CN111333635A - Rivaroxaban impurity reference substance and preparation method thereof - Google Patents
Rivaroxaban impurity reference substance and preparation method thereof Download PDFInfo
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- CN111333635A CN111333635A CN202010302690.1A CN202010302690A CN111333635A CN 111333635 A CN111333635 A CN 111333635A CN 202010302690 A CN202010302690 A CN 202010302690A CN 111333635 A CN111333635 A CN 111333635A
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Abstract
The invention discloses a rivaroxaban impurity reference substance, which is fully called as follows: (S)‑N1-methyl-N2- ((2-oxa-3- (4- (3-oxomorpholino) phenyl) -5-oxazolidinyl) methyl) phthalic acid diamide, and the invention also discloses a synthesis method of the impurity reference substance, which comprises the steps of reacting phthalic anhydride with a methylamine aqueous solution to generate 2- (methylcarbamoyl) benzoic acid, and then reacting the 2- (methylcarbamoyl) benzoic acid with rivaroxaban intermediate RVXB-3 through a coupling agent under the action of solid base to obtain the target rivaroxaban impurity reference substance. The rivaroxaban impurity disclosed by the invention is simple in preparation process and high in purity, and can provide a qualified rivaroxaban impurity reference substance for the quality control of rivaroxaban.
Description
Technical Field
The invention relates to a drug impurity, and particularly relates to a rivaroxaban impurity reference substance and a preparation method thereof.
Background
The type and content of impurities in the drug have great influence on the curative effect and safety of the drug, so the drug impurity spectrum must be comprehensively analyzed in the process of drug process development. The impurity profile is a general description of all known and unknown impurities present in a pharmaceutical product and includes not only identified impurities (i.e., impurities for which structural characteristics have been confirmed), specific impurities (i.e., identified or unidentified impurities for which a quality standard specifies an examination and has its own limits), but also potential impurities (i.e., impurities that may theoretically be generated during production or storage and are not necessarily present in the actual product).
Rivaroxaban (Rivaroxaban, structural formula shown in formula II) is the first global oral anticoagulant with high selectivity and direct factor Xa inhibition, is mainly used for preventing the formation of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) of patients after hip joint and knee joint replacement, is formally marketed in China in 6 months of 2009 and has the trade name of Bairuituo.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to solve the technical problem of providing a rivaroxaban impurity reference substance. The impurity reference substance is totally called as: (S) -N1-methyl-N2- ((2-oxa-3- (4- (3-oxomorpholino) phenyl) -5-oxazolidinyl) methyl) phthalamide.
According to the existing rivaroxaban process synthesis route and impurity spectrum analysis, the structure shown in the formula I is a potential process impurity in the rivaroxaban synthesis process, scientific evaluation on quality, safety and efficiency is required before the medicine is on the market, the medicine impurity is closely related to the medicine quality and the medicine safety, the impurity reference substance can help to determine the reasonable limit of the impurity, and the method plays a great promoting role in establishing a medicine inspection method and a quality standard.
The invention also aims to solve the technical problem of providing a method for preparing the impurity reference substance, which has simple process and high product purity, and provides a qualified impurity reference substance for the quality control of rivaroxaban.
The technical scheme is as follows: the invention provides a rivaroxaban impurity reference substance, wherein the structural formula of the impurity is shown as a formula I:
the invention also provides a preparation method of the rivaroxaban impurity reference substance, which comprises the following steps:
(1) mixing phthalic anhydride and a reaction solvent, adding methylamine water solution for reaction to generate 2- (methyl carbamyl) benzoic acid, wherein the reaction formula in the step 1) is as follows:
(2) under the action of solid alkali, reacting the 2- (methyl carbamoyl) benzoic acid prepared in the step 1) with RvXB-3 through a coupling agent to obtain rivaroxaban impurities with the structure shown in the formula I; the reaction formula of step 2) is as follows:
wherein the molar ratio of the phthalic anhydride to the methylamine in the step 1) is 1: 2-1: 5; the reaction solvent is one or more of N, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, acetone and acetonitrile; the reaction temperature is 25-60 ℃, and the reaction time is 2-5 hours.
Wherein, the coupling agent in the step 2) is isobutyl chloroformate, and the molar ratio of the isobutyl chloroformate to the RVXB-3 is 1: 1-3: 1; the solid alkali is sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; the molar ratio of the solid alkali to the RVXB-3 is 5: 1-8: 1; the reaction solvent is one or more of N, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, acetone and acetonitrile; the reaction temperature is 0-25 ℃, and the reaction time is 6-8 hours.
The reaction mechanism is as follows: the anhydrous solid base has two functions, on one hand, the anhydrous solid base can adsorb water in a methylamine water solution, greatly reduce the adverse effect of the water on the coupling agent isobutyl chloroformate, and simultaneously can play a role of an acid-binding agent to promote the coupling agent isobutyl chloroformate to react with 2- (methyl carbamoyl) benzoic acid to form mixed anhydride activated carboxyl. The solid alkali and the coupling agent are used together, so that the intermediate 2- (methyl carbamyl) benzoic acid does not need to be separated, the two-step reaction is continuously carried out, the synthetic steps are greatly simplified, and the solid alkali can be effectively separated from the product by simple filtration.
Has the advantages that: the preparation method of the rivaroxaban impurity reference substance shown in the structure of the formula I, provided by the invention, is simple in process and high in purity, and can provide a qualified impurity reference substance for quality control of rivaroxaban. The reaction conditions are mild, the two-step reaction can be carried out in one-pot reaction, the intermediate product does not need to be separated, and the steps are simple and efficient; the reaction yield is high.
Drawings
FIG. 1 is a NMR chart of a rivaroxaban impurity control of the present invention;
FIG. 2 shows mass spectrometry of rivaroxaban impurity control;
FIG. 3 is a high performance liquid chromatography of rivaroxaban impurity control.
Detailed Description
The sources of the drugs used in the present invention are as follows:
RVXB-3 is provided by Jiangsu Zhongbang pharmaceutical Co., Ltd; the rest of the drugs are purchased from Chinese herbs.
Example 1
The preparation method of the rivaroxaban impurity reference substance comprises the following steps:
1) phthalic anhydride (2mmol) and N, N-dimethylformamide (15mL) were added to a round-bottomed flask and dissolved with stirring, then methylamine solution (8mmol) was slowly added dropwise and stirred at 25 ℃ for 5 hours.
2) Adding sodium bicarbonate (14mmol) into the reaction liquid, stirring for 30min, cooling to 0 ℃, adding isobutyl chloroformate (4mmo1), continuing to stir for 30min, adding RVXB-3(2mmol), removing the solvent under reduced pressure after reacting for 8 h, adding water (20mL) and dichloromethane (30mL), separating an organic phase, washing the organic phase with saturated sodium bicarbonate and saturated sodium chloride in sequence, drying the organic phase with anhydrous sodium sulfate, concentrating the organic phase, and separating by column chromatography (dichloromethane and methanol are eluent) to obtain a white solid (yield is 65%).
Example 2
The preparation method of the rivaroxaban impurity reference substance comprises the following steps:
1) phthalic anhydride (2mmol) and acetone (20mL) were added to a round-bottom flask and dissolved with stirring, then methylamine solution (4mmol) was slowly added dropwise, reacted at 60 ℃ for 2 hours, and then cooled to room temperature.
2) Adding sodium carbonate (10mmol) into the reaction solution, stirring for 30min, adding isobutyl chloroformate (2mmol), stirring for 30min, adding RVXB-3(2mmol), reacting for 6 h, removing solvent under reduced pressure, adding water (20mL) and dichloromethane (30mL), separating organic phase, washing with saturated sodium bicarbonate and saturated sodium chloride, drying over anhydrous sodium sulfate, concentrating the organic phase, and separating by column chromatography (dichloromethane and methanol are eluent) to obtain white solid (yield 62%).
Example 3
The preparation method of the rivaroxaban impurity reference substance comprises the following steps:
1) phthalic anhydride (2mmol) and ethyl acetate (30mL) were added to a round-bottomed flask, stirred to dissolve, and then methylamine solution (10mmol) was slowly added dropwise, reacted at 40 ℃ for 4 hours, and then cooled to room temperature.
2) Adding potassium carbonate (16mmol) into the reaction liquid, stirring for 30min, adding isobutyl chloroformate (3mmol), continuing to stir for reaction for 30min, adding RVXB-3(2mmol), reacting for 6 h, removing the solvent under reduced pressure, adding water (20mL) and dichloromethane (30mL), separating an organic phase, washing with saturated sodium bicarbonate and saturated sodium chloride in turn, drying over anhydrous sodium sulfate, concentrating the organic phase, and separating by column chromatography (dichloromethane and methanol are eluent) to obtain a white solid (yield is 58%).
Example 4
The preparation method of the rivaroxaban impurity reference substance comprises the following steps:
1) phthalic anhydride (2mmol) and acetonitrile (40mL) were added to a 50mL round-bottomed flask and dissolved with stirring, followed by slow dropwise addition of methylamine solution (10mmol), reaction at 40 ℃ for 5 hours, and cooling to room temperature.
2) Adding potassium bicarbonate (12mmol) into the reaction liquid, stirring for 30min, adding isobutyl chloroformate (2.5mmol), continuing to stir for 30min, adding RVXB-3(2mmol), removing the solvent under reduced pressure after reacting for 6 h, adding water (20mL) and dichloromethane (30mL), separating an organic phase, washing with saturated sodium bicarbonate and saturated sodium chloride in sequence, drying over anhydrous sodium sulfate, concentrating the organic phase, and separating by column chromatography (dichloromethane and methanol are eluent) to obtain a white solid (yield 59%).
Example 5
The preparation method of the rivaroxaban impurity reference substance comprises the following steps:
1) phthalic anhydride (2mmol) and N, N-dimethylacetamide (40mL) were added to a 50mL round-bottomed flask, stirred to dissolve, and then a methylamine solution (10mmol) was slowly added dropwise, reacted at 45 ℃ for 3 hours, and then cooled to room temperature.
2) Adding potassium bicarbonate (12mmol) into the reaction liquid, stirring for 30min, adding isobutyl chloroformate (2.5mmol), continuing to stir for 30min, adding RVXB-3(1mmol), removing the solvent under reduced pressure after reacting for 6 h, adding water (20mL) and dichloromethane (30mL), separating an organic phase, washing with saturated sodium bicarbonate and saturated sodium chloride in sequence, drying over anhydrous sodium sulfate, concentrating the organic phase, and separating by column chromatography (dichloromethane and methanol are eluent) to obtain a white solid (yield is 63%).
Experimental example:
and (3) product characterization:
nuclear magnetic analysis was performed on the rivaroxaban impurity control prepared in example 1 above:
(1) nuclear magnetic analysis was performed on the rivaroxaban impurity control prepared in example 1: 1H-NMR (500MHz, d)6-DMSO)8.60(1H，t)，8.19(1H，m)，7.60(2H，d)，7.46(3H，m)，7.40(2H，d)，7.39(1H，m)，4.82(1H，m)，4.19(2H，s)，4.16(1H，t)，4.14(1H，t)，4.01(1H，m)，3.97(2H，m)，3.71(2H，m)，3.58(2H，m)，2.70(3H，d)。
(2) Mass spectrometry (ESI-MS) was performed on the rivaroxaban impurity control of example 1: m/z ═
453.2[ M + H ] +, M/z 475.2[ M + Na ] +, rivaroxaban impurity mass spectrum as shown in FIG. 2.
(3) The rivaroxaban impurity control of example 1 was subjected to hplc analysis, the hplc profile of the rivaroxaban impurity is shown in fig. 3, the corresponding data are shown in table 1, and the purity of the rivaroxaban impurity is 99.939% as shown in table 1.
TABLE 1
Detector A Chl 237nm
| Peak # | Retention time | Area of | Area% | Degree of separation | |
| 1 | 3.526 | 2932 | 0.024 | 0.000 | 966.640 |
| 2 | 11.420 | 11997366 | 99.939 | 24.101 | 51406.184 |
| 3 | 12.277 | 4341 | 0.036 | 3.413 | 26606.190 |
| Total of | 12004639 | 100.000 |
By analyzing the nuclear magnetic mass spectrum, the conclusion can be drawn that the obtained final product is a target product and the purity is more than 99%.
The nuclear magnetic hydrogen spectrum of the rivaroxaban impurity reference substance is shown in figure 1, the number and chemical shift of hydrogen protons on the nuclear magnetic hydrogen spectrum are consistent with the impurity structure of the rivaroxaban impurity reference substance, and the nuclear magnetic mass spectrum is analyzed to draw a conclusion that the obtained final product is a target product.
The rivaroxaban impurity reference substance prepared in the examples 2-5 is characterized, and the result is consistent with the impurity reference substance characterization conclusion in the example 1.
Claims (10)
1. The rivaroxaban impurity reference substance is characterized in that the structural formula of the impurity reference substance is shown as a formula I:
2. the method of preparing a rivaroxaban impurity control of claim 1, comprising the steps of:
1) mixing phthalic anhydride and a reaction solvent, and then adding a methylamine aqueous solution to react to generate 2- (methyl carbamoyl) benzoic acid;
2) under the action of solid alkali, reacting the 2- (methylcarbamoyl) benzoic acid prepared in the step 1) with RVXB-3 through a coupling agent to obtain a rivaroxaban impurity reference substance with a structure shown in a formula I.
3. The method according to claim 2, wherein the molar ratio of phthalic anhydride to methylamine in step 1) is 1: 2 to 1: 5.
4. The preparation method according to claim 2, wherein the reaction solvent in step 1) is one or more of N, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, acetone and acetonitrile.
5. The preparation method according to claim 2, wherein the reaction temperature in the step 1) is 25 ℃ to 60 ℃ and the reaction time is 2 to 5 hours.
6. The method according to claim 2, wherein the coupling agent in step 2) is isobutyl chloroformate, and the molar ratio of isobutyl chloroformate to RVXB-3 is 1: 1-3: 1.
7. The preparation method of claim 2, wherein the solid base used in step 2) is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
8. The method of claim 2, wherein the molar ratio of the solid base to the RVXB-3 in step 2) is from 5: 1 to 8: 1.
9. The preparation method according to claim 2, wherein the reaction solvent in step 2) is one or more selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, ethyl acetate, acetone, and acetonitrile.
10. The preparation method according to claim 2, wherein the reaction temperature in the step 2) is 0 ℃ to 25 ℃ and the reaction time is 6 to 8 hours.
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