Preparation method of dronedarone hydrochloride key intermediate JN-02

Abstract

The invention belongs to the technical field of drug synthesis, and particularly discloses a dronedarone hydrochloride key intermediate preparation method, which comprises: (1) dissolving an intermediate JN-01 in methanol, adding Pd / C, controlling the temperature, adding ammonium formate in batches, carrying out a stirring reaction, after the reaction is completed, concentrating the reaction liquid to a dry state, carrying out ethyl acetate-water extraction 2-5 times, merging the organic phases, and carrying out solid-liquid separation so as to obtain a crude product of dronedarone hydrochloride; washing with a saline solution, and spin-drying an organic phase; (2) dissolving the residue in isopropanol, heating, adding oxalic acid and n-heptane for crystallization, keeping the temperature, filtering, and drying a filter cake to obtain white powder, namely an intermediate JN-02; the ammonium formate is used for replacing formic acid, the solvent methanol is used for replacing ethanol, and it is accidentally found that the single impurity content in the product is greatly reduced, the purity of the intermediate is increased, and the method has great significance in control over the purity and quality of dronedarone hydrochloride API.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, relates to the synthesis of raw material drug intermediates, and specifically relates to a preparation method of 2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)-5-aminobenzofuran, a key intermediate of dronedarone hydrochloride. Background Art

[0002] Dronedarone hydrochloride, with the Chinese chemical name N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide hydrochloride, was developed by the French company Sanofi. It is an antiarrhythmic drug suitable for the treatment of sinus rhythm patients with a history of paroxysmal or persistent atrial fibrillation, reducing the risk of atrial fibrillation. Dronedarone hydrochloride tablets were first approved for marketing in the United States in 2009, and subsequently approved for marketing in Europe and China. Dronedarone hydrochloride has a similar chemical structure to amiodarone, both of which are multi-channel inhibitors with similar mechanisms of action, but dronedarone hydrochloride does not contain iodine atoms in its chemical structure, avoiding iodine-related adverse reactions and having broad prospects for clinical application.

[0003]

[0004] In the original process, the preparation process of the intermediate 2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)-5-aminobenzofuran (denoted as JN-02) is as follows: PtO 2 As catalyst, in H 2 It is prepared by pressure hydrogenation in atmosphere.

[0005]

[0006] The pressurized hydrogenation method recorded in the original research process has high requirements for equipment, requires the use of an autoclave, has high reaction energy consumption, and has a high safety risk factor; general factories do not have pressurized hydrogenation equipment and need to be upgraded and renovated for production. In addition, the precious metal catalyst PtO 2 The use of both increases the production cost; in addition, during the pressurized hydrogenation process, the solvent ethanol will be converted into acetaldehyde under the action of the catalyst, and acetaldehyde and compound JN-01 are easily reduced and aminated to produce a series of ethyl impurities; and due to the high temperature and pressure of the pressurized hydrogenation reaction, over-hydrogenated impurities will be produced. This series of impurities will eventually be converted into impurities of dronedarone hydrochloride API through derivatization, leading to API quality problems.

[0007] In response to the problems existing in the original research process, technicians have conducted some research on the synthesis of the intermediate 2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)-5-aminobenzofuran. Among them, Shi Chuangye et al. proposed using palladium carbon as a catalyst for catalytic hydrogenation reaction when conducting research on the synthesis process of dronedarone hydrochloride (Research on the Synthesis Process of Dronedarone Hydrochloride, Chinese Journal of Medicinal Chemistry, Vol. 34, No. 1, February 2024).

[0008]

[0009] The above method uses Pd / C to replace PtO 2 , avoiding pressurized hydrogenation, reducing the reaction temperature and improving safety. It solves the problems of pressurized production and expensive catalysts in the original research process. However, ethanol is used as the solvent in this process, and there is a possibility of producing acetaldehyde impurities under the action of the catalyst; in addition, formic acid is also used in the process, and formaldehyde impurities will inevitably be produced during the synthesis process. According to its records, the purity of the obtained compound 20 is 94%-98%. When the technicians repeated the process, they also found that there were large amounts of single impurities that were difficult to remove. Summary of the invention

[0010] In view of the deficiencies in the prior art, the object of the present invention is to provide a method for preparing 2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)-5-aminobenzofuran, a key intermediate of dronedarone hydrochloride. The present invention uses ammonium formate instead of formic acid and methanol instead of ethanol as a solvent. It is unexpectedly found that the content of single impurities in the product is greatly reduced and the purity of the intermediate is increased, which is of great significance for the control of the purity and quality of dronedarone hydrochloride API.

[0011] The present invention is achieved through the following technical solutions:

[0012] A method for preparing a key intermediate of dronedarone hydrochloride, 2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)-5-aminobenzofuran, comprises the following steps:

[0013] (1) The intermediate JN-01 was dissolved in methanol, Pd / C was added, and ammonium formate was added in batches under controlled temperature, and the reaction was stirred. After the reaction was completed, the reaction solution was concentrated to dryness, extracted with ethyl acetate-water 2-5 times, and the organic phases were combined, washed with brine, and the organic phase was spin-dried;

[0014] (2) The residue was dissolved in isopropanol, the temperature was raised, oxalic acid and n-heptane were added for crystallization, the temperature was kept, filtered, and the filter cake was dried to obtain a white powder, which was the intermediate JN-02;

[0015] The reaction equation is as follows:

[0016]

[0017] A further improvement of the present invention is:

[0018] The amount of Pd / C used is 0.04-0.1% of the mass of the intermediate JN-01.

[0019] Furthermore, the molar ratio of the intermediate JN-01, ammonium formate and oxalic acid is 1:5-10:2-3.

[0020] Furthermore, in step (1), the temperature is controlled at 20-30°C when adding ammonium formate, and the temperature of the stirring reaction is 20-30°C.

[0021] Furthermore, in step (2), the temperature is raised to 50-60°C; the insulation temperature is 20-30°C, and the insulation time is 2-5h; the drying temperature is 50-60°C, and the drying time is 4-6h.

[0022] The beneficial effects of the present invention are:

[0023] The present invention uses ammonium formate instead of formic acid and solvent methanol instead of ethanol, and the purity of the obtained JN-02 is above 99%, and the maximum single impurity content and the number of impurities are significantly reduced, which is of great significance for the control of the purity and quality of dronedarone hydrochloride API. Specifically:

[0024] 1. Ammonium formate is mainly used as a catalyst in the catalytic transfer hydrogenation reaction. It accelerates the reaction process by reducing the activation energy of the reaction, and the reaction time is reduced from 5 hours to 3 hours;

[0025] 2. Reducing the activation energy of the reaction can also reduce the reaction temperature from about 65°C to about 25°C, which reduces the probability of a series of impurities generated by the reaction with methanol and can effectively control the generation of impurities;

[0026] 3. The solvent is changed from ethanol to methanol, and acetaldehyde impurities will not be produced in the system, reducing the number of impurities;

[0027] 4. Lowering the reaction temperature can reduce energy consumption. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 HPLC spectrum of JN-02 obtained for Comparative Example 1;

[0029] Figure 2 HPLC spectrum of JN-02 obtained for Comparative Example 2;

[0030] Figure 3 HPLC spectrum of JN-02 obtained for Comparative Example 3;

[0031] Figure 4The HPLC spectrum of JN-02 obtained in Example 1;

[0032] Figure 5 The HPLC spectrum of JN-02 obtained in Example 2;

[0033] Figure 6 The HPLC spectrum of JN-02 obtained in Example 3; DETAILED DESCRIPTION

[0034] The present invention is described in detail below in conjunction with specific embodiments.

[0035] Comparative Example 1

[0036] The intermediate 2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)-5-aminobenzofuran was synthesized by the method described in the document "Study on the Synthesis Process of Dronedarone Hydrochloride" (Chinese Journal of Medicinal Chemistry, Vol. 34, No. 1, February 2024), specifically:

[0037] Add 5.0 g of the above compound JN-01, 50 ml of ethanol (10V), 0.3 g of Pd / C and 1.58 g of formic acid to the reaction bottle, raise the temperature to 60-70°C, and stir for 5 hours. Filter, control the temperature to 30-40°C, add 2.48 g of oxalic acid to the filtrate, and stir for 2 hours. Filter and dry to obtain 4.61 g of white solid. The impurity analysis of the product is shown in Tables 1 and 2.

[0038] Comparative Example 2

[0039] Add 5.0 g of the above compound JN-01, 50 ml of ethanol (10V), 0.3 g of Pd / C and 1.84 g of formic acid (1.5 mol) to the reaction bottle, raise the temperature to 60-70°C, and stir for 5 hours. Filter, control the temperature to 30-40°C, add 2.48 g of oxalic acid to the filtrate, and stir for 2 hours. Filter and dry to obtain 4.62 g of white solid. The impurity analysis of the product is shown in Tables 1 and 2.

[0040] Comparative Example 3

[0041] Add 5.0 g of the above compound JN-01, 50 ml (10 V) of ethanol, 0.3 g of Pd / C and 1.05 g of formic acid (1.0 mol) to the reaction bottle, raise the temperature to 60-70°C, and stir for 5 hours. Filter, control the temperature to 30-40°C, add 2.48 g of oxalic acid to the filtrate, and stir for 2 hours. Filter and dry to obtain 4.45 g of white solid. The impurity analysis of the product is shown in Tables 1 and 2.

[0042] Example 1

[0043] Add the above compound JN-015.0g, methanol 50ml (10V), wet Pd / C 0.2g to the reaction bottle, keep the temperature at 20-30°C, add ammonium formate 3.0g (5.0eq) in batches, and stir. After the reaction is completed by TLC monitoring, the reaction solution is concentrated to dryness, 50ml of water is added to the reaction solution, 30ml of ethyl acetate is added to extract 3 times, the organic phases are combined, 50mL of 20% brine is washed once, the organic phase is spin-dried, 50mL of isopropanol is added to the residue to dissolve, the temperature is raised to 50-60°C, 1.66g (2.3eq.) of oxalic acid is added, and 150mL of n-heptane is added for crystallization, 20-30°C is kept warm for 3.0h, filtered, and the filter cake is dried at 50-60°C for 5.0h to obtain 5.1g of white powder. The impurity analysis of the product is shown in Tables 1 and 2.

[0044] Example 2

[0045] In this embodiment, the amount of Pd / C used is 0.5 g, and the amount of ammonium formate is 6 g. Other operations are substantially the same as those in Implementation 1 and will not be described in detail herein.

[0046] Example 3

[0047] In this embodiment, the amount of Pd / C used is 0.3 g, the reaction solvent is ethanol, and other operations are substantially the same as those in Implementation 1, which will not be described in detail here.

[0048] Table 1 Comparison results of process and product purity of the embodiment and the comparative example

[0049]

[0050] Table 2 Impurity analysis results of the products of Examples and Comparative Examples

[0051]

[0052] As can be seen from Tables 1 and 2, the present invention uses ammonium formate instead of formic acid, and the purity of the prepared JN-02 is above 99%, and the maximum single impurity content is as low as 0.24%. On this basis, methanol solvent is used instead of ethanol to reduce the number of impurities, which is of great significance for the control of the purity and quality of dronedarone hydrochloride API.

Claims

1. A method for preparing a key intermediate of dronedarone hydrochloride, 2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)-5-aminobenzofuran, characterized in that: The following steps are involved: (1) The intermediate JN-01 was dissolved in methanol, Pd / C was added, and ammonium formate was added in batches under controlled temperature, and the reaction was stirred. After the reaction was completed, the reaction solution was concentrated to dryness, extracted with ethyl acetate-water 2-5 times, and the organic phases were combined, washed with brine, and the organic phase was spin-dried; (2) The residue was dissolved in isopropanol, the temperature was raised, oxalic acid and n-heptane were added for crystallization, the temperature was kept, filtered, and the filter cake was dried to obtain a white powder, which was the intermediate JN-02. The reaction equation is as follows:

2. A method for preparing a key intermediate of dronedarone hydrochloride, 2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)-5-aminobenzofuran, according to claim 1, characterized in that: The amount of Pd / C used is 0.04-0.1% of the mass of the intermediate JN-01.

3. A method for preparing a key intermediate of dronedarone hydrochloride, 2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)-5-aminobenzofuran, according to claim 1, characterized in that: The molar ratio of the intermediate JN-01, ammonium formate and oxalic acid is 1:5-10:2-3.

4. A method for preparing a key intermediate of dronedarone hydrochloride, 2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)-5-aminobenzofuran, according to claim 1, characterized in that: In step (1), the temperature is controlled at 20-30°C when adding ammonium formate, and the temperature of the stirring reaction is 20-30°C.

5. A method for preparing a key intermediate of dronedarone hydrochloride, 2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)-5-aminobenzofuran, according to claim 1, characterized in that: In step (2), the temperature is raised to 50-60°C; the insulation temperature is 20-30°C, and the insulation time is 2-5h; the drying temperature is 50-60°C, and the drying time is 4-6h.

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