CN114671836A - A kind of synthetic method of amiodarone impurity C - Google Patents

Abstract

A method for synthesizing amiodarone impurity C of the present invention comprises the following steps: (1) dissolving compound I in a solvent, under the action of a base, mix with N,N-diethyl-β-chloroethylamine hydrochloride The salt is subjected to substitution reaction to obtain intermediate 1; (2) intermediate 1 is dissolved in a solvent, and under the action of a base, reacts with elemental iodine to obtain amiodarone impurity C; the present invention is simple in operation and low in cost, and is synthesized according to the method. Amiodarone impurity C, as an impurity reference substance, provides a qualified, low-cost and easy-to-obtain reference substance for the quality control of amiodarone, and provides important guiding significance for the production of amiodarone drugs and safe medication.

Description

A kind of synthetic method of amiodarone impurity C

technical field

The invention belongs to the technical field of medicine, and in particular relates to a preparation method of amiodarone hydrochloride impurity C.

Background technique

Amiodarone, also known as amiodarone, amiodarone (or its hydrochloride CAS: 19774-82-4) is a third drug widely used in the treatment and prevention of ventricular and supraventricular arrhythmias. Antiarrhythmic drugs. The number of patients with cardiovascular disease in modern society has risen sharply, and the demand for such drugs is also increasing. Based on stable efficacy and low side effects, the market share of amiodarone hydrochloride continues to expand. Correspondingly, the research and synthesis method of amiodarone impurity have also been widely reported, and it is found that there are not many documents that the amiodarone European Pharmacopoeia EP impurity C synthesis method is reported at present. Therefore, it is of great significance to find a synthesis method of amiodarone impurity C with simple operation, low cost, easy separation and purification, and high yield. The following inventions are hereby proposed:

Amiodarone hydrochloride, its structural formula is as follows:

Amiodarone hydrochloride impurity C structural formula is as follows:

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

In the first step, compound I was dissolved in methanol, sodium iodide and sodium hydroxide were added, the temperature was lowered to -5 °C, and sodium hypochlorite was added dropwise. After the reaction was completed, the reaction was quenched with dilute hydrochloric acid. The yield of two iodine by-products was 11%. In the second step, N,N-diethyl-β-chloroethylamine hydrochloride is docked under the action of alkali, and the target product is obtained by the reaction. In the literature, the first step reaction yield is on the low side, impurities are many, and the polarities of the intermediate 1 and the upper two iodine by-products are similar, and separation and purification are difficult. Therefore it is very necessary to find a high yield, low cost, simple operation, easy separation and purification method to synthesize amiodarone impurity C, and it is of great significance to improve the drug quality standard.

SUMMARY OF THE INVENTION

In order to solve the above problems, the present invention discloses a kind of synthetic method of amiodarone impurity C with low cost, simple operation, high yield and easy separation and purification.

For achieving the above object, technical scheme of the present invention is as follows:

A kind of synthetic method of amiodarone impurity C, comprises the following steps:

(1) compound I is dissolved in solvent, under the action of alkali, carry out substitution reaction with N,N-diethyl-β-chloroethylamine hydrochloride to obtain intermediate 1;

(2) Intermediate 1 is dissolved in a solvent and reacted with elemental iodine under the action of a base to obtain amiodarone impurity C.

The concrete synthesis process route of amiodarone impurity C is as follows:

Further, in step (1), the molar ratio of the compound I to N,N-diethyl-β-chloroethylamine hydrochloride is 1:1.0-4.0, preferably, the compound I and N, The molar ratio of N-diethyl-β-chloroethylamine hydrochloride was 1:1.2.

Further, in step (1), the molar ratio of the base to the compound I is 1.0-4.0:1.0, preferably, the molar ratio of the base to the compound I is 2.0:1.0; the volume of the solvent and the compound I The ratio is 1.0-100.0:1.0, preferably, the volume ratio of the solvent to compound I is 30.0:1.0.

Further, in step (1), the alkali is one or more of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, preferably, the alkali is potassium carbonate ; Described solvent is one or more in toluene, water, acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, preferably, described solvent is the mixture of water and toluene .

Further, 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 The reaction time was 1 hour.

Further, in step (2), the mol ratio of described intermediate 1 and iodine elemental substance is 1:0.5-3.0, preferably, the mol ratio of described intermediate and iodine elemental substance is 1:0.9.

Further, 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 solvent and the intermediate The volume ratio of 1 is 1.0-100.0:1.0, preferably, the volume ratio of the solvent to the intermediate 1 is 20.0:1.0.

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

Further, in step (2), the temperature of the reaction is 0-30°C, preferably, the temperature of the reaction is 0-5°C; the reaction time is 2-12 hours, preferably, the reaction time is 2-12 hours. The time is 6 hours.

The beneficial effects of the present invention are:

The synthetic method of amiodarone impurity C of the present invention changes the synthetic route of first adding iodine and then docking N,N-diethyl-β-chloroethylamine hydrochloride in the original report document, and changing to first docking N, N-diethyl-β-chloroethylamine hydrochloride, and then react with iodine at low temperature to add iodine. The method has the advantages of high yield, simple operation, low cost and easy separation and purification. A qualified and low-cost impurity reference substance is provided for the quality control of amiodarone hydrochloride.

Description of drawings

Fig. 1 is the hydrogen nuclear magnetic spectrum of the product obtained in Example 4 of the present invention;

Fig. 2 is the mass spectrogram of the product obtained in Example 4 of the present invention;

Fig. 3 is the HPLC spectrogram of the product obtained in Example 4 of the present invention;

Fig. 4 is the synthetic process route of the present invention.

Detailed ways

Below in conjunction with the accompanying drawings and specific embodiments, the present invention will be further explained, and it should be understood that the following specific embodiments are only used to illustrate the present invention and not to limit the scope of the present invention.

Example 1

In a 500ml three-necked flask, add 10.0g (0.034mol) of compound I, add 100ml of water and 200ml of toluene; add 9.4g (0.068mol) of potassium carbonate, the system is cloudy white, heat up to 50-55°C, add 7.0g in batches (0.041mol) N,N-diethyl-β-chloroethylamine hydrochloride, the system gradually dissolved and cleared during the process. The temperature was raised to 80-85°C for 1 hour. TLC detected that the reaction was complete, the reaction solution was cooled, 50 ml of water was added, the organic phase was separated by layers, the aqueous phase was extracted with 100 ml*2 ethyl acetate, the combined organic phases were washed with 50 ml of saturated brine, dried by adding 20 g of anhydrous sodium sulfate, and filtered. The salt was removed, and the solvent was removed by concentration; 11.5 g of intermediate 1 was obtained by column chromatography (pure EA), the yield was 85%, and the HPLC purity was 95%.

Example 2

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

Example 3

In a 500ml three-necked flask, add 10.0g (0.034mol) of compound I, add 300ml of acetonitrile; add 18.7g (0.136mol) of potassium carbonate, the system is cloudy white, warm up to 50-55°C, add 23.4g (0.136mol) in batches ) N,N-diethyl-β-chloroethylamine hydrochloride, the system gradually dissolves and clears during the process. The temperature was raised to 80-85°C for 2 hours. TLC detected that the reaction was complete, the reaction solution was cooled, 50ml of water was added, the organic phase was separated by layers, the aqueous phase was extracted with 100ml*2 ethyl acetate, the combined organic phases were washed with 50ml of saturated brine, dried by adding 20g of anhydrous sodium sulfate, and filtered. The salt was removed, and the solvent was removed by concentration; 10.2 g of intermediate 1 was obtained by column chromatography (pure EA), the yield was 76.1%, and the HPLC purity was 90%.

Example 4

In a 500ml three-necked flask, add 230ml of methanol, add 11.5g (0.029mol) of intermediate 1, cool down to 0-5°C in an ice bath, and add 1.2g (0.029mol) of sodium hydroxide. Keeping the temperature at 0-5° C., 6.6 g (0.026 mol) of elemental iodine was added in 10 batches. After adding, the reaction was incubated for 6 hours, and the HPLC detection reaction showed that the remaining 15% of the raw material, the mono-iodine target product accounted for 75%, and the diiodine by-product accounted for 10%. Add 200ml of water to the system and stir for 10 minutes, concentrate at low temperature to remove most of the methanol solvent, add 200ml*2 of ethyl acetate for extraction, combine the organic phases by layering, add 50ml of saturated brine to wash the organic phase, add 20g of anhydrous sodium sulfate to the layered organic phase Dry and suction filter, concentrate the filtrate to dryness, obtain 12.3 g of crude product through column chromatography (pure EA), recrystallize with 60 ml of acetonitrile to obtain 10.2 g, add 100 ml of methanol to dissolve, dropwise add hydrochloric acid methanol to adjust the pH to 6, and a large amount of white solids are precipitated , stirred for 0.5 hours, suction filtered, the filter cake was rinsed with a small amount of methanol, and dried to obtain 9.4 g of the target product, the yield was 62.7%, and the HPLC purity was 98%.

Example 5

In a 500ml three-necked flask, add 230ml of methanol, add 11.5g (0.029mol) of intermediate 1, cool down to 5-10°C in an ice bath, and add 8.0g (0.058mol) of potassium carbonate. Keeping the temperature at 5-10° C., 7.4 g (0.029 mol) of elemental iodine was added in 10 batches. After adding, the reaction was incubated for 12 hours, and the HPLC detection reaction showed that the remaining 6% of the raw material, the mono-iodine target product accounted for 70%, and the diiodine by-product accounted for 20%. Add 200ml of water to the system and stir for 10 minutes, concentrate at low temperature to remove most of the methanol solvent, add 200ml*2 of ethyl acetate for extraction, combine the organic phases by layering, add 50ml of saturated brine to wash the organic phase, add 20g of anhydrous sodium sulfate to the layered organic phase Dry and suction filter, concentrate the filtrate to dryness, obtain 10.6g of crude product by column chromatography (pure EA), recrystallize with 60ml of acetonitrile to obtain 9.1g, add 100ml of methanol to dissolve, dropwise add hydrochloric acid methanol to adjust the pH to 6, and a large amount of white solids are precipitated , stirred for 0.5 hours, suction filtered, the filter cake was rinsed with a small amount of methanol, and dried to obtain 8.6 g of the target product, the yield was 57.3%, and the HPLC purity was 87%.

Example 6

In a 500ml three-necked flask, add 230ml of methanol, add 11.5g (0.029mol) of intermediate 1, cool down to 5-10°C in an ice bath, and add 2.8g (0.116mol) of lithium hydroxide. Keeping the temperature at 5-10° C., 6.6 g (0.026 mol) of elemental iodine was added in 10 batches. After adding, the reaction was incubated for 6 hours, and the HPLC detection reaction showed that the remaining 30% of the raw material, the mono-iodine target product accounted for 60%, and the diiodine by-product accounted for 10%. Add 200ml of water to the system and stir for 10 minutes, concentrate at low temperature to remove most of the methanol solvent, add 200ml*2 of ethyl acetate for extraction, combine the organic phases by layering, add 50ml of saturated brine to wash the organic phase, add 20g of anhydrous sodium sulfate to the layered organic phase Dry and suction filter, concentrate the filtrate to dryness, obtain 10.3 g of crude product through column chromatography (pure EA), recrystallize with 60 ml of acetonitrile to obtain 8.3 g, add 100 ml of methanol to dissolve, dropwise add hydrochloric acid methanol to adjust the pH to 6, and a large amount of white solids are precipitated , stirred for 0.5 hours, suction filtered, the filter cake was rinsed with a small amount of methanol, and dried to obtain 8.1 g of the target product, the yield was 54.0%, and the HPLC purity was 91%.

It should be noted that the above content only illustrates the technical idea of the present invention, and cannot limit the protection scope of the present invention. Several improvements and modifications can be made, which all fall within the protection scope of the claims of the present invention.

Claims (9)

1. a synthetic method of amiodarone impurity C, is characterized in that, comprises the following steps: (1) dissolving compound I in a solvent, and under the action of a base, carry out a substitution reaction with N,N-diethyl-β-chloroethylamine hydrochloride to obtain intermediate 1;

(2) Intermediate 1 is dissolved in a solvent, and under the action of alkali, reacts with elemental iodine to obtain amiodarone impurity C;

2. the synthetic method of a kind of amiodarone impurity C according to claim 1, is characterized in that, in step (1), described compound I and N,N-diethyl-β-chloroethylamine hydrochloride The molar ratio of the salt is 1:1.0-4.0. 3. the synthetic method of a kind of amiodarone impurity C according to claim 1, is characterized in that, in step (1), the mol ratio of described base and compound I is 1.0-4.0:1.0; The volume ratio of compound I is 1.0-100:1.0. 4. the synthetic method of a kind of amiodarone impurity C according to claim 1, is characterized in that, in step (1), described alkali is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide , one or more of lithium hydroxide; the solvent is one or more of toluene, water, acetonitrile, acetone, tetrahydrofuran, N,N-dimethylformamide and dimethyl sulfoxide. 5. the synthetic method of a kind of amiodarone impurity C according to claim 1, is characterized in that, in step (1), the temperature of described substitution reaction is 30-90 ℃, and the time of reaction is 1-6 hour . 6. the synthetic method of a kind of amiodarone impurity C according to claim 1, is characterized in that, in step (2), the mol ratio of described intermediate 1 and iodine elemental substance is 1:0.5-5.0. 7. the synthetic method of a kind of amiodarone EP impurity according to claim 1, is characterized in that, in step (2), the mol ratio of described alkali and intermediate 1 is 1.0-5.0:1.0; Described solvent The volume ratio to Intermediate 1 is 1.0-100:1.0. 8. the synthetic method of a kind of amiodarone impurity C according to claim 1, is characterized in that, in step (2), described alkali is potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide , one or more of lithium hydroxide; the solvent is one or more of methanol, ethanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, and ethyl acetate. 9. the synthetic method of a kind of amiodarone impurity C according to claim 1, is characterized in that, in step (2), the temperature of described reaction is 0-30 ℃, and the time of reaction is 2-12 hours.

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