CN111333635A - Rivaroxaban impurity reference substance and preparation method thereof - Google Patents

Abstract

The invention discloses a rivaroxaban impurity reference substance. The full name of the impurity reference substance is: ( S )-N1 ^- methyl- ^N2 -((2-oxa-3-(4-(3- oxomorpholino) phenyl)-5-oxazolidinyl) methyl) phthalamide, the invention also discloses the synthetic method of this impurity reference substance, comprises phthalic anhydride and methylamine aqueous solution The reaction generates 2-(methylcarbamoyl)benzoic acid, and then reacts with the rivaroxaban intermediate RVXB-3 through a coupling agent under the action of a solid base to obtain the target rivaroxaban impurity reference substance. The rivaroxaban impurity preparation process of the invention is simple and high in purity, and can provide a qualified rivaroxaban impurity reference substance for the quality control of rivaroxaban.

Description

A kind of rivaroxaban impurity reference substance and preparation method thereof

technical field

The invention relates to pharmaceutical impurities, in particular to a rivaroxaban impurity reference substance and a preparation method thereof.

Background technique

The type and content of impurities in a drug have a significant impact on the efficacy and safety of the drug. Therefore, a comprehensive analysis of the drug impurity profile must be carried out during the process of drug process development. The impurity profile is a general description of all known and unknown impurities present in a drug product, including not only identified impurities (that is, impurities whose structural characteristics have been confirmed), specific impurities (that is, those that are specified in the specification and have their own limits) Standard identified or unidentified impurities), but also potential impurities (that is, impurities that may be theoretically speculated to be generated during production or storage, but not necessarily present in actual products).

Rivaroxaban (Rivaroxaban, structural formula shown in formula II) is the world's first highly selective oral anticoagulant that directly inhibits factor Xa, mainly used to prevent deep vein thrombosis (DVT) in patients after hip and knee replacements And the formation of pulmonary embolism (PE), it was officially launched in China in June 2009 under the trade name Xarelto.

SUMMARY OF THE INVENTION

Purpose of the invention: The technical problem to be solved by the present invention is to provide a rivaroxaban impurity reference substance. The full name of the impurity reference substance: (S)-N ¹ -methyl-N2-((2-oxa-3-(4-(3-oxomorpholino)phenyl)-5-oxazolidine group) methyl) phthalamide.

According to the existing rivaroxaban process synthesis route combined with impurity spectrum analysis, the structure of formula I of the present invention is a potential process impurity in the rivaroxaban synthesis process, and the quality, safety and efficacy must be scientifically evaluated before the drug is put on the market. , drug impurities are closely related to drug quality and drug safety, and the impurity reference substance can help determine the reasonable limit of impurities, which will greatly promote the establishment of drug testing methods and quality standards. The rivaroxaban of the present invention The impurity reference substance is not only an important supplement to the impurity profile of rivaroxaban, but also provides an important reference for the monitoring of this impurity in the process development of rivaroxaban.

The technical problem to be solved in the present invention is to provide a method for preparing the impurity reference substance with a simple process and high product purity, so as to provide a qualified impurity reference substance for the quality control of rivaroxaban.

Technical scheme: The present invention provides a kind of rivaroxaban impurity reference substance, and this impurity structural formula is shown in formula I:

Another aspect of the present invention provides the preparation method of the above-mentioned rivaroxaban impurity reference substance, and the preparation method is as follows:

(1) after phthalic anhydride and reaction solvent are mixed, add methylamine aqueous solution to react, generate 2-(methylcarbamoyl) benzoic acid, step 1) reaction formula is as follows:

(2) under the action of solid base, the 2-(methylcarbamoyl) benzoic acid obtained in step 1) reacts with RvXB-3 through a coupling agent to obtain the rivaroxaban impurity of the structure shown in formula I ; The reaction formula of step 2) is as follows:

Wherein, step 1) the molar ratio of phthalic anhydride and methylamine is 1:2～1:5; the reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate One or more of ester, acetone and acetonitrile; the reaction temperature is 25°C to 60°C, and the reaction time is 2 to 5 hours.

Wherein, step 2) coupling agent is isobutyl chloroformate, the molar ratio of isobutyl chloroformate and RVXB-3 is 1: 1～3: 1; The solid base used is sodium carbonate, potassium carbonate, sodium bicarbonate and Potassium bicarbonate; the molar ratio of solid base to RVXB-3 is 5:1～8:1; the reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, acetone , one or more of acetonitrile; the reaction temperature is 0 ℃～25 ℃, and the reaction time is 6～8 hours.

Reaction mechanism: the anhydrous solid base of the present invention plays two roles at the same time. On the one hand, the anhydrous solid base can absorb water in the methylamine aqueous solution and greatly reduce the adverse effect of water on the coupling agent isobutyl chloroformate. The action of the acid binding agent promotes the reaction between the coupling agent isobutyl chloroformate and 2-(methylcarbamoyl) benzoic acid to form a mixed acid anhydride to activate the carboxyl group. By using the solid base and the coupling agent together, there is no need to separate the intermediate 2-(methylcarbamoyl)benzoic acid, and the two-step reaction is carried out continuously, which greatly simplifies the synthesis steps, and the solid base can be effectively separated from the product by simple filtration. .

Beneficial effects: the preparation method of the rivaroxaban impurity reference substance shown in the structure of formula I provided by the present invention has simple process and high purity, and can provide qualified impurity reference substance for the quality control of rivaroxaban. The reaction conditions of the invention are mild, the two-step reaction can be carried out in a one-pot reaction, the intermediate product does not need to be separated and reacted, the steps are simple and efficient, and the reaction yield is high.

Description of drawings

Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of rivaroxaban impurity reference substance of the present invention;

Fig. 2 rivaroxaban impurity reference substance carries out mass spectrometry analysis;

Figure 3. High performance liquid chromatogram of rivaroxaban impurity reference substance.

Detailed ways

The sources of medicines used in the present invention are as follows:

RVXB-3 was provided by Jiangsu Zhongbang Pharmaceutical Co., Ltd.; the rest of the drugs were purchased from Sinopharm.

Example 1

The preparation method of rivaroxaban impurity reference substance is as follows:

1) Phthalic anhydride (2 mmol) and N,N-dimethylformamide (15 mL) were added to a round-bottomed flask, stirred to dissolve, and then slowly added dropwise methylamine solution (8 mmol), followed by stirring at 25° C. for 5 hours.

2) After adding sodium bicarbonate (14mmol) to above-mentioned reaction solution, after stirring for 30min, cooling to 0°C, adding isobutyl chloroformate (4mmol) and continuing to stir and react for 30min, adding RVXB-3 (2mmol), reacting after 8 hours The solvent was removed under reduced pressure, water (20 mL) and dichloromethane (30 mL) were added, the organic phase was separated and washed successively with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the column chromatography ( Dichloromethane and methanol as eluents) isolated as a white solid (65% yield).

Example 2

The preparation method of rivaroxaban impurity reference substance is as follows:

1) Phthalic anhydride (2 mmol) and acetone (20 mL) were added to a round-bottomed flask, stirred and dissolved, and methylamine solution (4 mmol) was slowly added dropwise, reacted at 60° C. for 2 hours, and then cooled to room temperature.

2) Sodium carbonate (10mmol) was added to the above-mentioned reaction solution, isobutyl chloroformate (2mmol) was added after stirring for 30min and the reaction was continued for 30min, RVXB-3 (2mmol) was added, and the solvent was removed under reduced pressure after 6 hours of reaction, Water (20 mL) and dichloromethane (30 mL) were added, and the organic phase was separated and washed with saturated sodium bicarbonate and saturated sodium chloride successively, dried over anhydrous sodium sulfate, and the organic phase was concentrated. eluent) isolated as a white solid (62% yield).

Example 3

The preparation method of rivaroxaban impurity reference substance is as follows:

1) Phthalic anhydride (2 mmol) and ethyl acetate (30 mL) were added to a round-bottomed flask, stirred and dissolved, and methylamine solution (10 mmol) was slowly added dropwise, reacted at 40° C. for 4 hours, and then cooled to room temperature.

2) After adding potassium carbonate (16mmol) to the above-mentioned reaction solution, after stirring for 30min, add isobutyl chloroformate (3mmol) and continue stirring the reaction for 30min, add RVXB-3 (2mmol), and remove the solvent under reduced pressure after 6 hours of reaction , water (20 mL) and dichloromethane (30 mL) were added, the organic phase was separated and washed successively with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, the organic phase was concentrated, and subjected to column chromatography (dichloromethane and methanol). as eluent) isolated as a white solid (58% yield).

Example 4

The preparation method of rivaroxaban impurity reference substance is as follows:

1) Phthalic anhydride (2 mmol) and acetonitrile (40 mL) were added to a 50 mL round-bottomed flask, stirred to dissolve, methylamine solution (10 mmol) was slowly added dropwise, reacted at 40° C. for 5 hours, and then cooled to room temperature.

2) After adding potassium bicarbonate (12mmol) to above-mentioned reaction solution, after stirring for 30min, add isobutyl chloroformate (2.5mmol) and continue stirring reaction for 30min, add RVXB-3 (2mmol), react under reduced pressure after 6 hours The solvent was removed, water (20 mL) and dichloromethane (30 mL) were added, the organic phase was separated and washed with saturated sodium bicarbonate and saturated sodium chloride in turn, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the organic phase was subjected to column chromatography (dichloromethane). and methanol as eluent) isolated as a white solid (59% yield).

Example 5

The preparation method of rivaroxaban impurity reference substance is as follows:

1) Add phthalic anhydride (2mmol) and N,N-dimethylacetamide (40mL) to a 50mL round-bottomed flask, stir and dissolve, slowly add methylamine solution (10mmol) dropwise, and react at 45°C for 3 hours, Then cool to room temperature.

2) After adding potassium bicarbonate (12mmol) to above-mentioned reaction solution, after stirring for 30min, add isobutyl chloroformate (2.5mmol) and continue stirring reaction for 30min, add RVXB-3 (1mmol), react under reduced pressure after 6 hours The solvent was removed, water (20 mL) and dichloromethane (30 mL) were added, the organic phase was separated and washed with saturated sodium bicarbonate and saturated sodium chloride in turn, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the organic phase was subjected to column chromatography (dichloromethane). and methanol as eluent) isolated as a white solid (63% yield).

Experimental example:

Product Characterization:

The rivaroxaban impurity reference substance prepared in above-mentioned embodiment 1 is carried out nuclear magnetic analysis:

(1) Carry out nuclear magnetic analysis on the rivaroxaban impurity reference substance 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 analysis (ESI-MS) was performed on the rivaroxaban impurity reference substance in Example 1: m/z=

453.2[M+H]+, m/z=475.2[M+Na]+, the impurity mass spectrum of rivaroxaban is shown in Figure 2.

(3) carry out high performance liquid phase analysis to the rivaroxaban impurity reference substance of embodiment 1, the high performance liquid phase chromatogram of rivaroxaban impurity as shown in Figure 3, the corresponding data such as Table 1, as can be seen from Table 1 It was found to be 99.939% pure.

Table 1

Detector A Chl 237nm

peak# keep time area area% degree of separation Theoretical plate# 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 12004639 100.000

By analyzing the NMR spectrum, it can be concluded that the obtained final product is the target product, and the purity is greater than 99%.

The H NMR spectrum of the rivaroxaban impurity reference substance is shown in Figure 1. The number and chemical shift of the hydrogen protons on the H NMR spectrum are consistent with the impurity structure of the rivaroxaban impurity reference substance. It was concluded that the final product obtained was the target product.

The rivaroxaban impurity reference substance prepared in Examples 2-5 was characterized, and the results were consistent with the characterization conclusion of the impurity reference substance in Example 1.

Claims (10)

1. a rivaroxaban impurity reference substance, is characterized in that, the structural formula of this impurity reference substance is as shown in formula I:

2. the preparation method of rivaroxaban impurity reference substance according to claim 1, is characterized in that, this preparation method comprises the following steps: 1) after phthalic anhydride and reaction solvent are mixed, add methylamine aqueous solution to react and generate 2-(methylcarbamoyl) benzoic acid; 2) under the action of solid base, the 2-(methylcarbamoyl) benzoic acid obtained in step 1) is reacted with RVXB-3 by coupling agent to obtain the rivaroxaban impurity contrast of the structure shown in formula I Taste. 3. preparation method according to claim 2 is characterized in that, in step 1), the molar ratio of phthalic anhydride and methylamine is 1:2～1:5. 4. preparation method according to claim 2 is characterized in that, in step 1), reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, acetone, acetonitrile one or more of them. 5 . The preparation method according to claim 2 , wherein the reaction temperature in step 1) is 25° C. to 60° C., and the reaction time is 2 to 5 hours. 6 . 6. preparation method according to claim 2 is characterized in that, in step 2), coupling agent is isobutyl chloroformate, and the mol ratio of isobutyl chloroformate and RVXB-3 is 1: 1～3: 1 . 7. preparation method according to claim 2 is characterized in that, solid base used in step 2) is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. 8 . The preparation method according to claim 2 , wherein the molar ratio of the solid base to RVXB-3 in step 2) is 5:1 to 8:1. 9 . 9. preparation method according to claim 2 is characterized in that, in step 2), reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, ethyl acetate, acetone, acetonitrile one or more of them. 10 . The preparation method according to claim 2 , wherein the reaction temperature in step 2) is 0° C. to 25° C., and the reaction time is 6 to 8 hours. 11 .

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