WO2020181860A1 - Method for preparing rivaroxaban intermediate - Google Patents

Abstract

Provided is a method for preparing a rivaroxaban intermediate compound of formula (I), comprising dissolving a compound of formula (II) into an organic solvent, and subjecting same to an ammonolysis reaction using an C_3-4 alkyl primary amine as an ammonia source, so as to obtain a compound of formula I. The preparation method of the present invention is safer, more economical, simpler, and more environmentally friendly, and is suitable for industrialization.

Description

A kind of preparation method of rivaroxaban intermediate Technical field

The invention relates to the field of drug synthesis, in particular to a preparation method of rivaroxaban intermediates.

Background technique

Rivaroxaban is a new type of anticoagulant drug developed by Bayer. It is a highly selective oral drug for factor Xa inhibitors. Rivaroxaban can highly selectively and competitively inhibit free and bound factor Xa and prothrombin activity, and is used to prevent deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients after hip and knee joint replacement. It can also be used to prevent stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation, and reduce the risk of recurrence of coronary syndrome. Rivaroxaban was first launched in Canada in September 2008. It was subsequently approved in more than 120 countries around the world. The chemical name of rivaroxaban is 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-1,3- Oxazolin-5-yl)methyl)thiophene-2-carboxamide (CAS: 366789-02-8), its chemical structure is as follows:

US patent US7157456B2 discloses a synthetic route for preparing rivaroxaban via the amine intermediate (compound of formula I) shown in the figure below.

In the prior art, the intermediate compound of formula I is mainly obtained by amination of the imide compound of formula II in the presence of methylamine gas. However, the existing synthetic route of methylamine amination mainly has the following shortcomings:

1) Methylamine is a gas under normal pressure, and can form an explosive mixture when mixed with air, leading to higher safety risks in industrial production, and the methylamine waste gas during the production process will pollute the environment, which is not conducive to environmental protection;

2) The use of methylamine gas amination requires the use of a closed pressure-resistant reactor, which requires high production equipment and restricts the increase in productivity;

3) The amount of methylamine used for amine lysis is usually greater than 50 equivalents. After the reaction is completed, it is necessary to remove large excess methylamine residues through complicated procedures such as filtration, neutralization, extraction, and washing. The entire process is relatively cumbersome and the yield is relatively high. Low, high production cost;

4) The intermediate compound of formula I obtained by the methylamine amination process has a relatively high content of the impurity compound of formula III, which is difficult to remove, which is not conducive to controlling the quality of the subsequent rivaroxaban bulk drug.

Therefore, in order to overcome the shortcomings of the existing synthesis technology, it is necessary to develop a safer, economical, simple, environmentally friendly, and industrialized method for the production of high-quality intermediate formula I compounds.

Summary of the invention

The purpose of the present invention is to provide a method for preparing the rivaroxaban intermediate formula I compound that overcomes the deficiencies of the existing synthesis process, is safer, economical, simple, environmentally friendly, and suitable for industrialization.

The preparation method of formula I compound of the present invention comprises the following steps:

The compound of formula II is dissolved in an organic solvent, and the C _3-4 alkyl primary ammonia is used as the ammonia source for the ammonolysis reaction to obtain the compound of formula I

According to the preparation method of the present invention, the C _3-4 alkyl primary ammonia may be n-butylamine or n-propylamine.

According to the preparation method of the present invention, the organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, and tert-butanol, preferably ethanol.

According to the preparation method of the present invention, the mass-volume ratio of the compound of formula II (mass, g) to the organic solvent (volume, mL) is 1:5-10, preferably 1:6.

According to the preparation method of the present invention, the molar ratio of the compound of formula II to the _C3-4 alkyl primary ammonia is 1:8-15, preferably 1:11.

According to the preparation method of the present invention, wherein the ammonolysis reaction is carried out at a temperature of 60-100°C, preferably at a temperature of 75-80°C.

According to the preparation method of the present invention, after the ammonolysis reaction is completed, the reaction solution is cooled to 0-10°C, preferably 0-5°C, stirred and filtered to obtain the compound of formula I.

The present invention uses C _3-4 alkyl primary ammonia that is liquid at normal temperature and pressure as the ammonia source instead of methylamine, avoids the use of high-temperature and high-pressure equipment, improves process safety, reduces the amount of ammonia, and simplifies the process flow; The reaction yield is improved, the production cost is effectively reduced; the product is easy to purify, the content of the impurity compound of formula III is effectively reduced, and the product quality is improved.

Specific implementation plan

The following examples further explain the present invention, but they do not constitute a limitation or limitation to the scope of the present invention.

The equipment information and usage conditions used in the present invention are as follows:

HPLC chromatographic conditions are: instrument: high performance liquid chromatograph equipped with ultraviolet detector; chromatographic column: C18 4.6×250mm, 5μm; mobile phase: phosphate buffer solution-acetonitrile with pH=3.0; detection wavelength: 245nm; flow rate: 0.8mL /min; column temperature: 30℃; injection volume: 10μL; running time: 60min; diluent: acetonitrile-water-phosphoric acid (100:900:1).

The information of the main raw materials used in the embodiment of the present invention is as follows:

Example 1

Put the compound of formula II (42.1g), ethanol (252mL), and n-butylamine (47.2g, 8eq) into the reaction flask, raise the temperature to 75～80℃, keep the temperature for 8～12 hours, after the reaction is over, cool the reaction solution to At 0-5°C, keep stirring for 1 hour, filter the obtained solid, rinse the filter cake with ethanol (20 mL) and dry to obtain the intermediate compound of formula I (23.3 g) with a purity (HPLC) of 99.57% and a yield of 80%.

The characterization data of the intermediate compound of formula I prepared in Example 1 are as follows: mp: 149-151°C; [α] ²⁰ _D (C=0.01 g/mL, water) = -59.4°; TOF-MS (ES ⁺ ): 292.16[M+H]; ¹ H NMR (DMSO-d ⁶ , 400MHz) δ: 7.56 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 4.93～4.88 (m, 2H), 4.18(s, 2H), 4.15(m, 1H), 4.16(d, J=8.8Hz, 1H), 3.98～3.92(m, 3H), 3.71(t, J=5.2Hz, 2H), 3.14～3.10 (m, 2H); ¹³ C NMR (DMSO-d ⁶ , 100MHz) δ: 166.16, 153.98, 137.34, 136.57, 126.03, 118.70, 70.84, 67.87, 63.63, 49.17, 47.45, 42.32.

Example 2 to Example 9

According to the operation process of Example 1, under the condition that the dosage of the compound of formula II (42.1g) remains unchanged, the solvent and its dosage, the dosage of n-butylamine and the reaction temperature were changed. The results are shown in Table 1 below.

Table 1

Example number	Solvent and dosage	Dosage of n-butylamine	temperature reflex	Yield
2	Ethanol (252mL)	64.9g(11eq)	75～80℃	88%
3	Ethanol (252mL)	88.5g(15eq)	75～80℃	86%
4	Ethanol (421mL)	64.9g(11eq)	75～80℃	84%
5	Methanol (252mL)	64.9g(11eq)	60～65℃	78%
6	N-Propanol (252mL)	64.9g(11eq)	75～80℃	83%
7	Isopropanol (252mL)	64.9g(11eq)	75～80℃	82%
8	N-Butanol (252mL)	64.9g(11eq)	95～100℃	85%
9	Tert-Butanol (252mL)	64.9g(11eq)	75～80℃	81%

It can be seen from Table 1 that Example 2 is the best process condition.

After testing, the characterization data of the intermediate formula I compound prepared in Example 2 to Example 9 is consistent with the characterization data of the intermediate formula I compound prepared in Example 1.

Example 10: Using n-propylamine instead of n-butylamine under the above optimal process conditions

Put the compound of formula II (42.1g), ethanol (252mL), and n-propylamine (64.9g, 11eq) into the reaction flask, raise the temperature to 75～80℃, keep the reaction temperature for 20～24 hours, after the reaction, cool the reaction solution to 0 After stirring at ~5°C for 1 hour, the obtained solid was filtered, the filter cake was rinsed with ethanol (10 mL) and then dried to obtain the intermediate compound of formula I (23.9 g) with a purity (HPLC) of 99.8% and a yield of 82%.

After testing, the characterization data of the intermediate formula I compound prepared in Example 10 is consistent with the characterization data of the intermediate formula I compound prepared in Example 1.

The above embodiments are only a part of the preferred embodiments of the present invention. From a technical perspective, several optimizations in the implementation steps described should also be regarded as falling within the protection scope of the present invention.

Comparative example 1

Put isopropanol (250mL) into a 500mL autoclave, lower the temperature to 0～5℃, pass methylamine gas (170.5g) to saturation, then put the formula II compound (42.1g) into the reaction flask, and heat up to 35～40℃ , Keep the temperature for 4 hours, cool to 0～5℃, add methylamine gas to saturation, increase the temperature to 35～40℃, keep the temperature for 20～24 hours, after TLC control is qualified, cool to 0～5℃, Incubate and stir for 1 hour, filter, put the filter cake and isopropanol (100 mL) into the reaction flask, stir at room temperature for 1 hour, and filter to obtain the crude compound of formula I. Put the above crude product and isopropanol (100mL) into the reaction flask, lower the temperature to 0～5℃, pass in HCl gas to pH≤1, after ventilation, keep warm and stir for 1 hour, warm up to 70～75℃, keep warm and stir for 1 hour, Then, the temperature was lowered to 30～35℃, kept stirring for 1 hour, filtered, and the filter cake was dried. Put the above dry product and dichloromethane (200mL) into the reaction flask, add dropwise 20% NaOH aqueous solution at room temperature to adjust the pH ~8, stir until it is clear, stand to separate layers, extract the aqueous layer with dichloromethane (200mL) once, combine the organic layers, desolvate under reduced pressure, add isopropanol (100mL) after drying, and stir at room temperature for 2 After hours, filtered and dried, the intermediate compound of formula I (21.2g) was obtained with a purity (HPLC) of 99.19% and a yield of 73%.

After testing, the characterization data of the intermediate compound of formula I prepared in Comparative Example 1 is consistent with the characterization data of the intermediate compound of formula I prepared in Example 1.

Test Example 1 Purity inspection

The purity data of the intermediate compounds of formula I prepared in the above examples and comparative examples are shown in Table 2 below.

Table 2

Serial number	purity	Impurity compound of formula III	Other largest impurities
Comparative example 1	99.19%	0.50%	0.14%
Example 1	99.57%	0.19%	0.07%
Example 2	99.92%	0.02%	0.03%
Example 3	99.83%	0.03%	0.05%
Example 4	99.92%	0.02%	0.02%
Example 5	99.38%	0.01%	0.23%
Example 6	99.72%	0.13%	0.02%
Example 7	99.66%	0.15%	0.05%
Example 8	99.34%	0.13%	0.17%
Example 9	99.56%	0.25%	0.08%
Example 10	99.83%	0.02%	0.07%

It can be seen from Table 2 that the purity of the intermediate compound of formula I prepared according to the embodiment of the present invention is higher than that of the intermediate compound of formula I prepared in Comparative Example 1. The intermediate compound of formula I prepared according to the embodiment of the present invention has the impurity formula III The content of the compound is much lower than the content of the impurity compound of formula III in the intermediate compound of formula I prepared in Comparative Example 1; and the content of other largest impurities in the intermediate compound of formula I prepared according to the embodiment of the present invention is also lower than that of the comparative example 1. The prepared intermediate formula I compound has a low content of other largest impurities.

Claims (7)

1. The preparation method of the compound of formula I comprises the following steps:

   The compound of formula II is dissolved in an organic solvent, and the C _3-4 alkyl primary ammonia is used as the ammonia source for the ammonolysis reaction to obtain the compound of formula I

   
2. The method according to claim 1, wherein the _C3-4 alkyl primary ammonia is n-butylamine or n-propylamine.
3. The method according to claim 1 or 2, wherein the organic solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, and tert-butanol, preferably ethanol.
4. The method of claim 1 or 2, wherein the mass-volume ratio of the compound of formula II to the organic solvent is 1:5-10, preferably 1:6.
5. The method according to claim 1 or 2, wherein the molar ratio of the compound of formula II to _C3-4 alkyl primary ammonia is 1:8-15, preferably 1:11.
6. The method according to claim 1 or 2, wherein the ammonolysis reaction is carried out at a temperature of 60-100°C, preferably at a temperature of 75-80°C.
7. The method according to claim 1 or 2, wherein after the ammonolysis reaction is completed, the reaction solution is cooled to 0-10°C, preferably 0-5°C, stirred and filtered to obtain the compound of formula I.