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A kind of preparation method of rivaroxaban intermediate

A technology for rivaroxaban and intermediates, applied in the field of preparation of rivaroxaban intermediates, can solve the problem that the purity and impurity level cannot meet the quality requirements of raw material drug intermediates, affect the quality of rivaroxaban, and the compound is not easy to obtain and other problems, to achieve the effect of strong impurity removal ability, good process tolerance and low cost

Active Publication Date: 2021-08-31
ZHEJIANG HISOAR PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compound (VI) is a key intermediate for the synthesis of rivaroxaban. Such purity and impurity levels cannot meet the quality requirements of raw material drug intermediates, which seriously affects the quality of rivaroxaban. If additional purification operations are added, the cost will be greatly increased;
[0016] (2) After steps a) and b), the ee values ​​of compound (V) and the key intermediate compound (VI) are not improved, and the means to improve the ee value of rivaroxaban through subsequent reactions are also limited. In this case The ee value of rivaroxaban still mainly depends on the starting material compound (II), but compound (II) with high ee value (e.g. ee value ≥ 99.0%) is not easy to obtain, which inevitably increases the cost of the whole route;
[0017] (3) mixed solvent (toluene and ethanol have been used in step b) has been used in the reaction, and the solvent recovery cost is high during industrialized production

Method used

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  • A kind of preparation method of rivaroxaban intermediate
  • A kind of preparation method of rivaroxaban intermediate
  • A kind of preparation method of rivaroxaban intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1: the preparation of compound B

[0058] Add 92.6g of phthalimide potassium salt into a 1000mL reaction flask, add 400mL of (S)-epichlorohydrin, raise the temperature to 70°C, react for 1 hour, concentrate and recover the solvent, and wash the residue with 500mL of absolute ethanol Recrystallized to obtain 84g of compound B, HPLC purity: 95.1%, molar yield: 83%, ee value: 96.0%.

[0059] NMR data: 1 H-NMR (DMSO-d6) δ (ppm): 2.59 (1H, m), 2.76 (1H, m), 3.22 (1H, m), 3.78 (2H, d, J = 4.56Hz), 7.86 (2H, m),7.89(2H,m)

Embodiment 2

[0060] Embodiment 2: the preparation of compound B

[0061] Add 92.6g of phthalimide potassium salt into a 1000mL reaction flask, add 600mL of (S)-epichlorohydrin, raise the temperature to 40°C, react for 3 hours, concentrate and recover the solvent, and wash the residue with 500mL of absolute ethanol Recrystallization, recrystallization twice (500mL×2), obtained 65g of compound B, HPLC purity: 98.2%, molar yield: 64%, ee value: 97.5%.

[0062] The NMR data of Compound B prepared in Example 2 is consistent with the NMR data of Example 1.

Embodiment 3

[0063] Embodiment 3: the preparation of compound B

[0064] Add 92.6g of phthalimide potassium salt into a 1000mL reaction flask, add 600mL of (S)-epichlorohydrin, raise the temperature to 40°C, react for 3 hours, concentrate and recover the solvent, and wash the residue with 500mL of absolute ethanol Recrystallized once, and then recrystallized once with 200 mL of ethyl acetate to obtain 53 g of compound B, HPLC purity: 99.8%, molar yield: 52%, ee value: 98.5%.

[0065] The NMR data of Compound B prepared in Example 3 is consistent with the NMR data of Example 1.

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Abstract

The invention provides a method for preparing a rivaroxaban intermediate, comprising the following steps: (1) react compound A and compound B in alcohol or an aqueous alcohol solution to obtain compound C; (2) compound C and N,N ′-carbonyldiimidazole reaction, the reaction solvent is selected from acetonitrile or butyronitrile, to obtain a reaction solution containing compound D, cooling and crystallization, to obtain compound D

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of a rivaroxaban intermediate. Background technique [0002] Rivaroxaban tablets, trade name Xarelto (Xarelto), is an oral anticoagulant drug developed by Bayer AG of Germany, the active ingredient is Rivaroxaban (Rivaroxaban). The mechanism of action is to block the burst of thrombin generation by specifically directly inhibiting free and bound coagulation factor Xa, thereby inhibiting thrombus formation. Clinically, it is mainly used to prevent the formation of deep vein thrombosis and pulmonary embolism in patients after hip and knee replacement. It can also be used to prevent stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation, and reduce coronary syndrome. risk of recurrence. [0003] The chemical name of rivaroxaban is 5-chloro-N-{[(5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-1,3- Oxazolin-5-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/14
CPCC07B2200/07C07D413/14
Inventor 唐方辉梁朝倪治中赵富录李洪明
Owner ZHEJIANG HISOAR PHARMA
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