloromethane; separating out the aqueous phase, adjusting pH to 2-3 with 10% hydrochloric acid, extracting with ethyl acetate (200 mL×3) three times, mixing the organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating to dryness, recrystallizing with ethanol to obtain 219.2g (intermediate 7) as a white solid, yield 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):
Under the protection of nitrogen, adding intermediate 7 (30 g,0.10 mol), triethylamine (27.9 g, 0.28 mol) and dichloromethane (500 mL) into a reaction bottle, cooling to-10 ℃, dropwise adding isopropyl chloroformate (13.1 g,0.11 mol) at a temperature of not more than 0 ℃, reacting for 2 hours at 0 ℃ after the completion of the dropwise adding, cooling to-10 ℃, dropwise adding methanesulfonyl chloride (15.0 g,0.13 mol) at a temperature of not more than 0 ℃, reacting for 2 hours at 0 ℃ after the completion of the dropwise adding, obtaining a product containing intermediate 8, dropwise adding a dimethylamine aqueous solution (14.2 g,0.13 mol) with a mass concentration of 40% into the obtained product containing intermediate 8, keeping the temperature at a temperature of not more than 10 ℃, reacting for 3 hours after the completion of the dropwise adding, sequentially washing with 300mL of 2% diluted hydrochloric acid, washing with 300mL of 5% potassium carbonate, washing with saturated salt, separating an organic layer, drying with anhydrous sodium sulfate, filtering, concentrating to dryness, recrystallizing with methanol to obtain yellow solid (9 g) with a yield of intermediate 8) 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 procedure for the preparation of intermediate 5 using intermediate 3 in example 2 was identical, except that: starting from intermediate 9 (15 g,0.036 mol), 9.8g (intermediate 10) of a yellow oil was prepared in 67.8% yield; nuclear magnetic data of ：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 procedure for the preparation of intermediate 4 was identical to that of intermediate 3 in example 1, except that: 10.3g (intermediate 11) of a yellow oil was prepared starting from intermediate 10 (11.9 g,0.03 mol) in 87.6% yield and was used in the next step without purification;
5) Synthesis of 2S 4R-M:
The same hydrolysis process as in intermediate 4 of example 1, except that: using intermediate 11 (5.4 g, 0.014 mol) as a starting material, a pale yellow solid, 3.7g, was prepared in 76.7% yield.
The final product prepared in example 3 was subjected to nuclear magnetism and mass spectrometry characterization, and the results are shown in fig. 5 and 6; the obtained nuclear magnetic data is ：1HNMR(CDCl3,400MHz):δ1.73(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); mass spectrum data: 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 example is n-hexane, ethanol=1:1 (V/V); high performance liquid chromatograph: SHIMAZU LC-20AT;
Preparing a standard substance 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 a scale.
Preparing a solution of a to-be-detected product: accurately weighing three optical isomers of 25mg meropenem side chains respectively, putting the three optical isomers into a 50mL volumetric flask, adding a diluent to dissolve and dilute the mixture to a scale, and preparing three solutions to be tested.
Sample solution to be tested is prepared: accurately weighing 25mg of a mixed sample of meropenem side chain and three optical isomers in a 50mL volumetric flask, adding a diluent to dissolve and diluting to a scale.
Running 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 chromatography analysis, and recording the chromatogram and the peak area of a sample;
chromatographic conditions:
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: 1.0mL/min;
Detection wavelength: 270nm;
sample injection amount: 20. Mu.L;
Column temperature: 40 ℃;
Acquisition time: 35min;
respectively injecting a standard substance solution and a solution to be detected of three optical isomers of a meropenem side chain 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 meropenem side chain isomer in a 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 shown in figures 7-10 respectively; the retention times of meropenem side chains and their three optical isomers under this assay are shown in table 1.
TABLE 1 meropenem side chain and liquid phase retention times of three optical isomers
As can be seen from FIGS. 7 to 10 and Table 1, the chiral purity of the three optical isomers of meropenem side chain can reach 99% or more, and is expected to be used as a standard sample.
According to the above process, the sample solution to be measured is injected into a liquid chromatograph, liquid chromatography analysis is performed according to the above chromatographic conditions, the chromatogram and the sample peak area are recorded, the obtained chromatogram is shown in fig. 11, and the obtained retention time is shown in 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 to be slightly shifted compared to the pure product, indicating that the detection method allows efficient separation and identification of meropenem side chains and three optical isomers.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (5)
1. A method for preparing a meropenem side chain optical isomer, wherein the meropenem side chain optical isomer has a structural configuration shown in a formula III or a formula IV, and the method comprises the following steps:
When the meropenem side chain optical isomer has a structural configuration shown in a formula III, 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 chloroformate and dimethylamine, and carrying out amidation reaction to obtain an intermediate 2;
Mixing the intermediate 2, triethylamine, a third solvent and methanesulfonyl chloride, and carrying out sulfonylation reaction to obtain an intermediate 3;
the intermediate 1 has a structure represented by formula a:
The intermediate 2 has a structure represented by formula b:
the intermediate 3 has a structure represented by formula c:
Mixing the intermediate 3, sodium bromide, potassium iodide and a fifth solvent, and carrying out bromination reaction to obtain an intermediate 5;
the temperature of the bromination reaction is 100-120 ℃ and the time is 1-2 h;
mixing the intermediate 5 with potassium thioacetate, and carrying out 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 a formula III;
the intermediate 5 has a structure represented by formula e:
the intermediate 6 has a structure represented by formula f:
when the meropenem side chain optical isomer has a structural configuration shown in a 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 chloroformate, carrying out esterification reaction, mixing the obtained product with methanesulfonyl chloride, and carrying out sulfonylation reaction 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, and carrying out 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 a formula IV;
The intermediate 7 has a structure represented by 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:
2. the preparation method according to claim 1, wherein the molar ratio of cis-D-hydroxyproline to p-nitrobenzyl chloroformate is (0.6-1.0): 0.8-1.2; when the intermediate 1 is prepared, the amidation reaction temperature is-5-10 ℃ and the time is 1-6 h.
3. The preparation method according to claim 1, wherein 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) when preparing the intermediate 2: (0.12-0.2);
In the preparation of the intermediate 3, the molar ratio of the intermediate 2, triethylamine and methanesulfonyl chloride is (0.10-0.15): 0.13-0.25): 0.11-0.2.
4. The preparation method according to claim 1, wherein 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 when the intermediate 5 is prepared.
5. The preparation method according to claim 1, wherein the molar ratio of trans-L-hydroxyproline to p-nitrobenzyl chloroformate is (0.6-0.8) (0.8-1.0), the amidation reaction temperature is-5-10deg.C, and the time is 1-6 h;
in the preparation of the intermediate 8, the molar ratio of the intermediate 7 to the triethylamine to the isopropyl chloroformate to the methanesulfonyl chloride is (0.10-0.15): 0.2-0.4): 0.1-0.16: (0.11-0.2), the temperature of the esterification reaction is-5-10 ℃ and the time is 1-6 h;
in the preparation of the intermediate 9, the molar ratio of the intermediate 8 to dimethylamine is (0.1-0.2): 0.1-0.3.
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| 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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