CN113956199A - Impurity of Rosxastat, preparation method and application thereof - Google Patents
Impurity of Rosxastat, preparation method and application thereof Download PDFInfo
- Publication number
- CN113956199A CN113956199A CN202110679630.6A CN202110679630A CN113956199A CN 113956199 A CN113956199 A CN 113956199A CN 202110679630 A CN202110679630 A CN 202110679630A CN 113956199 A CN113956199 A CN 113956199A
- Authority
- CN
- China
- Prior art keywords
- solvent
- formula
- oxidation reaction
- compound
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 239000012535 impurity Substances 0.000 title abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims description 39
- 238000007254 oxidation reaction Methods 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 13
- 239000011630 iodine Substances 0.000 claims description 13
- 229910052740 iodine Inorganic materials 0.000 claims description 13
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 10
- 238000004537 pulping Methods 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 9
- 239000012074 organic phase Substances 0.000 claims description 9
- 150000008282 halocarbons Chemical class 0.000 claims description 8
- 239000012295 chemical reaction liquid Substances 0.000 claims description 7
- 238000003908 quality control method Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 claims description 4
- 229960000245 rasagiline Drugs 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims 1
- 241000220317 Rosa Species 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000003814 drug Substances 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 231100000024 genotoxic Toxicity 0.000 description 4
- 230000001738 genotoxic effect Effects 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 208000020832 chronic kidney disease Diseases 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 101710138860 Hypoxia-inducible factor prolyl hydroxylase Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 206010058116 Nephrogenic anaemia Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000011165 process development Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 206010062237 Renal impairment Diseases 0.000 description 1
- 244000178231 Rosmarinus officinalis Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- PMZXXNPJQYDFJX-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid Chemical compound CC#N.OC(=O)C(F)(F)F PMZXXNPJQYDFJX-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
- 239000004247 glycine and its sodium salt Substances 0.000 description 1
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 231100000219 mutagenic Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 231100000857 poor renal function Toxicity 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000012502 risk assessment Methods 0.000 description 1
- 238000012954 risk control Methods 0.000 description 1
- YOZBGTLTNGAVFU-UHFFFAOYSA-N roxadustat Chemical compound C1=C2C(C)=NC(C(=O)NCC(O)=O)=C(O)C2=CC=C1OC1=CC=CC=C1 YOZBGTLTNGAVFU-UHFFFAOYSA-N 0.000 description 1
- 229950008113 roxadustat Drugs 0.000 description 1
- 235000015067 sauces Nutrition 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229940029258 sodium glycinate Drugs 0.000 description 1
- WUWHFEHKUQVYLF-UHFFFAOYSA-M sodium;2-aminoacetate Chemical compound [Na+].NCC([O-])=O WUWHFEHKUQVYLF-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
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)
Abstract
The invention discloses impurities of a roxburgh rose and a preparation method and application thereof. The impurity of the roxasistat is a compound shown as a formula M1-Z6 and salt thereof. The preparation method can prepare the compound shown in the formula M1-Z6 with high yield.
Description
Technical Field
The invention relates to impurities of roxasistat, a preparation method and application thereof.
Background
Renal anemia is anemia due to impaired renal function and is a common complication of Chronic Kidney Disease (CKD). The total number of Chinese chronic kidney diseases is about 1.2 hundred million. The first globally marketed hypoxia inducible factor prolyl hydroxylase (HIF-PH) inhibitor is roxasistat (Roxadustat), which is a drug for treating renal anemia. The medicine is developed by the American FibroGen company, is sold on the market in China at 12 months in 2018, and is the first new anti-anemia medicine for oral treatment without intravenous iron supplement.
The preparation methods of the Rosesarta disclosed in the prior art have the disadvantages of complicated steps, low yield or use of noble metal catalysts and the like, so the inventor develops a preparation method of Rosesarta more suitable for industrial production, the raw materials are cheap and easy to obtain, the reaction steps are short, the yield is high, the post-treatment process is simple and convenient, and the specific synthetic route is as follows:
as a new drug on the market in recent years, there is still no research on intermediate process impurities in the process development process of the brand new preparation method of the aforementioned rosxastat. It is known that the research and control of impurities are an important work content for improving the purity of the medicine and controlling the quality of the medicine, and the impurities introduced by the production process are important sources of the medicine impurities. It is a challenging task to study the types and sources of impurities generated in novel synthetic routes not reported in the literature, and to achieve effective control of drug quality and purity. Therefore, impurities generated in the process are identified, and an efficient impurity synthesis route is developed, so that sufficient impurity reference substances can be obtained, and the smooth development of quality detection work of the bulk drugs in each batch can be ensured.
Disclosure of Invention
In the process development process of the brand-new preparation method of the Rosemastat, research on intermediate process impurities is still lacked, so that the invention provides the Rosemastat process impurities, the preparation method and the application thereof. The impurity compound can be used as a reference substance to carry out quality control on a roxasistat synthesis intermediate and a roxasistat bulk drug, and is very necessary to control the quality of the roxasistat bulk drug and even a finished product of a preparation.
During the development of the novel process for the preparation of the aforementioned Rosemary sauce, it was found that during process scale-up, a major process impurity (compound M1-Z6) was produced during the first oxidation step, which was entrapped in the intermediate M1-A
In addition, the method is difficult to effectively remove, and brings great adverse effect on the quality control of the raw materials of the roxasistat. The inventors obtained the impurity compound M1-Z6 using a preparative liquid phase separation purification method, and confirmed the structure of the impurity M1-Z6 by performing structure confirmation thereon. The impurity M1-Z6 contains aldehyde group of genotoxic warning structure, and the genotoxic impurity generated in the production process of the bulk drug needs to be analyzed and controlled according to the guiding principle of ICH M7(R1) (evaluating and controlling DNA reactivity (mutagenic) impurity in the drug to limit potential carcinogenic risk). The research on genotoxic impurities in the drug research and development process comprises analysis method research, analysis method verification, impurity limit setting, routine detection and the like, the source and destination of the impurities need to be traced, reasonable removal measures are made according to the properties of the impurities, and a large amount of impurity reference substances are used in the research.
Because the impurities M1-Z6 have novel structures, the preparation method is not reported in documents, but the efficiency of separating and purifying the prepared liquid phase is low, so that an impurity reference substance with enough quantity cannot be quickly obtained, and the requirements on risk assessment and control of genotoxic impurities are difficult to meet. In order to efficiently obtain a sufficient amount of high-purity impurity M1-Z6, the inventors developed a preparation method thereof so as to use it as a reference for quality control of a raw material drug of Rosemastat.
The invention provides a compound shown as a formula M1-Z6 or a salt thereof:
the invention also provides a preparation method of the compound shown as the formula M1-Z6, which comprises the following steps: in a solvent, carrying out oxidation reaction on a compound shown as a formula M3-A and elemental iodine shown as a following formula to obtain a compound shown as a formula M1-Z6;
in the oxidation reaction, the solvent is a conventional solvent for such reactions in the art; preferably, the solvent is a polar aprotic organic solvent; more preferably, the solvent is dimethyl sulfoxide.
In the oxidation reaction, the volume-mass ratio of the solvent to the compound shown as the formula M3-A can be 10-30 mL/g; e.g., 10mL/g, 20mL/g, or 30 mL/g; preferably, the volume-to-mass ratio of the solvent to the compound shown as the formula M3-A is 10-20 mL/g.
In the oxidation reaction, the molar ratio of the elemental iodine to the compound shown as the formula M3-A is the conventional dosage ratio in the reaction in the field; the molar ratio of the elemental iodine to the compound of formula M3-A may be (1.5-3.5): 1; e.g., 1.5:1, 2.5:1, or 3.5: 1; preferably, the molar ratio of the elemental iodine to the compound of formula M3-a may be 2.5: 1.
In the oxidation reaction, the reaction temperature of the oxidation reaction is 90-125 ℃; preferably, the reaction temperature of the oxidation reaction is 105-125 ℃; more preferably, the reaction temperature of the oxidation reaction is 120-125 ℃.
In the oxidation reaction, the reaction time of the oxidation reaction is related to the scale of the reaction, and the progress of the oxidation reaction can be monitored by a monitoring method (such as HPLC or TLC) which is conventional in the art, and the disappearance of the compound M3-A is generally monitored as the end point of the reaction. The reaction time of the oxidation reaction may be 5 hours.
In one embodiment of the present invention, in the oxidation reaction, the solvent is dimethyl sulfoxide; the volume-mass ratio of the solvent to the compound shown in the formula M3-A is 10-20 mL/g; the molar ratio of the elemental iodine to the compound represented by the formula M3-A is 2.5: 1; the reaction temperature of the oxidation reaction is 120-125 ℃.
The preparation method further comprises the following post-treatment steps: and after the oxidation reaction is finished, extracting, separating, washing and pulping the reaction liquid, concentrating an organic phase and then obtaining the compound shown in the formula M1-Z6.
In the work-up, the extraction of the reaction solution is carried out in a manner customary in the art, for example organic-aqueous extraction. The organic solvent for extraction is an ester solvent or a halogenated hydrocarbon solvent, and when the organic solvent is the ester solvent, the ester solvent is ethyl acetate or isopropyl acetate; when the organic solvent is a halogenated hydrocarbon solvent, the halogenated hydrocarbon solvent is dichloromethane or chloroform; preferably, the organic solvent for extraction is an ester solvent; more preferably, the organic solvent for extraction is ethyl acetate.
In the post-treatment, the washing solvent for washing may be a saturated saline solution.
In the post-treatment, the solvent for pulping is an ether solvent; preferably, the ether solvent is methyl tert-butyl ether.
The preparation method further comprises the following post-treatment steps: after the oxidation reaction is finished, extracting and separating the reaction liquid, washing an organic phase by saturated saline solution, concentrating the organic phase, and pulping to obtain a compound shown as a formula M1-Z6; the organic solvent for extraction is ethyl acetate; the solvent for pulping is methyl tert-butyl ether.
The invention also provides application of the compound shown as the formula M1-Z6 or salt thereof in quality control of the rasagiline.
In the present invention, preferably, in the application, the preparation process of the rasagiline base can be as follows:
the above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
In the present invention, the reaction temperature or the operation temperature which is not mentioned is generally room temperature, and room temperature is generally ambient temperature, for example, 0 ℃ to 40 ℃, preferably 10 ℃ to 30 ℃, more preferably 25 ℃.
In the present invention, compound SM2 was prepared according to CN201210152768.1 example D-7.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
the invention provides a compound shown as a formula M1-Z6. The compound of formula M1-Z6 is an impurity generated during the process of preparing the rosxastat. The invention also provides a preparation method of the compound shown as the formula M1-Z6 and a salt thereof. The preparation method can prepare the compound shown in the formula M1-Z6 with high yield.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The HPLC purity test method in the following examples is as follows:
the instrument equipment comprises: high performance liquid chromatograph, chromatographic column: watres Xbridge C18 (4.6X 100mm,3.5 μm), chromatographic conditions: mobile phase A: 0.08% aqueous formic acid, mobile phase B: acetonitrile/water/formic acid (900:100: 0.8); detection wavelength: 295 nm; column temperature: 40 ℃; flow rate: 1.0 ml/min; mobile phase elution gradient: 35min for 70% A/30% B to 20% A/80% B, then 4min for 20% A/80% B to 100% B, 10min for 100% B, and 1min for 70% A/30% B return, maintaining this gradient for 10min, 60 min.
The LC-MS detection conditions were as follows:
the instrument equipment comprises: agilent liquid chromatography mass spectrometer 1260/6120; an ion source: ESI; sample preparation: and (3) acetonitrile.
Test example 1: synthesis of Rosxastat
Synthesis of intermediate M1-A
3.1g (about 0.01mol) of the compound SM2 was heated in 31.0g (about 0.36mol) of N, N-Dimethylacetamide (DMA) to be completely dissolved at 60 ℃ to 70 ℃, and 4.8g (about 0.02mol) of sodium persulfate was dissolved in 9.6g of water (about 0.53mol), and then added to the above solution, followed by stirring for 1 hour. TLC monitors the reaction to be complete, the reaction liquid is cooled to room temperature, 50g of water is added, the mixture is stirred and filtered, and a filter cake is dried in vacuum to obtain 3.3g of off-white solid, the yield is 85.7%, and the purity is 98.46%.
MS(ESI)m/z：417.16[M+Na]+，1H-NMR(400MHz,DMSO-d6)δ11.66(d,J＝22.8Hz,1H),8.32(t,J＝9.0Hz,1H),7.68(dd,J＝14.5,2.2Hz,1H),7.44-7.57(m,3H),7.12-7.30(m,3H),4.88d,J＝34.0Hz,2H),4.44(q,J＝14.0,7.0Hz,2H),2.83(d,J＝40.0Hz,3H),1.97(d,J＝8.3Hz,3H),1.39(t,J＝7.1Hz,3H).
Synthesis of intermediate M2-A
3.0g (about 0.008mol) of intermediate M1-A was dissolved by heating to 30 deg.C-40 deg.C in tetrahydrofuran (10mL) and methanol (5 mL). Concentrated hydrochloric acid (5mL, 36% by mass hydrochloric acid) was added with stirring, and the mixture was stirred for 5 hours. TLC monitors the reaction to be complete, and the reaction solution is concentrated in vacuum until a large amount of solid is separated out, filtered, washed by a small amount of methanol and dried by suction to obtain 2.8g of white solid with the yield of 94.7 percent (calculated as hydrochloride) and the purity of 98.40 percent.
MS(ESI)m/z：353.16[M+H]+，1H-NMR(400MHz,DMSO-d6)：δ11.72(s,1H),9.32(s,2H),8.42(d,J＝9.1Hz,1H),7.75(d,J＝2.2Hz,1H),7.60(dd,J＝9.1,2.3Hz,1H),7.49(t,J＝7.9Hz,2H),7.27(t,J＝7.4Hz,1H),7.19(d,J＝7.7Hz,2H),4.67(s,2H),4.50(q,J＝7.1Hz,2H),2.74(s,3H),1.41(t,J＝7.1Hz,3H).
Synthesis of M3-A
2.5g (about 0.007mol) of intermediate M2-A was dissolved in acetic acid (25mL), 2.6g (0.04mol) of zinc powder was added, heated to 50 deg.C-60 deg.C, and stirred for 6 hours. TLC monitored the reaction completion, the reaction was filtered, the filter cake was washed with a mixed solvent of dichloromethane (20mL) and methanol (10mL), the filtrates were combined and concentrated to at least a small volume of solvent (e.g., the volume of the concentrate was about 2-3mL), isopropanol (4mL) and water (8mL) were added, the mixture was stirred and filtered, the filter cake was slurried in methanol/water (1:3/v: v, 12mL) and filtered to give 1.6g of an off-white solid with a yield of 76.7% and a purity of 96.90%.
MS(ESI)m/z：346.10[M+Na]+，1H-NMR(400MHz,DMSO-d6)：δ11.63(s,1H),8.32(d,J＝9.0Hz,1H),7.58(d,J＝2.0Hz,1H),7.55-7.44(m,3H),7.27(t,J＝7.4Hz,1H),7.19(d,J＝7.9Hz,2H),4.44(q,J＝7.1Hz,2H),2.64(s,3H),1.37(q,J＝7.3Hz,3H).
Synthesis of Rosxastat
1.5g of intermediate M3-A was added to 15g of ethanol, 1.4g of sodium glycinate was added, and the mixture was heated to 105 ℃ to 115 ℃ in a pressure-resistant vessel and stirred for 8 hours. Cooling the reaction liquid to room temperature, carrying out suction filtration, washing with a small amount of methanol, and draining to obtain crude product of the sodium salt of the roxasistat, dissolving the crude product of the sodium salt of the roxasistat with 25g of water, washing the water phase with 10mL of ethyl acetate, slowly adding acetic acid into the water phase under the stirring state, adjusting the pH to be less than 7, separating out a large amount of solids, carrying out suction filtration, washing the filter cake with water, draining, and carrying out vacuum drying to obtain 1.3g of finished product of the roxasistat, wherein the yield is 83.4%, and the purity is 99.57%.
MS(ESI)m/z：353.2[M+H]+，1H-NMR(400MHz,DMSO-d6)：δ13.28(s,1H),9.08(t,J＝5.8Hz,1H),8.25(t,J＝12.0Hz,1H),7.59(s,1H),7.55-7.41(m,3H),7.24(t,J＝7.3Hz,1H),7.16(d,J＝7.9Hz,2H),4.04(d,J＝5.9Hz,2H),2.68(s,3H).
Test example 2: preparation, separation and purification of impurity compound M1-Z6
750g (2.43mol) of SM2 and 5.5L of N, N-dimethylacetamide are added into a 20L reaction kettle, the temperature is raised to 60-65 ℃ by stirring, sodium persulfate aqueous solution (1130g of sodium persulfate is dissolved in 3.5L of water) is added dropwise, the internal temperature is raised to 80 ℃ after about 2 hours of dropwise addition, and the raw materials are completely reacted by TLC detection. The reaction solution is cooled to be lower than 40 ℃, 2.25L of water is added dropwise, the temperature is reduced to room temperature, the filtration is carried out, the washing is carried out (750mL multiplied by 3), the pumping is carried out, the material is dried in vacuum at 50 ℃ for 16 hours, the material drying is stopped, 727g of yellow solid is obtained, the intermediate M1-A is obtained, the yield is 76%, the purity is 93.53% by HPLC detection (retention time is 19.94min), and the content of M1-Z6 is 2.78% (retention time is 27.05 min). And (3) adding 2L of methyl tert-butyl ether into 200g of the intermediate M1-A, heating to 30-40 ℃, pulping for 1 hour, cooling to room temperature, filtering, and concentrating the filtrate in vacuum to obtain a concentrate, wherein the content of M1-Z6 is 6.26%. 1g of this concentrate was dissolved in deionized water and acetonitrile (about 1:1 ratio) to 50mg/mL, and subjected to separation and purification by preparative high performance liquid chromatography (manufactured by Shimadzu corporation, Japan, model: RFC-40) under the following conditions:
a chromatographic column: YMC Triart C187 μm 250 x 30mm i.d.
Mobile phase A: 0.1% aqueous TFA
Mobile phase B: 0.1% TFA acetonitrile: isopropanol (1:1)
Detection wavelength: 220nm and 254nm
Sample introduction amount: 40mg of
Column temperature: at room temperature
Flow rate: 30mL/min
Gradient elution method: the gradient was maintained for 2min at 60% A/40% B, then 0.5min from 60% A/40% B to 30% A/70% B, then 9.5min from 30% A/70% B to 100% B, and 0.5min from 100% B back to 60% A/40% B, and then 16 min.
The collected target peak solution (retention time: 8.5min) was concentrated in vacuo and lyophilized to give the impurity compound M1-Z631.0 mg as a white-like powder with a purity of 94.46% by HPLC and a retention time of 27.04 min.
M1-Z6 structural identification data:
MS(ESI)m/z：336.0875(M-H)；
1H-NMR(d6-DMSO，400Hz)：δ＝12.241(s,1H)，9.943(s,1H)，8.553(d,J＝2.4Hz,1H)，8.393(d,J＝9.2Hz,1H)，7.663(dd,J1＝8.8Hz,J2＝2.4Hz,1H)，7.517-7.557(m,2H)，7.341(t,J＝7.6Hz,1H)，7.240-7.360(m,2H)，4.497(q,J＝4.4Hz,2H)，1.408(t,J＝1.4Hz,3H)。
13C-NMR(d6-DMSO，400Hz)δ＝193.37，168.89，161.25，157.83，154.45，139.82，130.55，130.29，125.73，125.42，123.08，123.01，120.94，120.45，108.94，62.10，14.10。
example 1:
starting materials SM2(1.55g, ca. 5mmol) and urotropin (1.4g, ca. 10mmol) were added to trifluoroacetic acid (5mL) respectively, warmed to 85 deg.C, and stirred for 6 hours. No formation of M1-Z6 was detected by HPLC.
Example 2:
intermediate M2-A (1.76g, about 5mmol), tetrabutylammonium iodide (TBAI, 0.18g, about 0.5mmol), hydrogen peroxide (4.5g, about 40mmol) were added to N, N-dimethylacetamide (15mL) respectively, the temperature was raised to 100 ℃ and the mixture was stirred for 24 hours. The sample is detected by HPLC, and M1-Z6 accounts for 14% of the reaction liquid.
Example 3:
intermediate M3-A (1.62g, about 5mmol) and manganese dioxide (0.87g, about 10mmol) were added to acetonitrile (20mL), respectively, and the reaction was stirred at 50 ℃ for 12 hours. A sample was checked by HPLC for the absence of M1-Z6.
Example 4:
intermediate M3-A (4.9g, 15mmol) and elemental iodine (9.5g, 37.5mmol) were added to dimethyl sulfoxide (98mL) and the reaction was stirred at 110 ℃ for 5 hours. TLC monitors the reaction completion, after cooling, 500mL ethyl acetate and 500mL water are added, liquid separation is carried out, the organic phase is washed with saturated brine, and the organic phase is separated. The organic phase was concentrated in vacuo, slurried with methyl tert-butyl ether for 1 hour, filtered to give a yellow-green solid, which was dried in vacuo to give 2.55g of product in 50.2% yield. The solid obtained was tested by HPLC and had a purity of about 96.13% for M1-Z6, and the structural identification data was identical to that of test example 2.
Example 5: process condition groping
Using intermediate M3-A (2.43g) as a reaction material, and employing similar procedures of reaction and post-treatment in example 4, different amounts of iodine, solvent, and reaction temperature were selected to examine the oxidation reaction conditions, and the purity and yield of M1-Z6 were as shown in Table 1:
table 1:
as can be seen from Table 1, when the elemental iodine is 2.5 equivalents, the reaction temperature is 105-125 ℃, and the volume-to-mass ratio of dimethyl sulfoxide to M3-A is 10-20mL/g, the purity and yield of the obtained M1-Z6 are excellent. Particularly, when the elemental iodine is 2.5 equivalent, the reaction temperature is 120-125 ℃, and the volume mass ratio of the dimethyl sulfoxide to the M3-A is 20mL/g, the highest yield of the M1-Z6 is obtained.
Claims (10)
1. A compound of the formula M1-Z6:
2. a process for the preparation of a compound of formula M1-Z6 as claimed in claim 1, which comprises the steps of: in a solvent, carrying out oxidation reaction on a compound shown as a formula M3-A and elemental iodine shown as a formula to obtain a compound shown as a formula M1-Z6;
3. a process for the preparation of a compound of formula M1-Z6 as claimed in claim 2, wherein the process satisfies one or more of the following conditions:
in the oxidation reaction, the solvent is a polar aprotic organic solvent;
in the oxidation reaction, the volume-mass ratio of the solvent to the compound shown as the formula M3-A is 10-30 mL/g;
③ in the oxidation reaction, the molar ratio of the elementary iodine to the compound shown as the formula M3-A is (1.5-3.5): 1;
and fourthly, in the oxidation reaction, the reaction temperature of the oxidation reaction is 90-125 ℃.
4. A process for the preparation of a compound of formula M1-Z6 as claimed in claim 3, wherein the process satisfies one or more of the following conditions:
in the oxidation reaction, the solvent is dimethyl sulfoxide;
in the oxidation reaction, the volume-mass ratio of the solvent to the compound shown as the formula M3-A is 10-20 mL/g;
③ in the oxidation reaction, the molar ratio of the elementary iodine to the compound shown as the formula M3-A is 1.5:1, 2.5:1 or 3.5: 1;
and fourthly, in the oxidation reaction, the reaction temperature of the oxidation reaction is 105-125 ℃.
5. A process for the preparation of a compound of formula M1-Z6 as claimed in claim 4, wherein the process satisfies one or more of the following conditions:
in the oxidation reaction, the volume-mass ratio of the solvent to the compound shown as the formula M3-A is 10mL/g or 20 mL/g;
② in the oxidation reaction, the molar ratio of the elementary iodine to the compound shown in the formula M3-A is 2.5: 1;
thirdly, in the oxidation reaction, the reaction temperature of the oxidation reaction is 120-125 ℃;
in the oxidation reaction, the preparation method is characterized by further comprising the following post-treatment steps: and after the oxidation reaction is finished, extracting, separating, washing and pulping the reaction liquid, concentrating an organic phase and then obtaining the compound shown in the formula M1-Z6.
6. A process for the preparation of a compound of formula M1-Z6 as claimed in claim 2, wherein the solvent is dimethyl sulfoxide; the volume-mass ratio of the solvent to the compound shown in the formula M3-A is 10-20 mL/g; the molar ratio of the elemental iodine to the compound represented by the formula M3-A is 2.5: 1; the reaction temperature of the oxidation reaction is 120-125 ℃.
7. The process of claim 5 for the preparation of a compound of formula M1-Z6, wherein the post-treatment satisfies one or more of the following conditions:
the organic solvent for extraction is an ester solvent or a halogenated hydrocarbon solvent;
in the post-treatment, the washing solvent for washing is saturated salt water;
and thirdly, in the post-treatment, the solvent for pulping is an ether solvent.
8. A process for the preparation of a compound of formula M1-Z6 as claimed in claim 7, wherein the post-treatment satisfies one or more of the following conditions:
in the post-treatment, the organic solvent for extraction is an ester solvent or a halogenated hydrocarbon solvent; when the organic solvent is an ester solvent, the ester solvent is ethyl acetate or isopropyl acetate;
in the post-treatment, the organic solvent for extraction is an ester solvent or a halogenated hydrocarbon solvent; when the organic solvent is a halogenated hydrocarbon solvent, the halogenated hydrocarbon solvent is dichloromethane or chloroform;
③ in the post-treatment, the solvent for pulping is an ether solvent; the ether solvent is methyl tert-butyl ether.
9. A process for the preparation of a compound of formula M1-Z6 as claimed in claim 1, further comprising the following post-treatment steps: after the oxidation reaction is finished, extracting and separating the reaction liquid, washing an organic phase by saturated saline solution, concentrating the organic phase, and pulping to obtain a compound shown as a formula M1-Z6; the organic solvent for extraction is ethyl acetate; the solvent for pulping is methyl tert-butyl ether.
10. Use of a compound of formula M1-Z6, or a salt thereof, as defined in claim 1, for the quality control of rasagiline;
preferably, in the application, the preparation process of the rasagiline is as follows:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110679630.6A CN113956199A (en) | 2021-06-18 | 2021-06-18 | Impurity of Rosxastat, preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110679630.6A CN113956199A (en) | 2021-06-18 | 2021-06-18 | Impurity of Rosxastat, preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113956199A true CN113956199A (en) | 2022-01-21 |
Family
ID=79460250
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110679630.6A Pending CN113956199A (en) | 2021-06-18 | 2021-06-18 | Impurity of Rosxastat, preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113956199A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115420823A (en) * | 2022-08-29 | 2022-12-02 | 南京正济医药研究有限公司 | Method for measuring related substances in roxasistat |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106916105A (en) * | 2015-12-28 | 2017-07-04 | 徐州万邦金桥制药有限公司 | A kind of method that purifying can win U.S. |
| CN107954931A (en) * | 2016-10-17 | 2018-04-24 | 上海医药集团股份有限公司 | A kind of preparation method of Nuo get Si Ta |
| CN108341777A (en) * | 2017-01-23 | 2018-07-31 | 四川科伦博泰生物医药股份有限公司 | Compound of isobioquin group and its application |
| CN108424388A (en) * | 2018-04-19 | 2018-08-21 | 杭州科巢生物科技有限公司 | A kind of preparation method of chronic anaemia drug |
-
2021
- 2021-06-18 CN CN202110679630.6A patent/CN113956199A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106916105A (en) * | 2015-12-28 | 2017-07-04 | 徐州万邦金桥制药有限公司 | A kind of method that purifying can win U.S. |
| CN107954931A (en) * | 2016-10-17 | 2018-04-24 | 上海医药集团股份有限公司 | A kind of preparation method of Nuo get Si Ta |
| CN108341777A (en) * | 2017-01-23 | 2018-07-31 | 四川科伦博泰生物医药股份有限公司 | Compound of isobioquin group and its application |
| CN108424388A (en) * | 2018-04-19 | 2018-08-21 | 杭州科巢生物科技有限公司 | A kind of preparation method of chronic anaemia drug |
Non-Patent Citations (2)
| Title |
|---|
| CHRISTOPHER D. GILMORE等: "Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| 贾俊豪 等: "罗沙司他合成路线图解", 《山东化工》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115420823A (en) * | 2022-08-29 | 2022-12-02 | 南京正济医药研究有限公司 | Method for measuring related substances in roxasistat |
| CN115420823B (en) * | 2022-08-29 | 2023-09-29 | 南京正济医药研究有限公司 | Method for measuring related substances in roflumilast |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107235958A (en) | A kind of synthetic method for preparing PARP inhibitor Niraparib | |
| CN108947891A (en) | The method for safely preparing a Mo Fanselin and its tartrate using triphosgene | |
| CN113816904B (en) | Synthesis method of roxasistat and intermediate thereof | |
| CN104926790A (en) | High-purity Vonoprazan Fumarate compound, intermediate and impurity thereof and preparation methods of high-purity Vonoprazan Fumarate compound, intermediate and impurity | |
| CN108794351A (en) | A kind of preparation method of Mo Fanselin key intermediate | |
| CN113956199A (en) | Impurity of Rosxastat, preparation method and application thereof | |
| CN109678840A (en) | The preparation method of pomalidomide | |
| CN113185465A (en) | Preparation method of 4-ethyl-5-aminopyrimidine | |
| CN112154140B (en) | Compound and application thereof in synthesizing Brivaracetam (Brivaracetam) bulk drug | |
| CN112300073A (en) | Preparation method of isoquinoline derivative | |
| CN115960059A (en) | Method for synthesizing furosemide impurity D with high yield and high purity | |
| CN113956198A (en) | Impurity of roxasistat, preparation method and application thereof | |
| CN110437062B (en) | Synthetic method of neratide intermediate | |
| WO2022110612A1 (en) | Preparation method for s-configuration phenylethylamine hydrochloride compound | |
| CN113072541A (en) | Preparation method of targeted drug BLU-667 | |
| CN103450157A (en) | Preparation method for high-purity hydroxyfasudil semihydrate | |
| CN109879800B (en) | Preparation process of bepotastine drug intermediate | |
| CN107089942B (en) | The preparation method of tegafur, gimeracil and oteracil potassium impurity B CB | |
| CN107304204A (en) | A kind of method for preparing N- heterocyclic compounds | |
| CN111205285A (en) | Purification method and crystal form of berberine or berberine salt | |
| CN107831249B (en) | Preparation of thiabendazole morpholine salt and HPLC (high performance liquid chromatography) quality analysis method thereof | |
| CN111518061B (en) | Preparation method of (E) -3- (3-furyl) acrylic acid | |
| CN111825636B (en) | Timolol hydrate and process for preparing same | |
| JP6126102B2 (en) | Pure S-(−)-9-fluoro-6,7-dihydro-8- (4-hydroxypiperidin-1-yl) -5-methyl-1-oxo-1H, 5H-benzo [i, j] quinolidine -2-carboxylic acid L-arginine salt tetrahydrate and process for producing the same | |
| RU2363694C2 (en) | Improved method for separation and purification of indole-3-carbinol (i3c) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20220121 |