CN112321642A - Ruidexiwei related substance and preparation method and application thereof - Google Patents
Ruidexiwei related substance and preparation method and application thereof Download PDFInfo
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- CN112321642A CN112321642A CN202011037977.2A CN202011037977A CN112321642A CN 112321642 A CN112321642 A CN 112321642A CN 202011037977 A CN202011037977 A CN 202011037977A CN 112321642 A CN112321642 A CN 112321642A
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- reidesciclovir
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- 239000000126 substance Substances 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 14
- 229940079593 drug Drugs 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 10
- 239000012535 impurity Substances 0.000 claims abstract description 10
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 8
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 8
- 229940011051 isopropyl acetate Drugs 0.000 claims description 8
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 238000010828 elution Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 4
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 claims description 3
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 238000001514 detection method Methods 0.000 claims description 3
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 claims description 3
- 239000002777 nucleoside Substances 0.000 claims description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 150000003222 pyridines Chemical class 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- 239000013558 reference substance Substances 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000012071 phase Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- 208000025721 COVID-19 Diseases 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- RWWYLEGWBNMMLJ-MEUHYHILSA-N remdesivir Drugs C([C@@H]1[C@H]([C@@H](O)[C@@](C#N)(O1)C=1N2N=CN=C(N)C2=CC=1)O)OP(=O)(N[C@@H](C)C(=O)OCC(CC)CC)OC1=CC=CC=C1 RWWYLEGWBNMMLJ-MEUHYHILSA-N 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010187 selection method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- 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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
-
- 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
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
-
- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
-
- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
-
- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/8872—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample impurities
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- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Organic Chemistry (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a Reidesciclovir related substance, a preparation method and application thereof, wherein the related substance is a compound with a structure shown as a formula I. The invention discloses application of the Rudexilvir bulk drug as a reference substance for impurities in a preparation of the Rudexilvir bulk drug, and discloses a high performance liquid chromatography method for separating and measuring the Rudexilvir and a compound shown in a formula I.
Description
Technical Field
The invention relates to a preparation method and application of pharmaceutical impurities, in particular to a Reidesvir related substance and a preparation method and application thereof.
Background
Reidesciclovir (Remdesivir) is a nucleoside analogue with antiviral activity and is currently undergoing clinical studies on the treatment of a novel coronavirus (COVID-19) in several countries of the world. The structural formula of the Reidesciclovir is shown as follows:
the quality control of bulk drugs and preparations is always the key and difficult point in drug development, and the research on impurities is the key point in quality control. Starting materials, intermediates, reaction byproducts, degradation impurities and the like in the process of synthesizing the Reidesciclovir can be impurities remained in a final product (the Reidesciclovir), thereby influencing the quality of medicines. At present, research on related substances of the Reidesciclovir and research on a quality control analysis method are only reported in documents.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to research a synthesis process of the Reidesciclovir and provide a related substance generated by degradation in the synthesis process of the Reidesciclovir. Another object of the present invention is to provide a process for producing the related substance. The invention also aims to indicate the application of the related substances in the bulk drugs of the Reidesciclovir and the impurity reference products of the preparation thereof.
The technical scheme is as follows: the structure of the related substance of the Reidesciclovir is shown as the formula I:
the preparation method of the Reidesciclovir related substance comprises the following synthetic route:
in some embodiments, the method of making comprises:
1) in the step 1, n-butyl alcohol and Boc-L-alanine are subjected to condensation reaction in a system of dicyclohexylcarbodiimide and dichloromethane to obtain I-A;
2) in the step 2, the salt is formed after BOC is removed from the formula I-A in the presence of sulfuric acid, hydrochloric acid or trifluoroacetic acid to obtain I-B;
3) in the step 3, the formula I-B sequentially reacts with phenyl dichlorophosphate and p-nitrophenol under alkalinity to obtain I-C;
4) in step 4, formula I-C is reacted with the corresponding nucleoside in the presence of a Lewis acid and an organic base to provide the compound of formula I.
In some embodiments, the acid in step 2 of the preparation is hydrochloric acid.
In some embodiments, the base in step 3 of the preparation method is selected from the group consisting of N, N-diisopropylethylamine, triethylamine, pyridine, preferably triethylamine; the solvent is selected from one or more of tetrahydrofuran, isopropyl acetate, ethyl acetate, dichloromethane, dichloroethane, n-heptane and methyl tert-butyl ether, preferably one or more of isopropyl acetate, dichloromethane and methyl tert-butyl ether.
In some embodiments, in the preparation method, the base in step 4 is selected from one or more of N, N-diisopropylethylamine, triethylamine, pyridine and substituted pyridine, preferably one or two of N, N-diisopropylethylamine and triethylamine; the solvent is selected from one or more of N, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, isopropyl acetate, ethyl acetate, dichloromethane, dichloroethane, N-heptane and methyl tert-butyl ether, preferably one or more of isopropyl acetate, tetrahydrofuran and acetonitrile; the Lewis acid is selected from aluminum trichloride, ferric trichloride, titanium tetrachloride, magnesium chloride, stannic chloride, preferably magnesium chloride.
The application also provides application of the Rudexilvir related substance in a Rudexiliwei raw material impurity reference substance.
The application, namely a high performance liquid chromatography method for separating and measuring the Reidcisvir and the compound shown in the formula I comprises the following steps:
a. setting chromatographic conditions: performing gradient elution by using octadecylsilane chemically bonded silica as a chromatographic column filler, 0.1% phosphoric acid aqueous solution as a mobile phase A and acetonitrile as a mobile phase B;
b. solution preparation: dissolving a raw material of the Rudexiluwei in methanol to prepare a solution with the concentration of 0.1-1 mg/mL;
c. and (3) detection: and injecting the prepared Rudesiwei solution into a liquid chromatograph, recording a chromatogram and analyzing.
The use, the gradient elution procedure is as follows:
has the advantages that: the impurities prepared by the method are used as impurity reference substances in quality research of bulk drugs of the Reidesciclovir. The invention also provides a liquid chromatography analysis method for separating and measuring the Reidesciclovir and related substances (the compound shown in the formula I), which can quickly detect whether the related substances (the compound shown in the formula I) are contained in the bulk drugs and provides a new selection method for qualitatively and quantitatively detecting the Reidesciclovir bulk drugs.
Detailed Description
The Ruidexiwei bulk drug is made by Nanjing Zhengji pharmaceutical research Co.
Example 1
Weighing 11.2g of Boc-L-alanine, adding into a reaction bottle, sequentially adding 0.5g of 4-DMAP and 30g of dichloromethane, stirring, dissolving, clarifying, adding Dicyclohexylcarbodiimide (DCC), and stirring at normal temperature to react until the reaction is finished. After filtration, diluted hydrochloric acid washing and concentration, 13.4g of off-white solid was obtained.
13.4g of I-A, 15g of concentrated hydrochloric acid and 35 g of toluene are added into a reaction bottle, stirred and reacted for 2 hours at room temperature, then decompressed and concentrated to be dry at 50 ℃, and then n-heptane is added for stirring and dispersion, and the compound I-B20 g is obtained after filtration and drying.
20g of I-B, 120g of isopropyl acetate and 23.2g of phenyl dichlorophosphate are sequentially added into a reaction bottle, the temperature is reduced to-50 ℃, 23g of triethylamine is dropwise added, stirring is carried out for 1 hour after the addition is finished, 15.3g of p-nitrophenol is added, and then 15g of triethylamine is dropwise added. After the addition, the reaction mixture was allowed to react at room temperature for 2 hours, and then 0.5M hydrochloric acid solution was added to dilute the reaction mixture, followed by separation. The organic phase was washed twice with 5% sodium carbonate, washed once with saturated sodium chloride, concentrated and dried to obtain a solid-liquid mixture. 80g of isopropyl ether was added thereto, stirred at room temperature for 24 hours, filtered and dried to obtain 9.0g of the compounds I to C.
9.0g of the compounds I to C, 5.0g of nucleoside, 80g N, N-dimethylacetamide and 2.0g of magnesium chloride were added to the reaction flask. Then 6.3g N, N-diisopropylethylamine was added dropwise while controlling the internal temperature at 30 ℃. After 6 hours of reaction, 100g of water and 100g of 2-methyltetrahydrofuran were added and the layers were separated. The organic layer was washed with a 10% citric acid solution, a 10% sodium carbonate solution and a saturated aqueous sodium chloride solution in this order, and the solvent was removed by concentration under reduced pressure, followed by crystallization from isopropyl acetate to obtain 5.6g of the compound represented by formula I. HPLC purity: 98.6 percent; 1H NMR (500MHz, MeOD) δ 7.88(s,1H),7.32(t, J ═ 7.9Hz,2H), 7.23-7.14 (M,3H),6.93(d, J ═ 4.6Hz,1H),6.90(d, J ═ 4.6Hz,1H),4.81(d, J ═ 5.4Hz,2H), 4.46-4.34 (M,2H),4.31(dd, J ═ 11.5,5.3Hz,1H),4.19(t, J ═ 5.6Hz,1H), 4.11-3.96 (M,2H),3.88(dq, J ═ 14.3,7.2Hz,1H),1.57(dt, J ═ 14.6,6.7, 2H), 1.91.40 (t, 1H), 3.83H, t ═ 3H, t ═ 3H, 3.84H, t ═ 3H, t ═ 3H, t, 3HR＝7.533min
Analytical method
The instrument comprises the following steps: agilent 1100/1260 high performance liquid chromatograph
A chromatographic column: YMC-Pack ODS-A (250X 4.6mm,5 μm)
Mobile phase: mobile phase a of 0.1% aqueous phosphoric acid, mobile phase B of acetonitrile, linear gradient elution according to the following table:
detection wavelength: 238nm
Flow rate: 1mL/min
Column temperature: 30 deg.C
Sample introduction amount: 10 μ L
The substance (compound represented by formula I) prepared in the above example was weighed out precisely, dissolved in methanol and diluted to give a solution containing about 0.25mg per 1mL as a positioning solution.
Weighing a proper amount of the Reidesvir, adding the compound positioning solution shown in the formula I, and preparing a solution containing 0.5mg of the Reidesvir and about 2.5 mu g of the compound shown in the formula I in each 1mL as a system adaptive solution.
Weighing a proper amount of the Rudexiluwei, placing the Rudexiluwei in a measuring flask, dissolving the Rudexiluwei in acetonitrile, and diluting the solution into 0.5mg/mL solution to be used as a test solution.
And (3) determination: respectively injecting 10 mu L of compound positioning solution, system adaptability solution and Reidesciclovir test sample solution shown in formula I into a high performance liquid chromatograph, and recording chromatograms. The result shows that the method can realize good separation of the related substance (the compound shown in the formula I) and the Reidesvir, the Reidesvir peak is 8.1min, and the related substance (the compound shown in the formula I) peak is 6.5 min.
Claims (9)
1. A Reidesciclovir related substance is characterized in that the related substance has a structure shown in a formula I:
2. a process for the preparation of a reidesavir related substance as defined in claim 1, comprising the following synthetic route:
3. the production method according to claim 2,
1) in the step 1, n-butyl alcohol and Boc-L-alanine are subjected to condensation reaction in a system of dicyclohexylcarbodiimide and dichloromethane to obtain I-A;
2) in the step 2, the salt is formed after BOC is removed from the formula I-A in the presence of sulfuric acid, hydrochloric acid or trifluoroacetic acid to obtain I-B;
3) in the step 3, the formula I-B sequentially reacts with phenyl dichlorophosphate and p-nitrophenol under alkalinity to obtain I-C;
4) in step 4, formula I-C is reacted with the corresponding nucleoside in the presence of a Lewis acid and an organic base to provide the compound of formula I.
4. The method according to claim 3, wherein the acid in the step 2 is hydrochloric acid.
5. The method according to claim 3, wherein the base in step 3 is selected from the group consisting of N, N-diisopropylethylamine, triethylamine, pyridine; the solvent is one or more selected from tetrahydrofuran, isopropyl acetate, ethyl acetate, dichloromethane, dichloroethane, n-heptane and methyl tert-butyl ether.
6. The preparation method according to claim 3, wherein the base in step 4 is selected from one or more of N, N-diisopropylethylamine, triethylamine, pyridine and substituted pyridine; the solvent is one or more selected from N, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, isopropyl acetate, ethyl acetate, dichloromethane, dichloroethane, N-heptane and methyl tert-butyl ether; the Lewis acid is selected from aluminum trichloride, ferric trichloride, titanium tetrachloride, magnesium chloride and stannic chloride.
7. Use of the Reidcisvir related substance as defined in claim 1 in a Reidcisvir bulk drug impurity control.
8. The use according to claim 7, wherein the high performance liquid chromatography method for separating and measuring Reidesciclovir and Reidesciclovir-related substance according to claim 1 comprises the following steps:
a. setting chromatographic conditions: performing gradient elution by using octadecylsilane chemically bonded silica as a chromatographic column filler, 0.1% phosphoric acid aqueous solution as a mobile phase A and acetonitrile as a mobile phase B;
b. solution preparation: dissolving a raw material of the Rudexiluwei in methanol to prepare a solution with the concentration of 0.1-1 mg/mL;
c. and (3) detection: and injecting the prepared Rudesiwei solution into a liquid chromatograph, recording a chromatogram and analyzing.
9. Use according to claim 8, characterized in that the gradient elution procedure is as follows:
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