Rivaroxaban isopropylidene impurity reference substance and preparation method of reference substance

Abstract

The invention discloses a rivaroxaban isopropylidene impurity reference substance, and a structural formula of the impurity reference substance is shown in the specification. The invention also discloses a preparation method for the impurity reference substance, comprising the following steps: 4-(4-(5-(aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3-morpholine is reacted with mesityl oxide under basicconditions to obtain 4-(4-(5-(((2-methyl-4-oxypenta-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3-morpholinone; 4-(4-(5-(((2-methyl-4-oxypenta-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3-morpholinone is reacted with 5-chlorothiophene-2-formyl chloride under basic conditions to obtain the rivaroxaban isopropylidene impurity reference substance. The method provided by the invention achievesa simple process and high purity, and can provide qualified oxazolidine impurity reference substance for quality control of rivaroxaban.

Description

technical field

[0001] The invention relates to pharmaceutical impurities, in particular to a rivaroxaban propylidene impurity reference substance and a preparation method thereof. Background technique

[0002] Rivaroxaban (formula II) is an orally available, bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require cofactors (such as anticoagulant Blood enzyme III) to exert activity. Activation of factor X to factor Xa (FXa) through intrinsic and extrinsic pathways plays an important role in the blood coagulation cascade.

[0003]

[0004] The synthetic route of rivaroxaban is as follows:

[0005]

[0006] During the synthesis process of rivaroxaban according to the above route, a new isopropylidene impurity was found through impurity analysis. The impurity structure is shown in formula I. This impurity may be a process impurity of varoxaban medicine. This impurity and its synthesis have been reported in public infor...

Examples

Embodiment 1

[0027] The preparation method of the rivaroxaban mesopropylidene impurity reference substance is as follows:

[0028] 1) Take 4.5g (15mmol) of 4-(4-(5-(aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3-morpholinone, add 6.4g (60mmol) Sodium carbonate and 50mL water were stirred until completely dissolved, 1.47g (15mmol) mesityl oxide was added, stirred at 25°C for 12 hours, extracted with dichloromethane, and spin-dried to obtain a white powdery solid, which was obtained by column chromatography 4-( 4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3-morpholinone.

[0029] figure 1 is 4-(4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3- The proton nuclear magnetic resonance spectrum figure of morpholinone intermediate, by figure 1 It can be seen that this example successfully synthesized 4-(4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl ) phenyl) -3-morpholinone intermediate.

[0030] 2) Add 0.1g (0.25mmol) 4...

Embodiment 2

[0034] The preparation method of the rivaroxaban mesopropylidene impurity reference substance is as follows:

[0035] 1) Take 4.5g (15mmol) of 4-(4-(5-(aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3-morpholinone, add 3.2g (30mmol) Sodium bicarbonate and 50mL of water were stirred until completely dissolved, 2.93g (30mmol) of mesityl oxide was added, stirred at 25°C for 12 hours, extracted with dichloromethane, and spin-dried to obtain a white powdery solid, which was obtained by column chromatography 4- (4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3-morpholinone .

[0036] figure 1 is 4-(4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3- The proton nuclear magnetic resonance spectrum figure of morpholinone intermediate, by figure 1 It can be seen that this example successfully synthesized 4-(4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl ) phenyl) -3-morpholinone intermediate.

[0037] 2) Add 0.1g (0...

Embodiment 3

[0041] The preparation of rivaroxaban isopropylidene impurity reference substance is as follows:

[0042] 1) Take 4.5g (15mmol) 4-(4-(5-(aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3-morpholinone, add 1.2g (30mmol) Sodium hydroxide and 50mL of water were stirred until they were completely dissolved, 2.93g (30mmol) of mesityl oxide was added, stirred at 25°C for 12 hours, extracted with dichloromethane, and spin-dried to obtain a white powdery solid, which was obtained by column chromatography 4- (4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3-morpholinone .

[0043] figure 1 is 4-(4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3- The proton nuclear magnetic resonance spectrum figure of morpholinone intermediate, by figure 1It can be seen that this example successfully synthesized 4-(4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl ) phenyl) -3-morpholinone intermediate.

[0044] 2) Add 0.1g (0.25mmol)...

technical field

[0001] The invention relates to pharmaceutical impurities, in particular to a rivaroxaban propylidene impurity reference substance and a preparation method thereof. Background technique

[0002] Rivaroxaban (formula II) is an orally available, bioavailable factor Xa inhibitor that selectively blocks the active site of factor Xa and does not require cofactors (such as anticoagulant Blood enzyme III) to exert activity. Activation of factor X to factor Xa (FXa) through intrinsic and extrinsic pathways plays an important role in the blood coagulation cascade.

[0003]

[0004] The synthetic route of rivaroxaban is as follows:

[0005]

[0006] During the synthesis process of rivaroxaban according to the above route, a new isopropylidene impurity was found through impurity analysis. The impurity structure is shown in formula I. This impurity may be a process impurity of varoxaban medicine. This impurity and its synthesis have been reported in public infor...

Examples

Embodiment 1

[0027] The preparation method of the rivaroxaban mesopropylidene impurity reference substance is as follows:

[0028] 1) Take 4.5g (15mmol) of 4-(4-(5-(aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3-morpholinone, add 6.4g (60mmol) Sodium carbonate and 50mL water were stirred until completely dissolved, 1.47g (15mmol) mesityl oxide was added, stirred at 25°C for 12 hours, extracted with dichloromethane, and spin-dried to obtain a white powdery solid, which was obtained by column chromatography 4-( 4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3-morpholinone.

[0029] figure 1 is 4-(4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3- The proton nuclear magnetic resonance spectrum figure of morpholinone intermediate, by figure 1 It can be seen that this example successfully synthesized 4-(4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl ) phenyl) -3-morpholinone intermediate.

[0030] 2) Add 0.1g (0.25mmol) 4...

Embodiment 2

[0034] The preparation method of the rivaroxaban mesopropylidene impurity reference substance is as follows:

[0035] 1) Take 4.5g (15mmol) of 4-(4-(5-(aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3-morpholinone, add 3.2g (30mmol) Sodium bicarbonate and 50mL of water were stirred until completely dissolved, 2.93g (30mmol) of mesityl oxide was added, stirred at 25°C for 12 hours, extracted with dichloromethane, and spin-dried to obtain a white powdery solid, which was obtained by column chromatography 4- (4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3-morpholinone .

[0036] figure 1 is 4-(4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3- The proton nuclear magnetic resonance spectrum figure of morpholinone intermediate, by figure 1 It can be seen that this example successfully synthesized 4-(4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl ) phenyl) -3-morpholinone intermediate.

[0037] 2) Add 0.1g (0...

Embodiment 3

[0041] The preparation of rivaroxaban isopropylidene impurity reference substance is as follows:

[0042] 1) Take 4.5g (15mmol) 4-(4-(5-(aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3-morpholinone, add 1.2g (30mmol) Sodium hydroxide and 50mL of water were stirred until they were completely dissolved, 2.93g (30mmol) of mesityl oxide was added, stirred at 25°C for 12 hours, extracted with dichloromethane, and spin-dried to obtain a white powdery solid, which was obtained by column chromatography 4- (4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3-morpholinone .

[0043] figure 1 is 4-(4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl)phenyl)-3- The proton nuclear magnetic resonance spectrum figure of morpholinone intermediate, by figure 1It can be seen that this example successfully synthesized 4-(4-(5-(((2-methyl-4-oxopent-2-yl)aminomethyl)-2-oxo-3-oxazolidinyl ) phenyl) -3-morpholinone intermediate.

[0044] 2) Add 0.1g (0.25mmol)...

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