Preparation method of rivaroxaban intermediate

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a rivaroxaban intermediate. 4-(3-oxomorpholinyl) phenyl isocyanate, namely a compound 1, and (2s)-3-chloro-2-hydroxy propyl carbamic acid tert-butyl ester, namely a compound 2 are subjected to a reaction, and an intermediate (S)-tert-butyl-(2-oxo-3-(4-(3-carbonyl morpholine) phenyl) oxazoline-5-methylene) carbamate, namely a compound 3, is obtained. The reaction conditions are mild and stable, the intermediate can be prepared with high yield and high purity, the problems of long reaction time, high-temperature reaction and the like are avoided, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing a rivaroxaban intermediate. Background Technology

[0002] Rivaroxaban, developed by Bayer / Johnson & Johnson, is the world's first oral direct factor Xa inhibitor. In June 2009, it was approved for marketing in China under the brand name Xarelto. Subsequently, in July 2011, it received FDA approval for official marketing in the United States. Its chemical name is 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-1,3-oxazoline-5-yl)methyl)thiophene-2-carboxamide, and its molecular formula is C0. 19 H 18 ClN3O5S, CAS No.: 366789-02-8, has the following structural formula:

[0003]

[0004] Currently, several methods for preparing rivaroxaban, namely 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-1,3-oxazoline-5-yl)methyl)thiophene-2-carboxamide and its related intermediates, have been disclosed, including the following:

[0005] WO2012171343A1 discloses a novel method for synthesizing rivaroxaban intermediates, namely 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholin-3-one, comprising the following steps: cyclization of (2S)-3-chloro-2-hydroxypropylcarbamate tert-butyl ester in an inert solvent in the presence of lithium, followed by deesterification under hydrochloric acid or hydrogen chloride to obtain 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholin-3-one. This novel method offers mild reaction conditions, simple operation, easy purification, low production cost, environmental friendliness, and suitability for industrial production. However, the reaction to prepare compound 3 requires 24 hours, which is too long. The reaction route is as follows:

[0006]

[0007]

[0008] CN104098556A discloses a novel synthetic process for rivaroxaban. 4-(3-oxomorpholino)phenyl isocyanate reacts with (S)-N-Boc-2,3-aminoepoxypropane in the presence of lithium bromide and tri-n-butylphosphine oxide to form a cyclization reaction, followed by further de-Boc removal to yield 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholin-3-one, which is then used to synthesize rivaroxaban. The reaction route is as follows:

[0009]

[0010] Patent WO2013046211A1 describes a novel synthetic process for rivaroxaban, with the following reaction route:

[0011]

[0012] WO2013046211A1 discloses a reaction of (2S)-3-chloro-2-hydroxypropyl tert-butyl carbamate with 4-(4-aminophenyl)morpholin-3-one as a starting material. A key step involves cyclization with the expensive reagent lithium tert-butoxide to prepare the intermediate (S)-tert-butyl-(2-oxo-3-(4-(3-carbonylmorpholin)phenyl)oxazoline-5-methylene)carbamate. The reaction route is as follows:

[0013]

[0014] Analysis of the above routes reveals that compound (S)-tert-butyl-(2-oxo-3-(4-(3-carbonylmorpholine)phenyl)oxazoline-5-methylene)carbamate is a commonly used intermediate in the synthesis of rivaroxaban. However, existing synthetic routes for this intermediate suffer from problems such as excessively long reaction times, difficult purification, and the use of expensive lithium reagents. The structure of (S)-tert-butyl-(2-oxo-3-(4-(3-carbonylmorpholine)phenyl)oxazoline-5-methylene)carbamate is as follows:

[0015] Summary of the Invention

[0016] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing rivaroxaban intermediates. This method is simple, low-cost, has a high yield, produces easily purified products, and is suitable for industrial production.

[0017] To achieve the above objectives, the present invention is implemented through the following solution:

[0018] Under inert gas protection, anhydrous reaction solvent was added to a reaction vessel, stirred, and then 4-(3-oxomorpholino)phenyl isocyanate (compound 1) and (2S)-3-chloro-2-hydroxypropylcarbamate tert-butyl ester (compound 2) were added sequentially. The system was kept at temperature T, and NaH was added and stirred until compound 1 reacted completely. The temperature was then raised to solvent reflux and stirred until the reaction was complete. After post-treatment, the target product compound 3 was obtained. The reaction route is as follows:

[0019]

[0020] In a preferred embodiment, the molar ratio of compound 1, compound 2, and NaH is 1.00:(1.05~1.30):(1.00~1.50), preferably 1.00:1.10:1.20.

[0021] In a preferred embodiment, the anhydrous reaction solvent is one of tetrahydrofuran, acetonitrile, and 2-methyltetrahydrofuran, with tetrahydrofuran being preferred.

[0022] In a preferred embodiment, the reaction temperature T is -5 to 15°C, preferably -5 to 5°C.

[0023] In the preferred embodiment, the post-treatment is as follows: after the reaction is completed, the mixture is cooled to room temperature and the reaction solution is poured into water. It is then extracted with dichloromethane, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. The resulting residue is pulped with toluene at 70-80°C, cooled, filtered, and the filter cake is washed with n-hexane and dried under vacuum at 50-60°C to obtain compound 3.

[0024] In a preferred embodiment, the inert gas is either nitrogen or argon.

[0025] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0026] (1) This invention provides a new method for preparing rivaroxaban intermediates. The method is simple and convenient, with mild and stable reaction conditions. It can produce intermediates with high yield and high purity, avoiding problems such as long reaction time and high temperature reaction, and is suitable for industrial production. Detailed Implementation

[0027] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0028] Example 1

[0029] Under nitrogen protection, compound 1 (21.82 g, 100 mmol, 1.00 eq.) and compound 2 (23.06 g, 110 mmol, 1.10 eq.) were added to anhydrous tetrahydrofuran (200 mL), stirred to dissolve, and cooled to -5 to 5 °C. Then, 60% NaH (4.40 g, 110 mmol, 1.10 eq.) was added, and the temperature was maintained at -5 to 5 °C. The mixture was stirred at -5 to 5 °C for 2 to 3 hours. After the reaction of compound 1 was monitored by TCL until complete, the mixture was heated to reflux for 3 to 4 hours. After cooling, the reaction solution was poured into water (1000 mL), extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Toluene (100 mL) was added to the residue and stirred at 70–80 °C for 1–2 hours. The mixture was then cooled to 0–10 °C, stirred for 1 hour, and filtered. The filter cake was washed with n-hexane (50 mL) and dried under vacuum at 50–60 °C to obtain a white solid compound 3 with a yield of 97.3% and an HPLC purity of 98.93%.

[0030] Example 2

[0031] Under nitrogen protection, compound 1 (21.82 g, 100 mmol, 1.00 eq.) and compound 2 (23.06 g, 110 mmol, 1.10 eq.) were added to anhydrous tetrahydrofuran (200 mL), stirred to dissolve, and cooled to -5 to 5 °C. Then, 60% NaH (4.00 g, 100 mmol, 1.00 eq.) was added, and the temperature was maintained at -5 to 5 °C. The mixture was stirred at -5 to 5 °C for 2 to 3 hours. After the reaction of compound 1 was monitored by TCL until complete, the mixture was heated to reflux for 3 to 4 hours. After cooling, the reaction solution was poured into water (1000 mL), extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Toluene (100 mL) was added to the residue and stirred at 70–80 °C for 1–2 hours. The mixture was then cooled to 0–10 °C, stirred for 1 hour, and filtered. The filter cake was washed with n-hexane (50 mL) and dried under vacuum at 50–60 °C to obtain a white solid compound 3 with a yield of 95.5% and an HPLC purity of 98.91%.

[0032] Example 3

[0033] Under nitrogen protection, compound 1 (21.82 g, 100 mmol, 1.00 eq.) and compound 2 (23.06 g, 110 mmol, 1.10 eq.) were added to anhydrous tetrahydrofuran (200 mL), stirred to dissolve, and cooled to -5 to 5 °C. Then, 60% NaH (4.80 g, 120 mmol, 1.20 eq.) was added, and the temperature was maintained at -5 to 5 °C. The mixture was stirred at -5 to 5 °C for 2 to 3 hours. After the reaction of compound 1 was monitored by TCL until complete, the mixture was heated to reflux for 3 to 4 hours. After cooling, the reaction solution was poured into water (1000 mL), extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Toluene (100 mL) was added to the residue and stirred at 70–80 °C for 1–2 hours. The mixture was then cooled to 0–10 °C, stirred for 1 hour, and filtered. The filter cake was washed with n-hexane (50 mL) and dried under vacuum at 50–60 °C to obtain a white solid compound 3 with a yield of 98.5% and an HPLC purity of 98.95%.

[0034] Example 4

[0035] Under nitrogen protection, compound 1 (21.82 g, 100 mmol, 1.00 eq.) and compound 2 (23.06 g, 110 mmol, 1.10 eq.) were added to anhydrous tetrahydrofuran (200 mL), stirred to dissolve, and cooled to -5 to 5 °C. Then, 60% NaH (6.00 g, 150 mmol, 1.50 eq.) was added, and the temperature was maintained at -5 to 5 °C. The mixture was stirred at -5 to 5 °C for 2 to 3 hours. After the reaction of compound 1 was monitored by TCL until complete, the mixture was heated to reflux for 3 to 4 hours. After cooling, the reaction solution was poured into water (1000 mL), extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Toluene (100 mL) was added to the residue and stirred at 70–80 °C for 1–2 hours. The mixture was then cooled to 0–10 °C, stirred for 1 hour, and filtered. The filter cake was washed with n-hexane (50 mL) and dried under vacuum at 50–60 °C to obtain a white solid compound 3 with a yield of 97.1% and an HPLC purity of 98.90%.

[0036] Example 5

[0037] Under nitrogen protection, compound 1 (21.82 g, 100 mmol, 1.00 eq.) and compound 2 (23.06 g, 110 mmol, 1.10 eq.) were added to anhydrous acetonitrile (200 mL), stirred to dissolve, and cooled to 5–15 °C. Then, 60% NaH (4.80 g, 120 mmol, 1.20 eq.) was added, and the temperature was maintained at 5–15 °C. The mixture was stirred at 5–15 °C for 2–3 hours. After the reaction of compound 1 was monitored by TCL until complete, the mixture was heated to reflux for 3–4 hours. After cooling, the reaction solution was poured into water (1000 mL), extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Toluene (100 mL) was added to the residue and stirred at 70–80 °C for 1–2 hours. The mixture was then cooled to 0–10 °C, stirred for 1 hour, and filtered. The filter cake was washed with n-hexane (50 mL) and dried under vacuum at 50–60 °C to obtain a white solid compound 3 with a yield of 96.6% and an HPLC purity of 98.89%.

[0038] Example 6

[0039] Under nitrogen protection, compound 1 (21.82 g, 100 mmol, 1.00 eq.) and compound 2 (23.06 g, 110 mmol, 1.10 eq.) were added to anhydrous 2-methyltetrahydrofuran (200 mL), stirred to dissolve, and cooled to -5 to 5 °C. Then, 60% NaH (4.80 g, 120 mmol, 1.20 eq.) was added, and the temperature was maintained at -5 to 5 °C. The mixture was stirred at -5 to 5 °C for 2 to 3 hours. After the reaction of compound 1 was monitored by TCL until complete, the mixture was heated to reflux for 6 hours. After cooling, the reaction solution was poured into water (1000 mL), extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. Toluene (100 mL) was added to the residue and stirred at 70–80 °C for 1–2 hours. The mixture was then cooled to 0–10 °C, stirred for 1 hour, and filtered. The filter cake was washed with n-hexane (50 mL) and dried under vacuum at 50–60 °C to obtain a white solid compound 3 with a yield of 98.2% and an HPLC purity of 98.95%.

Claims

1. A method for preparing a rivaroxaban intermediate, characterized in that, The process includes the following steps: Under inert gas protection, anhydrous reaction solvent is added to a reaction vessel, stirred, and 4-(3-oxomorpholino)phenyl isocyanate (compound 1) and (2S)-3-chloro-2-hydroxypropylcarbamate tert-butyl ester (compound 2) are added sequentially. The system is then heated to a controlled temperature T, and NaH is added and stirred until compound 1 has completely reacted. The temperature is then raised to solvent reflux and stirred until the reaction is complete. After post-treatment, the target product compound 3 is obtained. The reaction route is as follows:

2. The preparation method according to claim 1, characterized in that, The molar ratio of compound 1, compound 2, and NaH is 1.00:(1.05~1.30):(1.00~1.50), preferably 1.00:1.10:1.

20.

3. The preparation method according to claim 1, characterized in that, The anhydrous reaction solvent is one of tetrahydrofuran, acetonitrile, and 2-methyltetrahydrofuran, preferably tetrahydrofuran.

4. The preparation method according to claim 1, characterized in that, The reaction temperature T is -5 to 15°C, preferably -5 to 5°C.

5. The preparation method according to claim 1, characterized in that, The post-processing is as follows: After the reaction is completed, the mixture is cooled to room temperature and the reaction solution is poured into water. It is then extracted with dichloromethane, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to remove the organic solvent. The resulting residue is pulped with toluene at 70-80°C, cooled, filtered, washed with n-hexane, and dried under vacuum at 50-60°C to obtain compound 3.

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