Preparation method of rivaroxaban

A technology for rivaroxaban and intermediates, applied in the field of preparation of rivaroxaban, can solve the problems of increasing raw material cost and production cost, not being suitable for large-scale production, etc., and achieves low pollution, short route and high yield Effect

Active Publication Date: 2015-10-14
NEW FOUNDER HLDG DEV LLC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] Both route 3 and route 4 require chiral separation, which is not suitable for large-scale production; at the same time, there is also a step of using expensive heavy metal palladium to carry out catalytic hydrogenation reduction of nitro, which increases the cost of raw materials and production costs

Method used

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  • Preparation method of rivaroxaban
  • Preparation method of rivaroxaban
  • Preparation method of rivaroxaban

Examples

Experimental program
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Effect test

Embodiment 1

[0059] Embodiment 1: Preparation of N-(4-aminophenyl)-2-(2-chloroethoxy)acetamide (formula III):

[0060]

[0061] In this embodiment, X=Cl in the above reaction formula.

[0062] Add 194.7g (1.8mol) of 1,4-diaminobenzene, 47.4g (0.6mol) of pyridine and 900ml of tetrahydrofuran into the reaction flask, stir evenly, cool down to 10°C to 20°C, and slowly add 2 -(2-Chloroethoxy)acetyl chloride 46.8g (0.3mol), the temperature of the dropping process was controlled at 10°C to 20°C, and the dropping time was controlled at 5 hours. Ethyl acetate:triethylamine=30:20:1, volume ratio) the raw materials basically disappear, stop the reaction, distill THF under reduced pressure (-0.1MPa~-0.09MPa) and recover excess 1,4-diaminobenzene, Add a mixed solvent of 600ml ethyl acetate and 300ml acetone, raise the temperature and reflux to dissolve the residual oil, drop to about 10°C for crystallization for 5 hours, filter, and dry under reduced pressure to obtain 61.8g of off-white intermedi...

Embodiment 2

[0064] Embodiment 2: Preparation of N-(4-aminophenyl)-2-(2-chloroethoxy)acetamide (formula III):

[0065] Add 129.8g (1.2mol) of 1,4-diaminobenzene, 31.6g (0.4mol) of pyridine and 600ml of tetrahydrofuran into the reaction flask, stir evenly, cool down to 10°C to 20°C, and slowly add 2 -(2-Chloroethoxy)acetyl chloride 31.2g (0.2mol), the temperature of the dropping process was controlled at 10°C to 20°C, and the dropping time was controlled at 3 hours. Ethyl acetate:triethylamine=30:20:1, volume ratio) the raw materials basically disappear, stop the reaction, distill THF under reduced pressure (-0.1MPa~-0.09MPa) and recover excess 1,4-diaminobenzene, Add a mixed solvent of 400ml ethyl acetate and 200ml acetone, raise the temperature and reflux to dissolve the residual oil, drop to about 10°C for crystallization for 5 hours, filter, and dry under reduced pressure to obtain 41.8g of off-white intermediate III, with a molar yield of 91.7 %, HPLC purity 97.8%.

[0066] The detec...

Embodiment 3

[0067] Embodiment 3: Preparation of 4-(4-aminophenyl)-3-morpholinone (formula IV):

[0068]

[0069] Add 45.6g (0.2mol) N-(4-aminophenyl)-2-(2-chloroethoxy)acetamide (formula III) prepared in Example 1, 250ml dichloromethane, 82.8g (0.6mol) potassium carbonate, 6.4g (0.02mol) tetrabutylammonium bromide, stir evenly, cool the reaction system to 0°C to 20°C, keep stirring for 5 hours, control in TLC (dichloromethane:methanol=20: 1, volume ratio), the raw materials basically disappeared. Remove insolubles by filtration, wash the organic layer with 80ml of purified water, separate the liquids, evaporate the organic layer to dryness under reduced pressure (-0.08MPa~-0.06MPa), add 150ml of acetone and stir for 3 hours, precipitate crystals, filter, and dry under reduced pressure to obtain 4-(4-aminophenyl)-3-morpholinone 35.2g, molar yield 91.6%, HPLC purity 98.5%.

[0070] The detection data of the title product obtained by mass spectrometry analysis is as follows: HR-MS (ESI)...

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Abstract

The invention discloses a preparation method of rivaroxaban, which includes the steps of 1) performing a one-step cyclization reaction to an intermediate, N-(4-aminophenyl)-2-(2-haloethyoxyl)acetamide, to prepare a key intermediate, 4-(4-aminophenyl)-3-morpholinone, of the rivaroxaban; 2) performing a series reactions comprising ring opening with an epoxide, a substitution reaction, a ring formation reaction and the like to the 4-(4-aminophenyl)-3-morpholinone to obtain an intermediate, 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one; and 3) performing a substitution reaction to the 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one with 2-chloroformyl-5-chlorothiophene to obtain the rivaroxaban. The whole preparation process is short in route, is high in yield, is less in pollution, can avoid usage of expensive metal palladium for nitroreduction and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of rivaroxaban. Background technique [0002] Thrombus is a local blood clot in a blood vessel. Arterial thrombosis can lead to myocardial infarction, stroke, acute coronary syndrome and peripheral arterial disease, etc.; venous thrombosis can cause pulmonary embolism. The traditional anticoagulant drugs heparin and warfarin are routine methods for the treatment and prevention of arterial and venous thrombosis. Large-scale clinical trials and clinical applications have established their status as traditional anticoagulant drugs. However, heparin is administered parenterally, and the patient's compliance is poor, so it is not suitable for long-term use. Heparin needs antithrombin to play its role, and has no effect on factor Xa in the prothrombin complex. Long-term application may lead to the risk of osteoporosis and potential heparin-media...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14C07C235/16C07C231/02C07D265/32C07D413/10
CPCY02P20/55C07D413/14C07C231/02C07C235/16C07D265/32C07D413/10
Inventor 王威徐虹窦麒麟
Owner NEW FOUNDER HLDG DEV LLC
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