CN101592615B - Method for measuring content of side chains of carbapenem compound - Google Patents
Method for measuring content of side chains of carbapenem compound Download PDFInfo
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- CN101592615B CN101592615B CN200810053289A CN200810053289A CN101592615B CN 101592615 B CN101592615 B CN 101592615B CN 200810053289 A CN200810053289 A CN 200810053289A CN 200810053289 A CN200810053289 A CN 200810053289A CN 101592615 B CN101592615 B CN 101592615B
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- nitrobenzyloxycarbonyl
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- -1 carbapenem compound Chemical class 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 26
- 238000012360 testing method Methods 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000011630 iodine Substances 0.000 claims abstract description 4
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 83
- 238000004448 titration Methods 0.000 claims description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 229920002472 Starch Polymers 0.000 claims description 11
- 239000008107 starch Substances 0.000 claims description 11
- 235000019698 starch Nutrition 0.000 claims description 11
- HPBXUFOSZBCEIQ-UHFFFAOYSA-N 6,7-dihydro-5h-pyrazolo[1,2-a][1,2,4]triazol-4-ium-6-thiol;chloride Chemical compound [Cl-].C1=NC=[N+]2CC(S)CN21 HPBXUFOSZBCEIQ-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 239000007853 buffer solution Substances 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical class C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 claims description 8
- 229960000907 methylthioninium chloride Drugs 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 239000007979 citrate buffer Substances 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- ZRBROGSAUIUIJE-UHFFFAOYSA-N azanium;azane;chloride Chemical compound N.[NH4+].[Cl-] ZRBROGSAUIUIJE-UHFFFAOYSA-N 0.000 claims description 6
- 238000003556 assay Methods 0.000 claims description 5
- 239000008351 acetate buffer Substances 0.000 claims description 4
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 claims description 4
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000008055 phosphate buffer solution Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 238000005303 weighing Methods 0.000 claims description 3
- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- 238000005259 measurement Methods 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 description 4
- JECWBBGYVBPHIH-IRXDYDNUSA-N (4-nitrophenyl)methyl (2s,4s)-4-acetylsulfanyl-2-[[(2-methylpropan-2-yl)oxycarbonyl-sulfamoylamino]methyl]pyrrolidine-1-carboxylate Chemical compound C1[C@@H](SC(=O)C)C[C@@H](CN(C(=O)OC(C)(C)C)S(N)(=O)=O)N1C(=O)OCC1=CC=C([N+]([O-])=O)C=C1 JECWBBGYVBPHIH-IRXDYDNUSA-N 0.000 description 3
- BWSWPOJRYCYBRQ-UHFFFAOYSA-N 4h-1,2,4-triazol-4-ium;chloride Chemical compound Cl.C=1N=CNN=1 BWSWPOJRYCYBRQ-UHFFFAOYSA-N 0.000 description 3
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 description 3
- TYMABNNERDVXID-DLYFRVTGSA-N Panipenem Chemical compound C([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1S[C@H]1CCN(C(C)=N)C1 TYMABNNERDVXID-DLYFRVTGSA-N 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229960002770 ertapenem Drugs 0.000 description 3
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000010606 normalization Methods 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- MRMBZHPJVKCOMA-YJFSRANCSA-N biapenem Chemical compound C1N2C=NC=[N+]2CC1SC([C@@H]1C)=C(C([O-])=O)N2[C@H]1[C@@H]([C@H](O)C)C2=O MRMBZHPJVKCOMA-YJFSRANCSA-N 0.000 description 2
- 229960003169 biapenem Drugs 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem 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](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 description 2
- 229960000895 doripenem Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 229960002182 imipenem Drugs 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000010813 internal standard method Methods 0.000 description 2
- 229960002260 meropenem Drugs 0.000 description 2
- 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 2
- STZCRXQWRGQSJD-GEEYTBSJSA-M methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 description 2
- 229940012189 methyl orange Drugs 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229950011346 panipenem Drugs 0.000 description 2
- KJFMBFZCATUALV-UHFFFAOYSA-N phenolphthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 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 description 1
- XWNSFEAWWGGSKJ-UHFFFAOYSA-N 4-acetyl-4-methylheptanedinitrile Chemical compound N#CCCC(C)(C(=O)C)CCC#N XWNSFEAWWGGSKJ-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical class ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 239000004153 Potassium bromate Substances 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 241001148470 aerobic bacillus Species 0.000 description 1
- 229960004543 anhydrous citric acid Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
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- 229910017053 inorganic salt Inorganic materials 0.000 description 1
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 235000019396 potassium bromate Nutrition 0.000 description 1
- 229940094037 potassium bromate Drugs 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- VQBIMXHWYSRDLF-UHFFFAOYSA-M sodium;azane;hydrogen carbonate Chemical compound [NH4+].[Na+].[O-]C([O-])=O VQBIMXHWYSRDLF-UHFFFAOYSA-M 0.000 description 1
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Landscapes
- Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
Abstract
The invention relates to a method for measuring the content of side chains of a carbapenem compound, which comprises the following steps: (1) dissolving the side chains of the carbapenem compound in a solvent; (2) titrating by using an iodine titrating solution; (3) correcting a titrating result by using a blank test; and (4) calculating the content of the side chains according to the following formula: X=(C(1/2I2)*(V-V0)*M)/W*100 percent. The measuring method has simple and quick operation, can accurately reflect the real content of the side chains, is suitable for measuring the content and can also be used for guiding a reaction progress.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to a method for measuring the content of side chains of carbapenem compounds.
Background
Along with the obvious antibiotic resistance problem in recent years, multi-drug resistant strains are frequently reported, and in addition to the need of more reasonable control on the use of antibiotics, the development of a new generation of novel anti-infective medicaments with high-efficiency antibacterial activity is urgently needed in clinic, and the appearance of carbapenem compounds meets the need. Carbapenem (carbapenem) compounds are novel structural beta-lactam antibiotics developed in the 70 s of the 20 th century. The methods are listed in succession, namely imipenem (imipenem), panipenem (panipenem), meropenem (meropenem), biapenem (biapenem), ertapenem (ertapenem), doripenem (doripenem) and the like. The medicine has super broad spectrum powerful antibiotic effect on gram-positive bacteria, gram-negative bacteria, aerobic bacteria, anaerobic bacteria, etc. and excellent tissue permeability, and has excellent curative effect on various bacterial infections and less toxic side effect. Has been receiving attention in recent years.
The structure of the carbapenem compound is composed of a mother nucleus and a side chain, the mother nucleus is basically the same, and the carbapenem compound is industrially produced; the side chain moieties are not identical but share the common feature that the side chains all contain thiol groups. The side chain is butted with the mother nucleus through the sulfydryl, and a product is obtained through a series of reactions. As most of the medicines are injections, the quality of the product is very important. The purity of the side chain intermediate directly affects the outcome of the docking reaction. If the purity of the side chain is measured inaccurately, the feeding ratio of the mother nucleus and the side chain cannot be determined, which causes waste of raw materials and great difficulty in post-treatment, and greatly increases the production cost; more seriously, the quality of the final product can be unqualified.
The synthesis of the side chain may generate a large amount of inorganic salts (such as sodium chloride, sodium carbonate and ammonium chloride) and organic salts (such as sodium acetate and sodium formate). Some side chains have high solubility in water, and a large amount of organic salts and inorganic salts coexist in the reaction solution, and the salts coexisting with the product are difficult to remove by a conventional method. Repeated purification is required to obtain a high-purity side chain, and even repeated purification cannot be verified as to whether or not a reasonable purity can be achieved, so that the separation in a true sense is very difficult.
In the prior art, the content of side chains of carbapenem compounds is generally determined by an HPLC method. However, the disadvantages of this method of content determination are evident: inorganic salts and organic salts generated in the reaction process have no absorption peak in HPLC, so that the content of a side chain cannot be accurately reflected by an HPLC area normalization method, and the detection cannot be accurately and quickly carried out due to the limitation of a reference substance.
Based on the huge application prospect of the carbapenem compound, people always and urgently hope to find a universal measuring method which is simple and rapid and can accurately reflect the real content of the side chain of the carbapenem compound.
Disclosure of Invention
In order to solve the problems, the invention provides a method for measuring the content of side chains of carbapenem compounds.
The determination method of the present invention comprises the steps of:
(1) dissolving side chains of the carbapenem compound in a solvent;
(2) calibrating with iodometric solution;
(3) correcting the titration result by using a blank test;
(4) the side chain content was calculated as follows: <math><mrow>
<mi>X</mi>
<mo>=</mo>
<mfrac>
<mrow>
<mi>C</mi>
<mrow>
<mo>(</mo>
<mn>1</mn>
<mo>/</mo>
<mn>2</mn>
<msub>
<mi>I</mi>
<mn>2</mn>
</msub>
<mo>)</mo>
</mrow>
<mo>×</mo>
<mrow>
<mo>(</mo>
<mi>V</mi>
<mo>-</mo>
<msub>
<mi>V</mi>
<mn>0</mn>
</msub>
<mo>)</mo>
</mrow>
<mo>×</mo>
<mi>M</mi>
</mrow>
<mi>W</mi>
</mfrac>
<mo>×</mo>
<mn>100</mn>
<mo>%</mo>
</mrow></math>
wherein,
: iodine titrant molar concentration;
v: the volume of iodine titration solution, ml, is consumed when the side chain of the carbapenem compound is titrated;
V0: the volume of iodometric solution consumed in titrating the blank, ml;
m: is the molar molecular weight of the side chain of the carbapenem compound;
w: weighing sample amount, mg;
x: the content of the sample to be tested is mg.
Wherein, the side chain of the carbapenem compound in step (1) is preferably selected from the following compounds:
compound 1: biapenem side chain: 6, 7-dihydro-6-mercapto-5H-pyrazolo [1, 2-a ] [1, 2, 4] triazoliumchloride;
compound 2: meropenem side chain: (2S, 4S) -4-mercapto-1- (p-nitrobenzyloxycarbonyl) -1-pyrrolidine-2- (N, N-dimethyl) formamide;
compound 3: panipenem side chain: (3S) -1- (p-nitrobenzyloxycarbonylacetimide) -3-mercaptopyrrolidine;
compound 4: ertapenem side chain: (2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- [ (3-p-nitrobenzyloxyacyl) phenylcarbamoyl ] -4-mercaptopyrrolidine;
compound 5: imipenem side chain: n- [ (N-p-nitrobenzyloxycarbonyl) iminomethylene ] aminoethylthiol;
compound 6: doripenem side chain: (2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- (N-sulfamoylamino) methyl-4-mercaptopyrrolidine;
compound 7: doripenem side chain: (2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- (N-p-nitrobenzyloxycarbonyl-4-sulfamoylamino) methyl-4-mercaptopyrrolidine;
compound 8: doripenem side chain: (2S, 4S) -1-tert-Butoxycarbonyl-2- (N-tert-butyloxycarbonyl-4-sulfamoylamino) methyl-4-mercaptopyrrolidine.
Further preferably selected from:
6, 7-dihydro-6-mercapto-5H-pyrazolo [1, 2-a ] [1, 2, 4] triazoliumchloride;
(2S, 4S) -4-mercapto-1- (p-nitrobenzyloxycarbonyl) -1-pyrrolidine-2- (N, N-dimethyl) formamide;
(3S) -1- (p-nitrobenzyloxycarbonylacetimide) -3-mercaptopyrrolidine;
(2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- [ (3-p-nitrobenzyloxyacyl) phenylcarbamoyl ] -4-mercaptopyrrolidine;
n- [ (N-p-nitrobenzyloxycarbonyl) iminomethylene ] aminoethylthiol;
(2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- (N-p-nitrobenzyloxycarbonyl-4-sulfamoylamino) methyl-4-mercaptopyrrolidine.
Most preferably:
6, 7-dihydro-6-mercapto-5H-pyrazolo [1, 2-a ] [1, 2, 4] triazoliumchloride.
The solvent in the step (1) is selected from: (a) water, (b) a buffer solution, (c) a mixed solvent of water and an organic solvent, (d) a mixed solvent of a buffer solution and an organic solvent; the water is preferably fresh boiled and cooled water; the buffer solution preferably has the pH value of 4-8, and is further preferably selected from ammonia-ammonium chloride buffer solution, citrate buffer solution, citric acid-disodium hydrogen phosphate, acetic acid-acetate buffer solution and phosphate buffer solution; the organic solvent is preferably selected from methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, dioxane and dimethylformamide, most preferably tetrahydrofuran.
In the step (2), the concentration of the iodometric solution is preferably 0.05-0.1 mol/L.
In the step (2), before titration with iodometric solution, a step of adding an indicator is further included, and the indicator is preferably starch or methylene blue indicator solution.
In the step (2), when the titration is carried out by using the iodometric titration solution, the method further comprises the step of adding an indicator when the end point is approached, wherein the indicator is preferably starch or methylene blue indicator solution.
The dosage of the side chain of the carbapenem compound is preferably 0.1-1 g; the dosage of the starch indicator liquid is preferably 1-5 ml; the dosage of the methylene blue indicator solution is preferably 0.05-0.3 ml.
When the iodometric solution is used for calibration, the judgment of the end point is as follows:
(1) adding starch indicator solution, and titrating until the solution is light blue and does not fade;
(2) adding methylene blue indicating liquid, and titrating until the solution is green and does not fade;
(3) without the addition of the indicator, the solution was titrated to a pale yellow color without fading.
HPLC (high performance liquid chromatography) determination is carried out on the organic compound, a normalization method is generally adopted, and the method has the characteristics of simplicity and quickness and is suitable for monitoring the reaction; for accurate assay, either internal or external standard methods are required. Generally, the HPLC assay method has advantages that chemical assay methods cannot match. However, the internal and external standard methods require satisfactory controls, which are very difficult for certain carbapenem compound side chains, such as 6, 7-dihydro-6-mercapto-5H-pyrazolo [1, 2-a ] [1, 2, 4] triazoliumchloride; moreover, since some side chains contain a large amount of salts which are not absorbed by HPLC, the purity of the side chains cannot be truly reflected by the normalization method. Therefore, a general method for measuring side chains of carbapenem compounds cannot be established by HPLC.
Considering that the impurities in the side chain product contained only inorganic and organic salts and no thiol group, the present inventors tried to determine the content by a method of detecting a side chain thiol group, i.e., a chemical assay. According to the characteristic that sulfydryl is easy to oxidize, oxidation is attempted by oxidizing agents such as potassium permanganate, potassium dichromate, potassium bromate and the like, and because the side chain structure of the carbapenem compound is complex and contains oxygen, nitrogen, double bonds and quaternary ammonium salt besides sulfydryl, satisfactory results cannot be obtained due to over-strong oxidizing of the oxidizing agents or other reasons. The analytical reasons may be that, in addition to the oxidation of the mercapto group, the nitrogen atom on the side chain is also oxidized to form a nitroxide, or the side chain is damaged by oxidation. For the above reasons, the method is determined by considering the characteristic that the sulfydryl is oxidized into the disulfide compound by using a relatively weak oxidant iodine, and the oxygen, the nitrogen, the double bond and the quaternary ammonium salt on the structure are not influenced, so that the satisfactory result is obtained.
The invention has the beneficial effects that:
(1) the determination method is simple to operate and easy to master, does not need any equipment, does not need a standard sample, and does not need complicated operation.
(2) The determination method is rapid, one sample can be tested only in a few minutes, and the method is suitable for accurately determining the content of the intermediate in a laboratory or an industrial production process; the method is not only suitable for content determination, but also can be used for guiding the reaction process.
(3) Because the impurities in the side chain product only contain inorganic salt and organic salt, and do not contain sulfydryl, the measurement cannot be interfered. Therefore, the method can accurately reflect the real content of the side chain, further accurately calculate the feed ratio and ensure the quality of the product.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples, which are not intended to limit the invention thereto.
Reagent: iodine, potassium iodide, arsenic trioxide, sodium hydroxide, phenolphthalein, starch, hydrochloric acid, sodium hydroxide, methyl orange, sulfuric acid and sodium bicarbonate are analytically pure.
Preparation of iodometric titration solution (0.05 mol/L): dissolving 13.0g of iodine, 36g of potassium iodide and 50ml of water, adding 3 drops of hydrochloric acid and a proper amount of water to form 1000ml of solution, shaking up, filtering by using a sintered glass filter, and storing in a brown bottle with a plug.
And (3) calibrating the iodometric solution: taking about 0.15g of standard arsenic trioxide dried to constant weight at 105 ℃, precisely weighing, adding 10ml of sodium hydroxide titration solution (1mol/L), slightly heating to dissolve, adding 20ml of water and 1 drop of methyl orange indicator solution, adding a proper amount of sulfuric acid titration solution (0.5mol/L) to change yellow into pink, adding 2g of sodium bicarbonate, 50ml of water and 2ml of starch indicator solution, and using the drops to measure until the solution shows bluish purple. Each 1ml of iodometric solution (0.05mol/L) corresponded to 4.946mg of arsenic trioxide. And calculating the concentration of the solution according to the consumption of the solution and the consumption of the arsenic trioxide. And (5) obtaining the product.
0.1mol/L iodometric titrant was prepared and calibrated in a similar manner to 0.05mol/L iodometric titrant.
Example 1
Preparing a starch indicating liquid: 0.5g of soluble starch is taken. Adding 5ml of water, stirring, slowly pouring into 100ml of boiling water, stirring with water, boiling for 2 min, cooling, and collecting supernatant.
Taking a compound 1: about 0.5g of 6, 7-dihydro-6-mercapto-5H-pyrazolo [1, 2-a ] [1, 2, 4] triazoliumchloride is precisely weighed, placed in a conical flask, added with 20ml of newly boiled and cooled water for dissolution, added with 2ml of starch indicator solution, shaken up, titrated by iodometric titration (0.05mol/L) until the solution becomes light blue, namely the end point of titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 1.
TABLE 16 determination results of 7, 7-dihydro-6-mercapto-5H-pyrazolo [1, 2-a ] [1, 2, 4] triazoliumchloride content
Example 2
Preparation of Ammonia-ammonium chloride buffer (pH 8.0): dissolving ammonium chloride 1.07g in water to 100ml, and adding dilute ammonia solution (1 → 30) to adjust pH to 8.0.
Taking a compound 1: about 0.3g of 6, 7-dihydro-6-mercapto-5H-pyrazolo [1, 2-a ] [1, 2, 4] triazoliumchloride is precisely weighed, placed in a conical flask, dissolved by adding 20ml of ammonia-ammonium chloride buffer solution, added with 3ml of starch indicator solution, shaken evenly, and titrated by iodometric titration (0.1mol/L) until the solution shows light blue, namely the end point of titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 2.
TABLE 26, 7-dihydro-6-mercapto-5H-pyrazolo [1, 2-a ] [1, 2, 4] triazoliumchloride content determination results
Example 3
Preparing methylene blue indicating liquid: methylene blue 0.5g was taken and dissolved in water to 100 ml.
Taking a compound 1: about 0.3g of 6, 7-dihydro-6-mercapto-5H-pyrazolo [1, 2-a ] [1, 2, 4] triazoliumchloride is precisely weighed, placed in a conical flask, added with 30ml of boiled and refrigerated water for dissolution, added with 3-5 drops of methylene blue indicator solution, shaken evenly, titrated by iodometric titration (0.05mol/L) until the solution turns green, namely the end point of titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 3.
TABLE 36 determination results of 7, 7-dihydro-6-mercapto-5H-pyrazolo [1, 2-a ] [1, 2, 4] triazoliumchloride content
Example 4
Taking a compound 2: about 0.1g of (2S, 4S) -4-mercapto-1- (p-nitrobenzyloxycarbonyl) -1-pyrrolidine-2- (N, N-dimethyl) formamide is precisely weighed, placed in an erlenmeyer flask, dissolved by 10ml of tetrahydrofuran, added with 10ml of newly boiled and cooled water, shaken well, and titrated by iodometric solution (0.05mol/L) until the solution becomes pale yellow, which is the end point of titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 4.
TABLE 4(2S, 4S) -4-mercapto-1- (p-nitrobenzyloxycarbonyl) -1-pyrrolidine-2- (N, N-dimethyl) carboxamide
Results of content measurement
Example 5
Preparation of citrate buffer (ph 6.2): taking 2.1% citric acid water solution, and adjusting pH to 6.2 with 50% sodium hydroxide solution.
Taking a compound 2: about 0.5g of (2S, 4S) -4-mercapto-1- (p-nitrobenzyloxycarbonyl) -1-pyrrolidine-2- (N, N-dimethyl) formamide is precisely weighed, placed in an erlenmeyer flask, dissolved by 30ml of ethanol, added with 20ml of citrate buffer solution, shaken well and titrated by iodometric solution (0.1mol/L) until the solution is pale yellow, namely the end point of the titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 5.
TABLE 5(2S, 4S) -4-mercapto-1- (p-nitrobenzyloxycarbonyl) -1-pyrrolidine-2- (N, N-dimethyl) carboxamide
Results of content measurement
Example 6
Preparation of acetate-acetate buffer (ph 4.6): dissolving 54.6g of sodium acetate in 50ml of water, adjusting the pH value to 4.6 by using glacial acetic acid, and diluting to 100ml by adding water to obtain the sodium acetate.
Taking a compound 2: about 0.1g of (2S, 4S) -4-mercapto-1- (p-nitrobenzyloxycarbonyl) -1-pyrrolidine-2- (N, N-dimethyl) formamide is precisely weighed, placed in a conical flask, dissolved by 10ml of acetone, added with 10ml of acetic acid-acetate buffer solution, shaken well, and titrated by iodometric solution (0.1mol/L) until the solution is pale yellow, namely the end point of the titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 6.
TABLE 6(2S, 4S) -4-mercapto-1- (p-nitrobenzyloxycarbonyl) -1-pyrrolidine-2- (N, N-dimethyl) carboxamide
Results of content measurement
Example 7
Taking a compound 3: about 0.1g of (3S) -1- (p-nitrobenzyloxycarbonylacetimide) -3-mercaptopyrrolidine is precisely weighed, placed in an erlenmeyer flask, dissolved by 10ml of acetonitrile, added with 10ml of water, shaken up, and titrated by iodometric solution (0.05mol/L) until the solution is light yellow, which is the end point of titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 7.
TABLE 7 measurement results of (3S) -1- (p-nitrobenzyloxycarbonylacetimide) -3-mercaptopyrrolidine content
Example 8
Preparation of citric acid-disodium hydrogen phosphate buffer (ph 4.0): liquid A: dissolving citric acid 21g or anhydrous citric acid 19.2g in water to 1000ml, and storing in refrigerator. B, liquid B: 71.63g of disodium hydrogen phosphate was taken and dissolved in 1000ml of water. Mixing 61.45ml of the first solution and 38.55ml of the second solution, and shaking up to obtain the final product.
Taking a compound 3: about 0.3g of (3S) -1- (p-nitrobenzyloxycarbonylacetimide) -3-mercaptopyrrolidine is precisely weighed, placed in an erlenmeyer flask, dissolved by 20ml of dimethylformamide, then 20ml of citric acid-disodium hydrogen phosphate is added, shaken up, and titrated by iodometric solution (0.1mol/L) until the solution is light yellow, namely the end point of titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 8.
TABLE 8 measurement results of (3S) -1- (p-nitrobenzyloxycarbonylacetimide) -3-mercaptopyrrolidine content
| Sample (I) | Measurement value (%) | Average (%) | RSD(％) |
| 1 | 98.47 | 98.52 | 98.37 | 98.45 | 0.08 |
| 2 | 98.59 | 98.67 | 98.52 | 98.59 | 0.08 |
| 3 | 98.83 | 98.75 | 98.88 | 98.82 | 0.07 |
Example 9
Taking a compound 3: about 0.1g of (3S) -1- (p-nitrobenzyloxycarbonylacetimide) -3-mercaptopyrrolidine is precisely weighed, placed in an erlenmeyer flask, dissolved by 10ml of dioxane, added with 10ml of water, shaken up, titrated by iodometric solution (0.05mol/L) until the solution is light yellow, namely the end point of titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 9.
TABLE 9 measurement results of the content of (3S) -1- (p-nitrobenzyloxycarbonylacetimide) -3-mercaptopyrrolidine
Example 10
Taking a compound 4: about 0.6g of (2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- [ (3-p-nitrobenzyloxyacyl) phenylcarbamoyl ] -4-mercaptopyrrolidine is precisely weighed, placed in an erlenmeyer flask, dissolved by 30ml of tetrahydrofuran, added with 30ml of water, shaken well, and titrated by iodometric solution (0.1mol/L) until the solution becomes pale yellow, which is the end point of the titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 10.
TABLE 10(2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- [ (3-p-nitrobenzyloxyacyl) phenylcarbamoyl ] -4-mercaptopyrrolidine
Results of content measurement
Example 11
Preparation of Ammonia-ammonium chloride buffer (pH 8.0): dissolving ammonium chloride 1.07g in water to 100ml, and adding dilute ammonia solution (1 → 30) to adjust pH to 8.0.
Taking a compound 4: about 0.4g of (2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- [ (3-p-nitrobenzyloxyacyl) phenylcarbamoyl ] -4-mercaptopyrrolidine is precisely weighed, placed in an erlenmeyer flask, dissolved by 30ml of methanol, added with 30ml of ammonia-ammonium chloride buffer solution, shaken well, and titrated by iodometric titration (0.1mol/L) until the solution becomes light yellow, which is the end point of the titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 11.
TABLE 11(2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- [ (3-p-nitrobenzyloxyacyl) phenylcarbamoyl ] -4-mercaptopyrrolidine
Results of content measurement
Example 12
Taking a compound 4: about 0.1g of (2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- [ (3-p-nitrobenzyloxyacyl) phenylcarbamoyl ] -4-mercaptopyrrolidine is precisely weighed, placed in an erlenmeyer flask, dissolved by 10ml of acetonitrile, added with 10ml of citrate buffer solution, shaken well and titrated by iodometric solution (0.05mol/L) until the solution becomes light yellow, which is the end point of the titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 12.
TABLE 12(2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- [ (3-p-nitrobenzyloxyacyl) phenylcarbamoyl ] -4-mercaptopyrrolidine
Results of content measurement
Example 13
Taking a compound 5: about 0.1g of N- [ (N-p-nitrobenzyloxycarbonyl) imino methylene ] amino ethyl mercaptan is precisely weighed, placed in a conical flask, dissolved by 10ml of acetonitrile, added with 10ml of citrate buffer solution, shaken up and titrated by iodometric titration (0.05mol/L) until the solution is light yellow, namely the end point of titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 13.
TABLE 13 measurement of N- [ (N-p-nitrobenzyloxycarbonyl) iminomethylene ] aminoethylthiol content
Example 14
Taking a compound 5: about 0.1g of N- [ (N-p-nitrobenzyloxycarbonyl) imino methylene ] amino ethyl mercaptan is precisely weighed, placed in a conical flask, dissolved by 10ml of acetonitrile, added with 10ml of citrate buffer solution, shaken up and titrated by iodometric titration (0.1mol/L) until the solution is light yellow, namely the end point of titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 14.
TABLE 14 measurement of N- [ (N-p-nitrobenzyloxycarbonyl) iminomethylene ] aminoethylthiol content
Example 15
Preparation of phosphate buffer (ph 7.0): taking 0.68g of disodium hydrogen phosphate, adding 29.1ml of 0.1mol/L sodium hydroxide, and diluting with water to 100ml to obtain the sodium hydrogen phosphate.
Taking a compound 5: about 0.1g of N- [ (N-p-nitrobenzyloxycarbonyl) imino methylene ] amino ethyl mercaptan is precisely weighed, placed in an erlenmeyer flask, dissolved by 10ml of tetrahydrofuran, added with 10ml of phosphate buffer solution, shaken up, titrated by iodometric solution (0.1mol/L) until the solution is light yellow, namely the end point of titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 15.
TABLE 15 measurement of N- [ (N-p-nitrobenzyloxycarbonyl) iminomethylene ] aminoethylthiol content
Example 16
Taking a compound 6: about 0.1g of (2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- (N-sulfamoylamino) methyl-4-mercaptopyrrolidine is precisely weighed, placed in an erlenmeyer flask, dissolved by 10ml of isopropanol, added with 10ml of phosphate buffer solution, shaken evenly, and titrated by iodometric titration (0.1mol/L) until the solution is pale yellow, namely the end point of the titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 16.
TABLE 16(2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- (N-sulfamoylamino) methyl-4-mercaptopyrrolidine
Results of content measurement
Example 17
Taking a compound 6: about 0.1g of (2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- (N-sulfamoylamino) methyl-4-mercaptopyrrolidine is precisely weighed, placed in a conical flask, dissolved by 10ml of ethanol, added with 10ml of water, shaken up, titrated by iodometric solution (0.05mol/L) until the solution becomes light yellow, namely the end point of titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 17.
TABLE 17(2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- (N-sulfamoylamino) methyl-4-mercaptopyrrolidine
Results of content measurement
Example 18
Taking a compound 7: about 0.1g of (2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- (N-p-nitrobenzyloxycarbonyl-4-sulfamoylamino) methyl-4-mercaptopyrrolidine is precisely weighed, placed in an erlenmeyer flask, dissolved by 10ml of tetrahydrofuran, added with 10ml of water, shaken and titrated by iodometric solution (0.1mol/L) until the solution becomes light yellow, which is the end point of the titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 18.
TABLE 18(2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- (N-p-nitrobenzyloxycarbonyl-4-sulfamoylamino) methyl-4-mercapto
Measurement results of pyrrolidine content
Example 19
Taking a compound 7: about 0.1g of (2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- (N-p-nitrobenzyloxycarbonyl-4-sulfamoylamino) methyl-4-mercaptopyrrolidine is precisely weighed, placed in an erlenmeyer flask, dissolved by 10ml of methanol, added with 10ml of water, shaken up, and titrated by iodometric solution (0.05mol/L) until the solution becomes light yellow, which is the end point of titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 19.
TABLE 19(2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- (N-p-nitrobenzyloxycarbonyl-4-sulfamoylamino) methyl-4-mercapto
Measurement results of pyrrolidine content
Example 20
Taking a compound 8: about 0.1g of (2S, 4S) -1-tert-butoxycarbonyl-2- (N-tert-butoxycarbonyl-4-sulfamoylamino) methyl-4-mercaptopyrrolidine is precisely weighed, placed in an erlenmeyer flask, dissolved by 10ml of isopropanol, added with 10ml of water, shaken well, and titrated by iodometric solution (0.05mol/L) until the solution becomes pale yellow, which is the end point of titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 20.
TABLE 20(2S, 4S) -1-tert-Butoxycarbonyl-2- (N-tert-butyloxycarbonyl-4-sulfamoylamino) methyl-4-mercaptopyrrolidine
Results of content measurement
Example 21
Taking a compound 8: about 0.1g of (2S, 4S) -1-tert-butoxycarbonyl-2- (N-tert-butoxycarbonyl-4-sulfamoylamino) methyl-4-mercaptopyrrolidine is precisely weighed, placed in an erlenmeyer flask, dissolved by 10ml of isopropanol, added with 10ml of water, shaken well, and titrated by iodometric solution (0.05mol/L) until the solution becomes pale yellow, which is the end point of titration. And correcting the titration result by using a blank test, and calculating the content of the sample. The results are shown in Table 21.
TABLE 21(2S, 4S) -1-tert-Butoxycarbonyl-2- (N-tert-butyloxycarbonyl-4-sulfamoylamino) methyl-4-mercaptopyrrolidine
Results of content measurement
Claims (7)
1. A method for measuring the content of side chains of carbapenem compounds is characterized by comprising the following steps:
(1) dissolving side chains of the carbapenem compound in a solvent;
(2) titrating with iodometric solution;
(3) correcting the titration result by using a blank test;
(4) the side chain content was calculated as follows:
in the formula,
is the molar concentration of the iodometric solution; v is the volume of iodine titration liquid consumed when the side chain of the carbapenem compound is titrated; v0Is the volume of iodometric solution consumed in titrating the blank; m is the molar molecular weight of the side chain of the carbapenem compound; w is sample weighing; x is the content of the tested sample;
wherein, the solvent in the step (1) is selected from: (a) water, (b) a buffer solution, (c) a mixed solvent of water and an organic solvent, (d) a mixed solvent of a buffer solution and an organic solvent;
the water is newly boiled and cooled; the organic solvent is selected from ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, dioxane and dimethylformamide;
the buffer solution has a pH value of 4-8, and is selected from ammonia-ammonium chloride buffer solution, citrate buffer solution, citric acid-disodium hydrogen phosphate, acetic acid-acetate buffer solution, and phosphate buffer solution; the organic solvent is tetrahydrofuran.
2. The method of claim 1, wherein the side chain of the carbapenem compound is selected from the group consisting of:
6, 7-dihydro-6-mercapto-5H-pyrazolo [1, 2-a ] [1, 2, 4] triazoliumchloride;
(2S, 4S) -4-mercapto-1- (p-nitrobenzyloxycarbonyl) -1-pyrrolidine-2- (N, N-dimethyl) formamide;
(3S) -1- (p-nitrobenzyloxycarbonylacetimide) -3-mercaptopyrrolidine;
(2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- [ (3-p-nitrobenzyloxyacyl) phenylcarbamoyl ] -4-mercaptopyrrolidine;
n- [ (N-p-nitrobenzyloxycarbonyl) iminomethylene ] aminoethylthiol;
(2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- (N-sulfamoylamino) methyl-4-mercaptopyrrolidine;
(2S, 4S) -1-p-nitrobenzyloxycarbonyl-2- (N-p-nitrobenzyloxycarbonyl-4-sulfamoylamino) methyl-4-mercaptopyrrolidine;
(2S, 4S) -1-tert-Butoxycarbonyl-2- (N-tert-butyloxycarbonyl-4-sulfamoylamino) methyl-4-mercaptopyrrolidine.
3. The method according to claim 2, wherein the side chain of the carbapenem compound is 6, 7-dihydro-6-mercapto-5H-pyrazolo [1, 2-a ] [1, 2, 4] triazoliumchloride.
4. The method according to claim 1, wherein the concentration of the iodometric solution in the step (2) is 0.05 to 0.1 mol/L.
5. The assay method according to claim 1, wherein in the step (2), before the titration with the iodometric solution, a step of adding an indicator is further included.
6. The method according to claim 1, wherein the step (2) further comprises a step of adding an indicator near the end point of the titration with the iodometric solution.
7. The assay of claim 5 or 6, wherein the indicator is a starch or methylene blue indicator.
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