CN110818700A - Oxazolidone derivative and preparation method thereof - Google Patents
Oxazolidone derivative and preparation method thereof Download PDFInfo
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Abstract
The invention relates to an oxazolidinone compound impurity 5-chloro-nitrogen- [ [ (5S) -2-oxo-3- [ 4-acetamidophenyl ] -1, 3-oxazolidine-5-yl ] methyl ] thiophene-2-formamide (formula I) in rivaroxaban, wherein the impurity is obtained by taking 4-aminoacetanilide (formula II) and (S) -N-epoxypropylphthalimide (formula III) as raw materials through ring-opening coupling, ring closing, protecting group removal and condensation reaction. The formula I can be applied to the quality control of rivaroxaban raw material medicines and the qualitative and quantitative research and detection of impurities.
Description
Technical Field
The invention relates to an oxazolidinone derivative, in particular to an oxazolidinone compound impurity 5-chlorine-nitrogen- [ [ (5S) -2-oxo-3- [ 4-acetamidophenyl ] -1, 3-oxazolidine-5-yl ] methyl ] thiophene-2-formamide in rivaroxaban production.
Background
Rivaroxaban (Rivaroxaban), chemical name 5-chloro-nitrogen- ({ (5S) -2-oxo-3- [ -4- (3-oxo-4-morpholinyl) phenyl ] -1, 3-oxazolidin-5-yl } methyl) -2-thiophene-carboxamide, CAS number: 366789-02-8, the structural formula is shown as follows:
rivaroxaban, a novel anticoagulant drug developed by bayer/qiangsheng corporation, is the first oral direct factor Xa inhibitor worldwide. Rivaroxaban is essentially different from fondaparinux sodium/heparin in that it does not require the participation of antithrombin III, directly antagonizes free and bound factor Xa to reduce thrombin activation and thus prolong clotting time, and it not only blocks clot formation but also destroys established clots. In hip or knee replacements, venous blood in the legs does not flow well back to the heart and tends to form a thrombus, and rivaroxaban helps prevent the formation and further development of this thrombus. Rivaroxaban tablets only need to be taken orally once a day, and the dosage of the drug does not need to be adjusted, so that compared with other similar drugs, the rivaroxaban tablets do not need to be monitored continuously and have better compliance.
Patent CN1906191 reports that rivaroxaban can be obtained by using 4- (4-aminophenyl) -3-morpholinone and (S) -N-epoxypropylphthalimide as starting materials through ring-opening coupling, ring closing, de-protecting group to form salt, condensation with 5-chlorothiophene-2-formyl chloride and acetic acid refining.
In the process of preparing rivaroxaban by using the route optimization conditions, the inventor finds that a byproduct (formula I) is generated in the reaction, and the compound is similar to rivaroxaban in structure and is difficult to completely remove.
Zeitangyan et al reported 8 possible impurities of rivaroxaban and studied their synthesis. Patent WO2012035057 also describes a method for the synthesis of 2 possible impurities of rivaroxaban. In patent CN104892593, 5 possible related substances are determined by means of impurity enrichment, destructive experiment, column chromatography, HPLC, structure confirmation and the like, and 2 possible methods for synthesizing impurities are disclosed. However, none of these prior art impurities have been analyzed to identify the impurities described in the present invention.
The isolation and identification of this impurity (formula I) is therefore very important for the quality control of rivaroxaban. The compound needs to be studied.
Disclosure of Invention
The invention aims to confirm the structure of the impurity in rivaroxaban, determine the limit of the impurity in the quality standard of rivaroxaban and provide a method for preparing the impurity standard.
The inventor prepares industrialized rivaroxaban by optimizing conditions in the prior art, and detects and analyzes the product prepared by the method by using high performance liquid chromatography, and finds that one impurity is difficult to completely remove. The impurity is 5-chlorine-nitrogen- [ [ (5S) -2-oxo-3- [ 4-acetamidophenyl ] -1, 3-oxazolidin-5-yl ] methyl ] thiophene-2-formamide which is confirmed by spectral analysis, and the chemical structural formula is shown as the following formula I:
formula I
Impurity (formula I) mass spectra results are as follows: MS-ESI (m/z): [ M + H ]]+393.9, corresponding to the molecular weight of the target compound formula I. The map is shown in figure 1.
The carbon spectrum and the hydrogen spectrum are analyzed as follows:
1H-NMR（CDCl3）δ（ppm）：2.021（s，3H，C1-H），3.576-3.603（t，2H，C11-H），3.780-3.818（m，1H，C10-H），4.113-4.157（t，1H，C10-H），4.789-4.824（m，1H，C9-H），7.179-7.189（d，1H，C15-H），7.430-7.452（d，2H，C6-H+C6＇-H），7.556-7.578（d，2H,C5-H +C5＇-H），7.676-7.686（d，1H，C14-H），8.954-8.981（t，1H，N18-H），9.937（s，1H，N3-H). The map is shown in FIG. 2.13C-NMR（CDCl3）δ（ppm）：23.847（C1），42.282（C11），47.569（C10），71.162（C9），118.482（C5+C5＇），119.333（C6+C6＇），127.991（C15），128.405（C14），133.338（C13），133.542（C7），135.280（C4），138.503（C16），154.180（C8），160.859（C12），168.190（C2). The map is shown in FIG. 3.
The impurities (shown in formula I) in the rivaroxaban bulk drug are analyzed and detected by adopting a high performance liquid chromatography, a chromatographic column is a C18 column, a mobile phase A is a 0.01mol/L phosphoric acid solution, a mobile phase B is an acetonitrile solution, elution is carried out by adopting a gradient elution mode, and the gradient elution procedure is as follows:
| time (min) | A（%） | B（%） |
| 0 | 98 | 2 |
| 5 | 80 | 20 |
| 10 | 80 | 20 |
| 35 | 60 | 40 |
| 40 | 40 | 60 |
| 40.1 | 98 | 2 |
| 45 | 98 | 2 |
Other chromatographic conditions were: the flow rate is 1ml/min, the column temperature is 40 ℃, and the wavelength is 250 nm.
According to chromatograms of a rivaroxaban test sample solution and an impurity sample solution shown in formula I, the content of the impurity shown in formula I in the rivaroxaban sample is 0.11%, and other impurities except 1 impurity is less than 0.05% and less than 0.02%. Therefore, the control of the impurity of formula I is very important in the quality control of rivaroxaban.
Impurity formula I contains no alert structure, is not a genotoxic impurity, and is a single impurity in the bulk drug standard with a defined acceptance criterion. The impurity standard of the formula I is determined to be less than 0.15% according to the daily dosage of the rivaroxaban tablet and the impurity content in the rivaroxaban bulk drug.
The present invention provides a process for the preparation of the compound of formula I above:
1) reacting the compound II with the compound III to obtain an intermediate IV;
2) reacting the intermediate IV prepared in the step 1) with N, N-carbonyldiimidazole to obtain an intermediate V;
3) reacting the intermediate V prepared in the step 2) with a methylamine solution to obtain an intermediate VI;
4) and 3) reacting the intermediate VI prepared in the step 3) with 5-chlorothiophene-2-formic acid or 5-chlorothiophene-2-formyl chloride under the action of a condensing agent to obtain the target compound shown in the formula I.
The condensing agent is selected from one or more of N, N-carbonyl diimidazole, dicyclohexyl carbodiimide, diisopropyl carbodiimide and 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride, preferably 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride;
the condensation reaction in the step 4) comprises a catalyst, wherein the catalyst is one or more of N, N-dimethyl pyridine, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazol, N-hydroxysuccinimide and N-hydroxyphthalimide, and preferably 1-hydroxybenzotriazole;
the methylamine solution in the step 3) is one or more of methylamine, methylamine water solution or methylamine methanol solution, preferably methylamine water solution;
the reaction temperature of the step 1), the step 2) and the step 3) is 40-120 ℃, the reaction temperature of the step 4) is-20-60 ℃, wherein the reflux reaction is preferred in the step 1), the step 2) and the step 3), and the reaction temperature of the step 4) is preferably 20-40 ℃;
the reaction solvent in the step 1) is alcohol or a mixed solution of alcohol and water, the alcohol is one or more of methanol, ethanol and isopropanol, and preferably the isopropanol
The reaction solvent in the step 2) is tetrahydrofuran, toluene or dichloromethane, preferably tetrahydrofuran
The reaction solvent in the step 3) is alcohol, the alcohol is one or more of methanol, ethanol and isopropanol, and preferably methanol
The reaction solvent in the step 4) is N, N-dimethylformamide or water, preferably N, N-dimethylformamide;
the molar ratio of the compound II to the compound III in the step 1) is 1: 0.9-2.0, preferably 1: 1.2;
the mol ratio of the intermediate IV to the N, N-carbonyl diimidazole in the step 2) is 1: 1.2-5.0, preferably 1: 4.0;
the mol ratio of the intermediate V to the methylamine solution in the step 3) is 1: 1.0-6.0, preferably 1: 3.5;
the mol ratio of the intermediate VI in the step 4) to the 5-chlorothiophene-2-formic acid or the 5-chlorothiophene-2-formyl chloride to the condensing agent to the catalyst is 1: 0.9-2.0: 1.0-2.0, preferably 1:1.2:1.3: 1.5.
Drawings
FIGS. 1-3 are spectrograms of formula I obtained in accordance with an embodiment of the present invention, wherein:
FIG. 1 is a mass spectrum;
FIG. 2 is a nuclear magnetic hydrogen spectrum;
FIG. 3 is a nuclear magnetic carbon spectrum;
FIG. 4 is a high performance liquid chromatogram of rivaroxaban drug obtained in example 1 of the present invention;
FIG. 5 is a high performance liquid chromatogram of formula I obtained in example 6;
Detailed Description
The present application is described in further detail below with reference to specific embodiments and the attached drawings. The following examples are intended to be illustrative of the present application only and should not be construed as limiting the present application.
The reagents and starting materials used in the present invention are commercially available.
Example 1 preparation of rivaroxaban starting material
The method comprises the following steps: in a 500ml three-necked flask, 10g of 4- (4-aminophenyl) -3-morpholinone, 12.68g of (S) -N-epoxypropylphthalimide and 200ml of isopropanol were charged, heated to reflux, and reacted at reflux for 16 hours. The system was cooled to room temperature, filtered, the solid washed with 10ml isopropanol and air dried at 70 ℃ for 8h to give 18.37g of a white solid in 89.3% yield.
Step two: 18.30g of the above white solid, 30.01g N, N-carbonyldiimidazole and 220ml of tetrahydrofuran were charged in a 500ml three-necked flask, heated to reflux, and reacted under reflux for 4 hours. The system was cooled to room temperature, filtered, the solid washed with 20ml tetrahydrofuran and air dried at 60 ℃ for 8h to give 17.55g of off-white solid in 90.0% yield.
Step three: heating 17.00g of the off-white solid, 12.53g of methylamine water solution and 360ml of methanol to reflux, carrying out reflux reaction for 2 hours, cooling to 15 ℃, adjusting the pH to be = 1-2 by using concentrated sulfuric acid, and filtering to obtain 11.24g of the white solid with the yield of 85.0%.
Step four: 11.00g of the above white solid, 7.10g of 5-chlorothiophene-2-carboxylic acid, 8.35g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 6.76g of 1-hydroxybenzotriazole, 13.03g N, N-diisopropylethylamine and 44ml of N, N-dimethylformamide were put into a 250ml three-necked flask and reacted for 3 hours at room temperature, after the reaction was completed, the reaction mixture was added to 176ml of water, filtered, and the solid was dried by blowing at 70 ℃ for 8 hours to obtain a white-like solid, and then recrystallized from 200ml of a glacial acetic acid-acetonitrile mixture at a volume ratio of 5:1 to obtain a white-like solid, and then from glacial acetic acid to obtain 10.08g of a white-like powdery solid, with a yield of 68.9% and a purity of 99.74% (area normalization).
EXAMPLE 2 preparation of Compounds of formula I
The method comprises the following steps: in a 500ml three-necked flask, 10g (0.066 mol) of 4-aminoacetanilide, 17.59g (0.086 mol) of 4- (4-aminophenyl) morpholin-3-one and 200ml of isopropanol were added, heated to reflux and reacted for 16 hours under reflux. The system was cooled to room temperature, filtered, the solid washed with 10ml isopropanol and air dried at 70 ℃ for 8h to give 22.07g of a yellow solid in 93.8% yield.
Step two: 22g (0.062 mol) of the yellow solid described above, 40.38g (0.249 mol) of N, N-carbonyldiimidazole and 220ml of tetrahydrofuran were charged into a 500ml three-necked flask, heated to reflux and reacted at reflux for 4 hours. The system was cooled to room temperature, filtered, the solid washed with 20ml tetrahydrofuran and air dried at 60 ℃ for 8h to give 18.12g of off-white solid in 76.7% yield.
Step three: 18.00g (0.047 mol) of the off-white solid, 17.20g (0.166 mol) of an aqueous methylamine solution and 360ml of methanol were heated to reflux, reacted overnight under reflux, and the reacted solution was spin-dried to obtain an oil.
Step four: after the oily substance was dissolved in 120ml of N, N-dimethylformamide, 5.58g of 5-chlorothiophene-2-carboxylic acid, 6.60g of 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride and 5.34g of 1-hydroxybenzotriazole were added with stirring to react at room temperature for 2 hours, after the reaction was completed, filtration was carried out, the solid was washed with 12ml of N, N-dimethylformamide and air-dried at 70 ℃ for 8 hours to obtain 9.36g of an off-white solid, which was recrystallized from 200ml of a glacial acetic acid-acetonitrile mixture having a volume ratio of 5:1 to obtain 7.06g of an off-white solid powdery compound with a purity of 98.5%.
EXAMPLE 3 preparation of Compounds of formula I
The method comprises the following steps: in a 500ml three-necked flask, 20g (0.133 mol) of 4-aminoacetanilide, 35.18g (0.173 mol) of 4- (4-aminophenyl) morpholin-3-one, 360ml of absolute ethanol and 40ml of water were charged, heated to reflux, and reacted at reflux overnight. The system was cooled to room temperature, filtered, the solid washed with 20ml absolute ethanol and air dried at 70 ℃ for 8h to give 42.26g of a yellow solid with a yield of 89.8%.
Step two: 42.26g (0.12 mol) of the above yellow solid, 77.51g (0.478 mol) of N, N-carbonyldiimidazole and 400ml of methylene chloride were put into a 500ml three-necked flask, heated to reflux, and reacted under reflux for 4 hours 10 h. The reaction was concentrated to dryness, 400ml of tetrahydrofuran was added to the residue, stirred at room temperature for 1h, filtered, the solid was washed with 40ml of tetrahydrofuran and air-dried at 60 ℃ for 8h to give 35.88g of off-white solid in 79.1% yield.
Step three: 35.00g (0.091 mol) of the off-white solid, 33.4g (0.323 mol) of methylamine methanol solution and 700ml of methanol were heated to reflux, and the reaction was performed overnight under reflux, and the reacted solution was spin-dried to obtain an oil.
Step four: after the oily substance was dissolved in 240ml of N, N-dimethylformamide, 10.85g of 5-chlorothiophene-2-carboxylic acid, 12.83g of 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride and 10.38g of 1-hydroxybenzotriazole were added with stirring to react at room temperature for 2 hours, after the reaction was completed, the mixture was filtered, the solid was washed with 25ml of N, N-dimethylformamide and air-dried at 70 ℃ for 8 hours to obtain 19.04g of an off-white solid, which was recrystallized from 400ml of a glacial acetic acid-acetonitrile mixture having a volume ratio of 5:1 to obtain 14.52g of an off-white solid powdery compound with a purity of 98.8%.
EXAMPLE 4 preparation of Compounds of formula I
The method comprises the following steps: in a 500ml three-necked flask, 20g (0.133 mol) of 4-aminoacetanilide, 35.18g (0.173 mol) of 4- (4-aminophenyl) morpholin-3-one and 400ml of isopropanol were added, heated to reflux and reacted at reflux overnight. The system was cooled to room temperature, filtered, the solid washed with 20ml isopropanol and air dried at 70 ℃ for 8h to give 40.15g of a yellow solid in 85.3% yield.
Step two: 40.15g of the above yellow solid, 73.64g of N, N-carbonyldiimidazole and 400ml of tetrahydrofuran were charged in a 500ml three-necked flask, heated to reflux, and reacted under reflux for 4 hours. The system was cooled to room temperature, filtered, the solid washed with 40ml tetrahydrofuran and air dried at 60 ℃ for 8h to give an off-white solid 34.22g with a yield of 79.4%.
Step three: 34.22g of the above off-white solid, 32.66g of an aqueous methylamine solution and 700ml of methanol were heated to reflux, reacted overnight under reflux, and the reacted solution was spin-dried to obtain an oil.
Step four: after the oily substance was dissolved in 240ml of N, N-dimethylformamide, 10.61g of 5-chlorothiophene-2-carboxylic acid, 8.45g of diisopropylcarbodiimide and 7.85g N-hydroxysuccinimide were added with stirring to react at room temperature for 2 hours, after the reaction was completed, the mixture was filtered, the solid was washed with 25ml of N, N-dimethylformamide and air-dried at 70 ℃ for 8 hours to obtain 18.54g of an off-white solid, and then recrystallized from 400ml of a glacial acetic acid-acetonitrile mixed solution at a volume ratio of 5:1 to obtain 13.32g of an off-white solid powdery compound with a purity of 98.8%.
EXAMPLE 5 preparation of Compounds of formula I
The method comprises the following steps: in a 500ml three-necked flask, 20g (0.133 mol) of 4-aminoacetanilide, 35.18g (0.173 mol) of 4- (4-aminophenyl) morpholin-3-one and 400ml of isopropanol were added, heated to reflux and reacted at reflux overnight. The system was cooled to room temperature, filtered, the solid washed with 20ml isopropanol and air dried at 70 ℃ for 8h to give 43.62g of a yellow solid in 92.7% yield.
Step two: 43.62g of the above yellow solid, 80.00g N, N-carbonyldiimidazole and 420ml of tetrahydrofuran were charged in a 500ml three-necked flask, heated to reflux, and reacted under reflux for 4 hours. The system was cooled to room temperature, filtered, the solid washed with 40ml tetrahydrofuran and air dried at 60 ℃ for 8h to give an off-white solid 36.32g with a yield of 79.1% 77.6%.
Step three: 36.32g of the above off-white solid, 34.76g of an aqueous methylamine solution and 700ml of methanol were heated to reflux, reacted overnight under reflux, and the reacted solution was spin-dried to obtain an oil.
Step four: after the oily matter is dissolved by 240ml of N, N-dimethylformamide, 11.26g of 5-chlorothiophene-2-formic acid, 10.85g N, N-carbonyldiimidazole and 11.27g N-hydroxyphthalimide are added under stirring to react for 2 hours at room temperature, after the reaction is finished, the mixture is filtered, the solid is washed by 25ml of N, N-dimethylformamide and dried by blowing at 70 ℃ for 8 hours to obtain 19.77g of off-white solid, and then 400ml of glacial acetic acid-acetonitrile mixed liquid with the volume ratio of 5:1 is used for recrystallization to obtain 15.87g of off-white solid powdery compound with the purity of 97.6%.
Example 6: detection of rivaroxaban and compounds of formula I by high performance liquid chromatography
The chromatographic conditions were as follows:
a chromatographic column: octadecylsilane chemically bonded silica as filler (Purospher Star RP-18 endcapped, 4.0 mm. times.55 mm, 3 μm)
Mobile phase: using 0.01mol/L phosphoric acid solution (85% phosphoric acid 11.5g or 6.7ml, diluted with water to 10.0L) as mobile phase A, and acetonitrile as mobile phase B
Flow rate: 1ml/min
Column temperature: 40 deg.C
Wavelength: 250nm
Gradient elution order:
| time (min) | A（%） | B（%） |
| 0 | 98 | 2 |
| 5 | 80 | 20 |
| 10 | 80 | 20 |
| 35 | 60 | 40 |
| 40 | 40 | 60 |
| 40.1 | 98 | 2 |
| 45 | 98 | 2 |
Preparing a rivaroxaban sample: weighing a proper amount of rivaroxaban sample obtained in example 1, precisely weighing, adding acetonitrile-water (60: 40) to dissolve and dilute the sample to prepare a solution containing about 1mg of rivaroxaban in 1ml, and shaking up to obtain the rivaroxaban. HPLC sample introduction 5 μ l, chromatogram recording shown in figure 4
Table 1: FIG. 4 related parameters of detection spectra
| Peak number | Retention time | Area of | Theoretical plate number (USP) | Tailing factor | Degree of separation (USP) | |
| 1 | 10.742 | 803 | 49530 | 1.042 | / | 120 |
| 2 | 11.428 | 1983 | 27065 | 0.962 | 2.915 | 191 |
| 3 | 12.154 | 2914 | 77767 | 1.233 | 3.210 | 466 |
| 4 | 13.229 | 1822 | 103002 | 1.157 | 6.340 | 317 |
| 5 | 15.060 | 609 | 99000 | 1.138 | 10.272 | 88 |
| 6 | 21.232 | 4582 | 165571 | 0.905 | 30.849 | 587 |
| 7 | 22.617 | 726 | 222907 | 1.051 | 6.919 | 109 |
| 8 | 25.623 | 635 | 293446 | 0.896 | 15.786 | 94 |
| 9 | 27.307 | 11906 | 213135 | 1.066 | 7.913 | 1393 |
| 10 | 27.637 | 820 | 306604 | 1.094 | 1.513 | 114 |
| 11 | 28.060 | 3741 | 219196 | 1.063 | 1.923 | 433 |
| 12 | 28.793 | 29016 | 217397 | 1.060 | 3.014 | 3222 |
| 13 | 29.498 | 25371409 | 210867 | 0.941 | 2.796 | 2651294 |
| 14 | 33.336 | 1279 | 386097 | / | 16.279 | 172 |
| 15 | 33.532 | 1216 | 377918 | / | 0.905 | 166 |
| 16 | 33.728 | 1341 | 555362 | / | 0.980 | 214 |
| 17 | 35.235 | 2548 | 585665 | 1.060 | 8.255 | 394 |
| 18 | 38.275 | 588 | 933594 | 1.105 | 17.743 | 111 |
| Total of | 25437939 | 2659485 |
Impurity formula I sample preparation: weighing a proper amount of rivaroxaban impurity sample of the formula I, precisely weighing, adding acetonitrile-water (60: 40) for dissolving and diluting to prepare a solution containing 0.15 mu g of rivaroxaban impurity in each 1ml, and shaking up to obtain the rivaroxaban impurity. HPLC sample introduction 5 μ l, chromatogram recording shown in figure 5
Table 2: FIG. 5 related parameters of the detection map
| Peak number | Retention time | Area of | Theoretical plate number (USP) | Tailing factor | Degree of separation (USP) | |
| 1 | 6.352 | 2348 | 3849 | 0.919 | / | 141 |
| 2 | 10.022 | 8728 | 27312 | / | 11.255 | 1044 |
| 3 | 10.224 | 7206 | 40829 | / | 0.906 | 1033 |
| 4 | 10.940 | 1861 | 41584 | 1.093 | 3.434 | 239 |
| 5 | 13.905 | 43572 | 70951 | 1.199 | 14.010 | 5712 |
| 6 | 19.186 | 28295 | 107974 | 1.294 | 23.873 | 3310 |
| 7 | 23.339 | 3863 | 64830 | 1.346 | 13.839 | 275 |
| 8 | 25.350 | 1115 | 139484 | 0.952 | 6.302 | 111 |
| 9 | 26.551 | 12442 | 177971 | 1.112 | 4.593 | 1344 |
| 10 | 27.681 | 29527 | 181797 | 1.140 | 4.417 | 3056 |
| 11 | 28.745 | 98622834 | 188542 | 1.039 | 4.058 | 998546 |
| 12 | 31.259 | 2249 | 241306 | 1.026 | 9.680 | 242 |
| 13 | 33.978 | 1026 | 421130 | / | 11.721 | 130 |
| Total of | 10005064 | 1015183 |
According to the results shown in the attached figures 4 and 5, the content of the impurity of formula I in the rivaroxaban sample is 0.11% by using the peak area calculation of an external standard method, and the content of other impurities except 1 impurity is less than 0.02% by about 0.05%.
The foregoing is a more detailed description of the present application in connection with specific embodiments thereof, and it is not intended that the present application be limited to the specific embodiments thereof. For those skilled in the art to which the present application pertains, several simple deductions or substitutions may be made without departing from the concept of the present application, and all should be considered as belonging to the protection scope of the present application.
Claims (12)
1. Formula (II)
Application of compound in quality control of valsa production
2. Use according to claim 1, characterized by the formula
The weight of the rivaroxaban drug is not more than 0.15 percent of the weight of the rivaroxaban drug.
3. The compound of claim 1 of the formulaThe preparation method of the compound comprises the following steps:
1) reacting the compound II with the compound III to obtain an intermediate IV;
2) reacting the intermediate IV prepared in the step 1) with N, N-carbonyldiimidazole to obtain an intermediate V;
3) reacting the intermediate V prepared in the step 2) with a methylamine solution to obtain an intermediate VI;
4) the intermediate VI prepared in the step 3) reacts with 5-chlorothiophene-2-formic acid or 5-chlorothiophene-2-formyl chloride under the action of a condensing agent to obtain a compound formula
。
4. The production method according to claim 3, wherein the condensing agent in the step 4) is one or more selected from the group consisting of N, N-carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride.
5. The method according to claim 3, wherein the condensation reaction of step 4) comprises a catalyst.
6. The preparation method according to claim 5, wherein the catalyst is one or more of N, N-lutidine, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazol, N-hydroxysuccinimide and N-hydroxyphthalimide.
7. The method according to claim 3, wherein the methylamine solution in step 3) is one or more selected from methylamine, an aqueous methylamine solution and a methylamine methanol solution.
8. The method according to claim 3, wherein the reaction temperature in the step 1), the step 2), and the step 3) is 40 to 120 ℃ and the reaction temperature in the step 4) is-20 to 60 ℃.
9. The method according to claim 3, wherein the reaction solvent in step 1) is an alcohol or a mixed solution of an alcohol and water, the reaction solvent in step 2) is tetrahydrofuran, toluene or dichloromethane, the reaction solvent in step 3) is an alcohol, and the reaction solvent in step 4) is N, N-dimethylformamide or water.
10. The method according to claim 9, wherein the alcohol is one or more selected from methanol, ethanol, and isopropanol.
11. The process according to claim 3, wherein the molar ratio of the compound II to the compound III in step 1) is 1: 0.9-2.0, the molar ratio of the intermediate IV to N, N-carbonyldiimidazole in step 2) is 1: 1.2-5.0, and the molar ratio of the intermediate V to the methylamine solution in step 3) is 1: 1.0-6.0.
12. The preparation method as claimed in claim 6, wherein the molar ratio of the intermediate VI in step 4) to the 5-chlorothiophene-2-carboxylic acid or 5-chlorothiophene-2-carbonyl chloride to the condensing agent to the catalyst is 1: 0.9-2.0: 1.0-2.0.
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| CN106432218A (en) * | 2015-12-18 | 2017-02-22 | 重庆植恩药业有限公司 | Rivaroxaban impurities and preparing method and application thereof |
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