A synthetic method for amiodarone impurity C

Abstract

The invention discloses a method for synthesizing an amiodarone impurity C, comprising the following steps: (1) dissolving a compound I in a solvent, and reacting the compound I with N,N-diethyl-β-chloroethylamine hydrochloride under the action of a base to obtain an intermediate 1; (2) dissolving the intermediate 1 in a solvent, and reacting the compound I with an iodine element under the action of a base to obtain the amiodarone impurity C. The method is simple to operate and low in cost. The amiodarone impurity C synthesized according to the method is used as an impurity reference substance, providing a qualified, low-cost and easily available reference substance for the quality control of amiodarone, and providing important guiding significance for the production and safe use of amiodarone drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a method for preparing an impurity C of amiodarone hydrochloride. Background Art

[0002] Amiodarone (Amiodarone) is also known as amiodarone, and amiodarone (or its hydrochloride CAS: 19774-82-4) is a third-class antiarrhythmic drug widely used in the treatment and prevention of ventricular and supraventricular arrhythmias. In modern society, the number of patients with cardiovascular diseases has increased significantly, and the demand for this type of drug is also increasing. Based on stable efficacy and low side effects, the market share of amiodarone hydrochloride continues to expand. Corresponding research and synthesis methods of amiodarone impurities have also been widely reported. It is found that there are not many documents reporting on the synthesis method of amiodarone European Pharmacopoeia EP impurity C. Therefore, it is of great significance to find a method for synthesizing amiodarone impurity C that is simple to operate, low in cost, easy to separate and purify, and has a high yield. The following invention is specially proposed:

[0003] Amiodarone hydrochloride has the following structural formula:

[0004]

[0005] The structural formula of the impurity C of amiodarone hydrochloride is as follows:

[0006]

[0007] Bioorganic & Medicinal Chemistry Letters 18 (2008) 5920–5922 publicly reported a method for synthesizing amiodarone impurity C as follows:

[0008]

[0009] In the first step, compound I is dissolved in methanol, sodium iodide and sodium hydroxide are added, sodium hypochlorite is added dropwise after cooling to -5°C, and the reaction is quenched with dilute hydrochloric acid. The intermediate 1 is purified by post-treatment, with a yield of 25%, and the yield of the above two iodine byproducts is 11%. In the second step, N,N-diethyl-β-chloroethylamine hydrochloride is docked under the action of a base to obtain the target product. In the literature, the yield of the first step reaction is low, there are many impurities, and the generated intermediate 1 and the above two iodine byproducts have similar polarity, which makes separation and purification difficult. Therefore, it is very necessary to find a method with high yield, low cost, simple operation, and easy separation and purification to synthesize amiodarone impurity C, which is of great significance to improving drug quality standards. Summary of the invention

[0010] In order to solve the above problems, the present invention discloses a method for synthesizing amiodarone impurity C which has low cost, simple operation, high yield and is easy to separate and purify.

[0011] To achieve the above object, the technical solution of the present invention is as follows:

[0012] A method for synthesizing amiodarone impurity C comprises the following steps:

[0013] (1) Compound I is dissolved in a solvent, and subjected to a substitution reaction with N,N-diethyl-β-chloroethylamine hydrochloride in the presence of a base to obtain intermediate 1;

[0014] (2) Intermediate 1 is dissolved in a solvent and reacts with iodine in the presence of a base to obtain amiodarone impurity C.

[0015] The specific synthetic process route of amiodarone impurity C is as follows:

[0016]

[0017] Furthermore, in step (1), the molar ratio of compound I to N,N-diethyl-β-chloroethylamine hydrochloride is 1:1.0-4.0. Preferably, the molar ratio of compound I to N,N-diethyl-β-chloroethylamine hydrochloride is 1:1.2.

[0018] Furthermore, in step (1), the molar ratio of the base to compound I is 1.0-4.0:1.0, preferably, the molar ratio of the base to compound I is 2.0:1.0; the volume ratio of the solvent to compound I is 1.0-100.0:1.0, preferably, the volume ratio of the solvent to compound I is 30.0:1.0.

[0019] Furthermore, in step (1), the base is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide, preferably, the base is potassium carbonate; the solvent is one or more of toluene, water, acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide, preferably, the solvent is a mixture of water and toluene.

[0020] Furthermore, in step (1), the temperature of the substitution reaction is 30-90° C., preferably, the temperature of the substitution reaction is 80-85° C., and the reaction time is 1-6 hours, preferably, the reaction time is 1 hour.

[0021] Furthermore, in step (2), the molar ratio of the intermediate 1 to the iodine element is 1:0.5-3.0, preferably, the molar ratio of the intermediate to the iodine element is 1:0.9.

[0022] Furthermore, in step (2), the molar ratio of the base to the intermediate 1 is 1.0-5.0:1.0, preferably, the molar ratio of the base to the intermediate 1 is 1.0:1.0; the volume ratio of the solvent to the intermediate 1 is 1.0-100.0:1.0, preferably, the volume ratio of the solvent to the intermediate 1 is 20.0:1.0.

[0023] Furthermore, in step (2), the base is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide, and preferably, the base is sodium hydroxide; the solvent is one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, and ethyl acetate, and preferably, the solvent is methanol.

[0024] Furthermore, in step (2), the reaction temperature is 0-30° C., preferably, the reaction temperature is 0-5° C.; the reaction time is 2-12 hours, preferably, the reaction time is 6 hours.

[0025] The beneficial effects of the present invention are:

[0026] The synthesis method of the amiodarone impurity C of the present invention changes the synthesis route of first adding iodine and then docking N, N-diethyl-β-chloroethylamine hydrochloride in the original reported literature, and changes it to first docking N, N-diethyl-β-chloroethylamine hydrochloride and then reacting with iodine element at low temperature to add iodine. The method has high yield, simple operation, low cost, and is easy to separate and purify. A qualified and low-cost impurity reference substance is provided for the quality control of amiodarone hydrochloride. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the H NMR spectrum of the product obtained in Example 4 of the present invention;

[0028] Figure 2 is the mass spectrum of the product obtained in Example 4 of the present invention;

[0029] Figure 3 This is the HPLC spectrum of the product obtained in Example 4 of the present invention;

[0030] Figure 4 This is the synthetic process route of the present invention. DETAILED DESCRIPTION

[0031] The present invention will be further explained below in conjunction with the accompanying drawings and specific embodiments. It should be understood that the following specific embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0032] Example 1

[0033] In a 500ml three-necked flask, add 10.0g (0.034mol) of compound I, 100ml of water and 200ml of toluene; add 9.4g (0.068mol) of potassium carbonate, the system is turbid white, heat to 50-55°C, add 7.0g (0.041mol) of N,N-diethyl-β-chloroethylamine hydrochloride in batches, and the system gradually dissolves and becomes clear during the process. Heat to 80-85°C and react for 1 hour. TLC detection shows that the reaction is complete, the reaction solution is cooled, 50ml of water is added, the organic phase is separated by layers, the aqueous phase is extracted with 100ml*2 ethyl acetate, the organic phases are combined and washed with 50ml of saturated brine, 20g of anhydrous sodium sulfate is added for drying, the salt is removed by filtration, and the solvent is removed by concentration; 11.5g of intermediate 1 is obtained by column chromatography (pure EA), the yield is 85%, and the HPLC purity is 95%.

[0034] Example 2

[0035] In a 500ml three-necked flask, add 10.0g (0.034mol) of compound I and 100ml of acetone; add 1.4g (0.034mol) of sodium hydroxide, the system is turbid white, heat to 50-55°C, add 11.7g (0.068mol) of N,N-diethyl-β-chloroethylamine hydrochloride in batches, and the system gradually dissolves and becomes clear during the process. Heat to 80-85°C and react for 1.5 hours. TLC detection shows that the reaction is complete, the reaction solution is cooled, 50ml of water is added, the organic phase is separated by layers, the aqueous phase is extracted with 100ml*2 ethyl acetate, the organic phases are combined and washed with 50ml of saturated brine, 20g of anhydrous sodium sulfate is added for drying, the salt is removed by filtration, and the solvent is removed by concentration; 10.7g of intermediate 1 is obtained by column chromatography (pure EA), the yield is 79.9%, and the HPLC purity is 94%.

[0036] Example 3

[0037] In a 500ml three-necked flask, add 10.0g (0.034mol) of compound I and 300ml of acetonitrile; add 18.7g (0.136mol) of potassium carbonate, the system is turbid white, heat to 50-55°C, add 23.4g (0.136mol) of N, N-diethyl-β-chloroethylamine hydrochloride in batches, and the system gradually dissolves and becomes clear during the process. Heat to 80-85°C and react for 2 hours. TLC detection shows that the reaction is complete, the reaction solution is cooled, 50ml of water is added, the organic phase is separated by layers, the aqueous phase is extracted with 100ml*2 ethyl acetate, the organic phases are combined and washed with 50ml of saturated brine, 20g of anhydrous sodium sulfate is added for drying, the salt is removed by filtration, and the solvent is removed by concentration; 10.2g of intermediate 1 is obtained by column chromatography (pure EA), the yield is 76.1%, and the HPLC purity is 90%.

[0038] Example 4

[0039] In a 500ml three-necked flask, add 230ml methanol, add 11.5g (0.029mol) of intermediate 1, cool to 0-5℃ in an ice bath, add 1.2g (0.029mol) of sodium hydroxide. Keep the temperature at 0-5℃, and add 6.6g (0.026mol) of elemental iodine in 10 batches. After adding, keep warm and react for 6 hours. HPLC detection reaction shows that the raw material remains 15%, the monoiodine target product accounts for 75%, and the diiodine by-product accounts for 10%. 200 ml of water was added to the system and stirred for 10 minutes. Most of the methanol solvent was removed by low temperature concentration. 200 ml of ethyl acetate was added for extraction. The organic phases were separated and combined, and 50 ml of saturated brine was added to wash the organic phase. 20 g of anhydrous sodium sulfate was added to the separated organic phases, dried and filtered, and the filtrate was concentrated to dryness. 12.3 g of crude product was obtained by column chromatography (pure EA). 10.2 g was obtained by recrystallization with 60 ml of acetonitrile. 100 ml of methanol was added to dissolve it, and hydrochloric acid and methanol were added dropwise to adjust the pH to 6. A large amount of white solid precipitated. Stir for 0.5 hour, filter, add a small amount of methanol to the filter cake for elution, and dry to obtain 9.4 g of the target product with a yield of 62.7% and a purity of 98% by HPLC.

[0040] Example 5

[0041] In a 500ml three-necked flask, add 230ml methanol, add 11.5g (0.029mol) of intermediate 1, cool to 5-10°C in an ice bath, add 8.0g (0.058mol) of potassium carbonate. Keep the temperature at 5-10°C, and add 7.4g (0.029mol) of elemental iodine in 10 batches. After the addition, keep the reaction warm for 12 hours. HPLC detection of the reaction shows that the raw material remains 6%, the monoiodine target product accounts for 70%, and the diiodine by-product accounts for 20%. 200 ml of water was added to the system and stirred for 10 minutes. Most of the methanol solvent was removed by low temperature concentration. 200 ml of ethyl acetate was added for extraction. The organic phases were separated and combined, and 50 ml of saturated brine was added to wash the organic phase. 20 g of anhydrous sodium sulfate was added to the separated organic phases, dried and filtered, and the filtrate was concentrated to dryness. 10.6 g of crude product was obtained by column chromatography (pure EA). 9.1 g was obtained by recrystallization with 60 ml of acetonitrile. 100 ml of methanol was added to dissolve it, and hydrochloric acid and methanol were added dropwise to adjust the pH to 6. A large amount of white solid precipitated. It was stirred for 0.5 hour, filtered, and the filter cake was rinsed with a small amount of methanol. 8.6 g of the target product was obtained by drying. The yield was 57.3% and the HPLC purity was 87%.

[0042] Example 6

[0043] In a 500ml three-necked flask, add 230ml methanol, add 11.5g (0.029mol) of intermediate 1, cool to 5-10°C in an ice bath, add 2.8g (0.116mol) of lithium hydroxide. Keep the temperature at 5-10°C, and add 6.6g (0.026mol) of elemental iodine in 10 batches. After the addition, keep the temperature for 6 hours. HPLC detection of the reaction shows that the raw material remains 30%, the monoiodine target product accounts for 60%, and the diiodine by-product accounts for 10%. 200 ml of water was added to the system and stirred for 10 minutes. Most of the methanol solvent was removed by low temperature concentration. 200 ml of ethyl acetate was added for extraction. The organic phases were separated and combined, and 50 ml of saturated brine was added to wash the organic phase. 20 g of anhydrous sodium sulfate was added to the separated organic phases, dried and filtered, and the filtrate was concentrated to dryness. 10.3 g of crude product was obtained by column chromatography (pure EA). 8.3 g was obtained by recrystallization with 60 ml of acetonitrile. 100 ml of methanol was added to dissolve it, and hydrochloric acid and methanol were added dropwise to adjust the pH to 6. A large amount of white solid precipitated. The mixture was stirred for 0.5 hour, filtered, and the filter cake was rinsed with a small amount of methanol. 8.1 g of the target product was obtained by drying. The yield was 54.0% and the HPLC purity was 91%.

[0044] It should be noted that the above content only illustrates the technical idea of ​​the present invention and cannot be used to limit the protection scope of the present invention. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications all fall within the protection scope of the claims of the present invention.

Claims

1. A method for synthesizing an amiodarone impurity C, characterized in that: The following steps are involved: (1) Compound I is dissolved in a solvent, and subjected to a substitution reaction with N,N-diethyl-β-chloroethylamine hydrochloride in the presence of a base to obtain intermediate 1; ； (2) Intermediate 1 is dissolved in a solvent and reacts with iodine in the presence of a base to obtain amiodarone impurity C; ； In step (1), the molar ratio of compound I to N,N-diethyl-β-chloroethylamine hydrochloride is 1:1.0-4.0; In step (1), the molar ratio of the base to compound I is 1.0-4.0:1.0; In step (1), the base is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide; In step (1), the temperature of the substitution reaction is 30-90° C., and the time of the substitution reaction is 1-6 hours; In step (2), the molar ratio of the intermediate 1 to the iodine element is 1:0.5-5.0; In step (2), the molar ratio of the base to the intermediate 1 is 1.0-5.0:1.0; In step (2), the base is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide; In step (2), the reaction temperature is 0-30° C. and the reaction time is 2-12 hours.

2. The method for synthesizing an amiodarone impurity C according to claim 1, characterized in that: In step (1), the volume ratio of the solvent to compound I is 1.0-100:1.

0.

3. The method for synthesizing an amiodarone impurity C according to claim 1, characterized in that: In step (1), the solvent is one or more of toluene, water, acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide.

4. The method for synthesizing an amiodarone impurity C according to claim 1, characterized in that: In step (2), the volume ratio of the solvent to the intermediate 1 is 1.0-100:1.

0.

5. The method for synthesizing an amiodarone impurity C according to claim 1, characterized in that: In step (2), the solvent is one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, and ethyl acetate.

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