Amiodarone hydrochloride injection and preparation method thereof

Abstract

The present invention relates to amiodarone hydrochloride injection and a preparation method thereof. On the one hand, it relates to an amiodarone hydrochloride injection, which comprises amiodarone hydrochloride 50mg, benzyl alcohol 20mg, 100mg Tween-80, and water for injection is added to 3ml in an appropriate amount. The injection preparation method is: dissolve benzyl alcohol with an appropriate amount of water for injection, and set aside; mix amiodarone hydrochloride, Tween-80, and propylene glycol evenly, heat, and add water for injection thereto under insulation and stirring to dissolve the material; slowly add benzyl alcohol solution to amiodarone hydrochloride solution under insulation and stirring, add water for injection to the full amount, and adjust the pH value of the liquid to 3-3.2; fill nitrogen into the liquid under continuous stirring and allow the liquid to cool naturally, filter with a microporous filter membrane, and then fill the liquid into an ampoule under nitrogen filling conditions, seal it, and obtain it. The present invention also relates to a preparation method of the injection and their pharmaceutical uses. The injection of the present invention has excellent performance.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and relates to a drug for treating heart diseases, especially for treating severe arrhythmias, and is particularly suitable for atrial arrhythmias with rapid ventricular rhythms, tachycardia of WPW syndrome, severe ventricular arrhythmias, cardiopulmonary resuscitation of ventricular fibrillation-related cardiac arrest ineffective with external defibrillation, and other heart diseases, and specifically relates to a stable amiodarone hydrochloride, and a preparation method and pharmaceutical use thereof. Further, the present invention also relates to an amiodarone hydrochloride injection with excellent properties, and a preparation method and pharmaceutical use thereof. Background Art

[0002] Amiodarone Hydrochloride, its chemical name is: (2-butyl-3-benzofuranyl) [4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl] ketone hydrochloride. Its molecular formula is C25H29I2NO3·HCl, its molecular weight is 681.77, and its chemical structure is:

[0003]

[0004] Amiodarone hydrochloride is a white to slightly yellow crystalline powder, odorless; it is easily soluble in chloroform, soluble in ethanol, slightly soluble in acetone, and almost insoluble in water. The melting point of amiodarone hydrochloride is 158-162°C, and it decomposes when it melts.

[0005] Amiodarone hydrochloride is the most widely used antiarrhythmic drug in clinical practice. It is a cardiac ion multichannel blocker with Class III pharmacological effects as the main one, and has the electrophysiological effects of Class I, II, and IV antiarrhythmic drugs. Intravenous injection shows that the pharmacological effects of Class I, Class II, and Class IV are faster, and the onset time of Class III pharmacological effects is longer. The therapeutic effect on severe and fatal arrhythmias is very obvious. Currently, oral tablets and capsules are commonly used, but amiodarone hydrochloride is slowly and incompletely absorbed in the gastrointestinal tract, with large individual differences, unstable bioavailability, and an absolute bioavailability of only 50%. The oral onset and clearance are slow, and it takes several days to weeks for it to take effect. In cases where oral administration is not suitable and severe arrhythmias occur, it can take effect within 30 minutes after intravenous administration, and the onset of effect is significantly accelerated.

[0006] The prior art discloses some methods for preparing amiodarone hydrochloride. For example, CN104262304A (Chinese patent application No. 201410463582.7, Yang Jun) provides a method for synthesizing amiodarone hydrochloride, a class of anti-cardiac drugs, using salicylaldehyde as a starting material, and reacting with 2-halogenated hexanoic acid alkyl ester, p-methoxybenzoyl chloride, iodine and 2-diethylamino chloroethane hydrochloride in sequence under the action of a catalyst to gradually obtain 2-butylbenzofuran, 2-butyl-3-(4-hydroxybenzoyl)benzofuran, 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran and (2-butyl-3-benzofuranyl)[4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]methanone hydrochloride, i.e. amiodarone hydrochloride. It is believed that the synthesis method of the invention has simple process, convenient operation, good safety performance and high yield.

[0007] CN107382925B (Chinese patent application No. 201710595820.3, Wanrun) relates to a method for preparing amiodarone hydrochloride, which mainly uses 2-hydroxybenzaldehyde and 2-bromohexanoic acid alkyl ester as raw materials to prepare 2-butylbenzofuran, and uses 2-butylbenzofuran as raw material to prepare amiodarone hydrochloride through Friedel-Crafts acylation, demethylation, iodination, etherification and salt formation. It is believed that the raw materials of the invention method are cheap and easy to obtain, the process is simple, and high-purity and high-yield 2-butylbenzofuran and amiodarone hydrochloride can be obtained, the cost is low, the wastewater is small, and it is suitable for industrial production.

[0008] CN109988131A (Chinese patent application No. 201711472369.2, Puli) relates to a method for preparing amiodarone hydrochloride, wherein the synthesis of the intermediate 2-butylbenzofuran is prepared by Sonogashira coupling cyclization reaction of 2-classical phenol and 1-acetylene in an organic solvent under the action of a catalyst, a co-catalyst and an acid binding agent, wherein the molar ratio of 2-classical phenol to 1-acetylene is 1:0.9-1.3, the reaction temperature is 30°C-60°C, and the reaction time is 12-38 hours. It is believed that the inventive method simplifies the operation, improves the convenience of operation and the stability of the product compared to the existing production process. By controlling the catalyst and material ratio, the purity and yield of each intermediate are improved, and the product does not need column chromatography purification, which saves costs while improving production efficiency, and provides convenience for industrial large-scale production.

[0009] CN109988132B (Chinese Patent Application No. 201910313325.8, Hengkang) provides a method for preparing amiodarone hydrochloride, using methyl parahydroxybenzoate as the main raw material, and sequentially undergoing substitution reaction, etherification reaction, hydrolysis reaction, chlorination reaction, Friedel-Crafts reaction, amination reaction and acidification to obtain amiodarone hydrochloride. It is believed that the preparation method provided by the invention method does not require the process of demethoxylation under the action of anhydrous aluminum chloride, reducing the use of anhydrous aluminum chloride in one step, greatly reducing environmental pollution, and while using dichlorothionyl to chlorinate the carboxyl group of 3,5-diiodo-4-(2-hydroxyethoxy)-benzoic acid, the terminal hydroxyl group is chlorinated, shortening the synthesis route. It is believed that the preparation method provided by the invention has a simple process, low cost, low pollution and high yield.

[0010] CN113527236A (Chinese patent application No. 202110960663.8, Hongsen) discloses a method for preparing amiodarone hydrochloride, including: using 2-butylbenzofuran and p-acetoxybenzaldehyde as raw materials, aldol reaction occurs under Lewis acid catalysis and heating conditions, and the product undergoes hydroxyl oxidation, deacetylation and iodination reaction simultaneously under the conditions of iodine and alkali, and then the product reacts with N, N-diethylchloroethylamine and forms salts to obtain amiodarone hydrochloride. It is believed that the inventive method only requires the use of a catalytic amount of Lewis acid, does not require the participation of strongly acidic aluminum chloride, the reaction conditions are milder, there are fewer by-products, it is easy to post-process, and the three wastes are greatly reduced; the operation of the entire route is simple, and the reagents used are cheap, easy to obtain, and non-toxic, which is very suitable for industrial production.

[0011] Multiple versions of the Chinese Pharmacopoeia include amiodarone hydrochloride and its preparations, including injections, tablets, and capsules. There are also powder injections, dispersible tablets and other dosage forms on the market in China. However, as recorded in the Chinese Pharmacopoeia's amiodarone hydrochloride raw materials and injections, amiodarone hydrochloride has a low melting point and decomposes when it melts. The control limit of impurity II of the injection-related substances is as high as 1.6%, while the control limit of impurity D (the same impurity as the above-mentioned impurity II) of the amiodarone hydrochloride injection-related substances in the United States Pharmacopoeia USP2021 is as high as 3%, indicating that amiodarone has poor stability, especially the diethylaminoethyl part is easy to break.

[0012] An amiodarone hydrochloride injection with the trade name Cordarone (H20181049, Sanofi-Aventis France) has been used clinically for many years. The specification of the Cordarone injection is 3ml:0.15g, containing 150mg amiodarone hydrochloride, 60mg benzyl alcohol, 300g polysorbate 80, and water for injection added to 3.0ml.

[0013] The prior art discloses some methods for preparing amiodarone hydrochloride injection. For example, CN104414970A (Chinese patent application No. 201310408517.X, Lisite) discloses an amiodarone hydrochloride injection and a preparation method thereof, which is prepared by amiodarone hydrochloride accounting for 5.00% by volume of the injection, benzyl alcohol accounting for 2.0% by volume of the injection, HS-15 accounting for 5.00% to 15% by volume of the injection, and water for injection. Preparation method of amiodarone hydrochloride injection: take 30-40℃ water for injection, add 5.00% to 15% HS-15 by volume of the injection, stir evenly, then add 2.0% benzyl alcohol by volume of the injection, stir evenly, maintain the solvent temperature at 30-40℃, slowly add 5.00% amiodarone hydrochloride by weight volume of the injection until it is completely dissolved, add water for injection to the full amount, adjust the pH value to 3.5-5.5 with sodium hydroxide, filter with 0.22μm microporous filter membrane, and then fill and seal. It is believed that the invention adopts a new prescription and process, and the product made is not only of stable quality but also greatly improves the safety of clinical medication.

[0014] CN104887619A (Chinese patent application No. 201410074784.2, Puli) relates to amiodarone hydrochloride injection and its preparation method. Amiodarone hydrochloride injection contains 1mg to 2mg of amiodarone hydrochloride and 5 to 15mg of polyamide-amine dendrimer in each ml of injection. The pH value is adjusted to 3.5 to 4 by a pH regulator, and the osmotic pressure regulator adjusts the osmotic pressure to isotonic.

[0015] CN112472668A (Chinese Patent Application No. 202011207802.1, Sunrise) discloses a method for preparing amiodarone hydrochloride injection, the method comprising the following steps: weighing the prescription amount of polysorbate, amiodarone hydrochloride, benzyl alcohol and water for injection; while controlling part of the water for injection at a temperature within the range of 60-75°C and filling with nitrogen, adding polysorbate to obtain a polysorbate solution and adding amiodarone hydrochloride to the polysorbate solution to obtain an amiodarone hydrochloride solution, then cooling the amiodarone hydrochloride solution to room temperature and adding benzyl alcohol, and replenishing the remaining part of the water for injection to obtain a medicinal solution; the medicinal solution is sterilized and filtered; while filling with nitrogen, the filtered medicinal solution is filled into a container, wherein the method does not use a sterilization step. It is believed that the method can prepare an amiodarone hydrochloride injection with a low impurity content with high production efficiency.

[0016] CN114917187A (Chinese Patent Application No. 202210651954.3, Hongsen) discloses a method for preparing amiodarone hydrochloride injection, including: adding a solubilizer and a stabilizer to a dispensing tank for heating, then adding amiodarone hydrochloride, stirring until all the solids are dissolved, adding water for injection, and then the liquid medicine is deoxygenated with nitrogen and then sterilized and filtered before entering the potting process, and the potting process pots the sterilized liquid medicine to obtain a semi-finished product, and the semi-finished product is packaged after passing the lamp inspection and high-voltage discharge leak detection to obtain a finished product. It is believed that the preparation method is easy to operate, has good process safety, high aseptic guarantee capability, stable product quality, and is green and pollution-free.

[0017] However, those skilled in the art still expect to have a new method for preparing amiodarone hydrochloride with excellent properties, such as a new method for preparing stable amiodarone hydrochloride; and / or, those skilled in the art still expect to have a new method for preparing amiodarone hydrochloride injection and amiodarone hydrochloride injection with excellent properties. Summary of the invention

[0018] The object of the present invention is to provide an amiodarone hydrochloride with excellent properties, for example, to provide an amiodarone hydrochloride with better stability. Another object of the present invention is to provide a method for preparing such amiodarone hydrochloride, and the pharmaceutical use of the prepared amiodarone hydrochloride; and / or, the object of the present invention is to provide an amiodarone hydrochloride injection with excellent properties, and their preparation methods and uses. It has been unexpectedly found that the method of the present invention can be used to prepare amiodarone hydrochloride with some or some excellent properties, such as better stability, and some amiodarone hydrochloride injections with excellent properties. The present invention is completed based on such findings.

[0019] To this end, the first aspect of the present invention provides a compound (or a crystalline compound thereof) having a chemical structure shown in Formula VII below:

[0020]

[0021] According to the first aspect of the present invention, the compound has a melting point of 181-185°C, for example, 182-184°C.

[0022] According to the compound described in the first aspect of the present invention, using Cu-Kα radiation, in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 7.03°±0.20°, 11.31°±0.20°, 15.07°±0.20°, 16.88°±0.20°, 17.62°±0.20°, 18.77°±0.20°, 21.73°±0.20°, 21.94°±0.20°, 22.63°±0.20°, 23.42°±0.20°, 24.78°±0.20°, and 27.42°±0.20°.

[0023] According to the compound described in the first aspect of the present invention, using Cu-Kα radiation, in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 7.03°±0.10°, 11.31°±0.10°, 15.07°±0.10°, 16.88°±0.10°, 17.62°±0.10°, 18.77°±0.10°, 21.73°±0.10°, 21.94°±0.10°, 22.63°±0.10°, 23.42°±0.10°, 24.78°±0.10°, and 27.42°±0.10°.

[0024] According to the compound described in the first aspect of the present invention, using Cu-Kα radiation, in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 7.03°, 11.31°, 15.07°, 16.88°, 17.62°, 18.77°, 21.73°, 21.94°, 22.63°, 23.42°, 24.78°, and 27.42°.

[0025] According to the first aspect of the present invention, the compound is prepared by a method comprising the following steps:

[0026] Stir 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran, methanol and toluene until dissolved, add diethylamine, heat the reactants and stir until the reaction is complete;

[0027] Add water to the reactant, wash and separate the layers with water while keeping warm and stirring, discard the water layer, and continue to wash the obtained organic layer with water to obtain a toluene layer, and cool;

[0028] Add concentrated hydrochloric acid dropwise to the toluene layer to adjust the pH to 1-2, add more toluene, raise the temperature again, evaporate part of the solvent under reduced pressure until material precipitates, stop distillation, slowly lower the temperature, filter, and dry to obtain the product.

[0029] According to the first aspect of the present invention, the compound is prepared by a method comprising the following steps:

[0030] Add 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran, methanol and toluene to the reaction bottle at room temperature, stir to dissolve, add diethylamine, heat the reactant to 75°C, stir and react for 6 hours;

[0031] Add water to the reactant, stir at 75°C to wash and separate the layers, discard the water layer, and continue to wash the obtained organic layer with water to obtain a toluene layer, which is then cooled to 40°C;

[0032] Add concentrated hydrochloric acid to the toluene layer to adjust the pH to 1-2, add more toluene, raise the temperature to 75°C, evaporate part of the solvent under reduced pressure until material precipitates, stop distillation, slowly lower the temperature to 10°C, filter, and dry to obtain.

[0033] According to the first aspect of the present invention, the compound is prepared by a method comprising the following steps:

[0034] Add 4.8 g of 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran, 5 ml of methanol, and 40 ml of toluene to a reaction flask at room temperature, stir to dissolve, add 2.3 g of diethylamine, heat the reactant to 75°C, stir and react for 6 hours;

[0035] Add 40 ml of water to the reactant, stir at 75°C to wash and separate the layers, discard the water layer, and add 40 ml of water to the obtained organic layer to wash once to obtain a toluene layer, and cool to 40°C;

[0036] Add concentrated hydrochloric acid dropwise to the toluene layer to adjust the pH to 1-2, add 40 ml of toluene, raise the temperature to 75°C, evaporate part of the solvent under reduced pressure until material precipitates, stop distillation, slowly cool to 10°C, filter, and dry the wet product under reduced pressure at 60°C for 8 hours.

[0037] According to the first aspect of the present invention, the compound is prepared by a method comprising the following steps:

[0038] Stir 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran, methanol and toluene until dissolved, add diethylamine, heat the reactants and stir until the reaction is complete;

[0039] Add cyclohexane and acetone to the reactants, stir evenly, then add water, wash and separate the layers with water while keeping warm and stirring, discard the water layer, continue to wash the obtained organic layer with water to obtain a toluene layer, and cool;

[0040] Add concentrated hydrochloric acid to the toluene layer to adjust the pH to 1-2, add toluene, cyclohexane and acetone, raise the temperature again, evaporate part of the solvent under reduced pressure until material precipitates, stop distillation, slowly cool down, filter and dry to obtain.

[0041] According to the first aspect of the present invention, the compound is prepared by a method comprising the following steps:

[0042] Add 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran, methanol and toluene to the reaction bottle at room temperature, stir to dissolve, add diethylamine, heat the reactant to 75°C, stir and react for 6 hours;

[0043] Add cyclohexane and acetone to the reactants, stir evenly, then add water, stir at 75°C to wash and separate the layers, discard the water layer, continue to wash the obtained organic layer with water to obtain a toluene layer, and cool to 40°C;

[0044] Add concentrated hydrochloric acid to the toluene layer to adjust the pH to 1-2, add toluene, cyclohexane and acetone, then raise the temperature to 75°C, evaporate part of the solvent under reduced pressure until material precipitates, stop distillation, slowly cool to 10°C, filter and dry to obtain.

[0045] According to the first aspect of the present invention, the compound is prepared by a method comprising the following steps:

[0046] Add 4.8 g of 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran, 5 ml of methanol, and 40 ml of toluene to a reaction flask at room temperature, stir to dissolve, add 2.3 g of diethylamine, heat the reactant to 75°C, stir and react for 6 hours;

[0047] Add 15 ml of cyclohexane and 15 ml of acetone to the reactant, stir evenly, then add 40 ml of water, stir at 75°C to wash and separate the layers, discard the water layer, add 40 ml of water to the obtained organic layer, wash it once more, obtain the toluene layer, and cool it to 40°C;

[0048] Concentrated hydrochloric acid was added dropwise to the toluene layer to adjust the pH value to 1-2, and 40 ml of toluene, 15 ml of cyclohexane and 15 ml of acetone were added. The temperature was raised to 75°C, and part of the solvent was evaporated under reduced pressure until material precipitated. The distillation was stopped, and the temperature was slowly lowered to 10°C. The product was filtered and dried under reduced pressure at 60°C for 8 hours.

[0049] According to the compound of the first aspect of the present invention, the 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran is prepared by a method comprising the following steps:

[0050] Step 1: Preparation of methyl 3,5-diiodo-4-hydroxybenzoate

[0051] Add 5 g of methyl p-hydroxybenzoate and 40 ml of methanol to a reaction bottle at room temperature, stir to dissolve, add 5.65 g of sodium acetate and 3.5 ml of water, stir to dissolve, then add 15 g of iodine, heat to 75°C and react for 2 hours;

[0052] Add sodium hydroxide solution (2.8 g of sodium hydroxide and 100 ml of water) to the reaction solution, and keep the temperature at 75°C to react for 2 hours;

[0053] Slowly cool to room temperature, add 5.3 g of 25% sodium bisulfite solution dropwise until the color of the liquid fades, stir and crystallize for 1 hour, filter, and dry the wet product at 50°C with hot air for 8 hours to obtain the title compound;

[0054] Step 2: Preparation of 3,5-diiodo-4-(2-hydroxyethoxy)-benzoic acid methyl ester

[0055] Add 12 g of methyl 3,5-diiodo-4-hydroxybenzoate and 50 ml of DMF to a reaction bottle at room temperature, stir to dissolve, add 12.5 g of potassium carbonate, raise the temperature to 80°C, add 9.7 g of 2-chloroethanol dropwise within 1.2 hours, continue to heat and react for 1 hour, and remove potassium carbonate by hot filtration;

[0056] DMF was evaporated under reduced pressure in a water bath at 75°C, and then 100 ml of toluene and 80 ml of water were added, stirred evenly, allowed to stand to separate into layers, and the aqueous layer was discarded;

[0057] Add 80 ml of 1% potassium carbonate solution to the toluene layer, wash three times at 50°C, and discard the potassium carbonate washing solution;

[0058] Add 80 ml of water to the toluene layer, wash twice at 50°C, and discard the water layer;

[0059] Toluene was evaporated under reduced pressure at 60°C in a water bath until the concentrate solidified, then 50ml of methanol was added, dissolved at 50°C, 60ml of water was added dropwise, and crystallization was carried out for 12 hours;

[0060] After stirring for 2 hours, the crystals were filtered and the wet product was dried in hot air at 50°C for 6 hours to obtain the title compound;

[0061] Step 3: Preparation of 3,5-diiodo-4-(2-hydroxyethoxy)-benzoic acid

[0062] Add 10 g of methyl 3,5-diiodo-4-(2-hydroxyethoxy)benzoate, 100 ml of methanol, and a sodium hydroxide solution (2.2 g of sodium hydroxide + 50 ml of water) to a reaction flask at room temperature, heat the reactants to 55°C, and hydrolyze for 3 hours;

[0063] The water bath temperature was controlled at 55°C, methanol and part of the water were evaporated under reduced pressure, 120 ml of water was added, and the mixture was stirred and dissolved at room temperature. A 10% hydrochloric acid solution was added to adjust the pH to about 2.0, and a solid was precipitated. The solid was filtered and the wet product was dried at 50°C with hot air for 8 hours to obtain the title compound.

[0064] Step 4: Preparation of 3,5-diiodo-4-(2-chloroethoxy)-benzoyl chloride

[0065] 6.5 g of 3,5-diiodo-4-(2-hydroxyethoxy)-benzoic acid, 80 ml of toluene, and 2 drops of DMF were added to the reaction flask at room temperature. The reaction mixture was heated to 117°C and the toluene was refluxed for 1 hour to remove moisture.

[0066] Under nitrogen protection, the reactants were slowly cooled to 80°C, 9 g of thionyl chloride was added, and then the reactants were kept at 85°C for 15 hours;

[0067] Remove toluene and excess thionyl chloride by vacuum distillation in a 70°C water bath. After almost all distillation is completed, add 50 ml of dichloromethane and mix well. Continue to remove dichloromethane by vacuum distillation to obtain the title compound.

[0068] Step 5: Preparation of 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran

[0069] Add 50 ml of dichloromethane to the 3,5-diiodo-4-(2-chloroethoxy)-benzoyl chloride obtained in the previous step to obtain a dichloromethane solution of 3,5-diiodo-4-(2-chloroethoxy)-benzoyl chloride for standby use;

[0070] Under nitrogen protection, add 2.8 g of anhydrous aluminum chloride and 40 ml of dichloromethane to another dry reaction bottle, slowly cool to -5°C, add the dichloromethane solution of the compound dropwise within 20 minutes, maintain -5°C and allow the reaction to proceed for 1 hour;

[0071] Under the condition of maintaining the temperature at -5°C, 2.7 g of 2-butylbenzofuran was added dropwise within 40 minutes. After the addition was completed, the reaction was continued at -5°C for 12 hours;

[0072] Add 50 ml of 1% hydrochloric acid solution to the reactant at room temperature, stir and separate the layers, wash the dichloromethane layer once with 50 ml of 1% hydrochloric acid solution, wash the dichloromethane layer once with 50 ml of water, and separate the layers to obtain the dichloromethane layer;

[0073] Add 50 ml of 2% sodium bicarbonate solution to the dichloromethane layer and wash it twice. Add 50 ml of water to the separated dichloromethane layer and wash it twice. Separate the layers to obtain the dichloromethane layer. Remove the dichloromethane by distillation under reduced pressure to obtain the title compound.

[0074] Further, the second aspect of the present invention provides a method for preparing the compound of formula VII (or its crystalline compound):

[0075]

[0076] The method comprises the following steps:

[0077] Stir 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran, methanol and toluene until dissolved, add diethylamine, heat the reactants and stir until the reaction is complete;

[0078] Add water to the reactant, wash and separate the layers with water while keeping warm and stirring, discard the water layer, and continue to wash the obtained organic layer with water to obtain a toluene layer, and cool;

[0079] Add concentrated hydrochloric acid dropwise to the toluene layer to adjust the pH to 1-2, add more toluene, raise the temperature again, evaporate part of the solvent under reduced pressure until material precipitates, stop distillation, slowly lower the temperature, filter, and dry to obtain the product.

[0080] The method according to the second aspect of the present invention comprises the following steps:

[0081] Add 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran, methanol and toluene to the reaction bottle at room temperature, stir to dissolve, add diethylamine, heat the reactant to 75°C, stir and react for 6 hours;

[0082] Add water to the reactant, stir at 75°C to wash and separate the layers, discard the water layer, and continue to wash the obtained organic layer with water to obtain a toluene layer, which is then cooled to 40°C;

[0083] Add concentrated hydrochloric acid to the toluene layer to adjust the pH to 1-2, add more toluene, raise the temperature to 75°C, evaporate part of the solvent under reduced pressure until material precipitates, stop distillation, slowly lower the temperature to 10°C, filter, and dry to obtain.

[0084] The method according to the second aspect of the present invention comprises the following steps:

[0085] Add 4.8 g of 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran, 5 ml of methanol, and 40 ml of toluene to a reaction flask at room temperature, stir to dissolve, add 2.3 g of diethylamine, heat the reactant to 75°C, stir and react for 6 hours;

[0086] Add 40 ml of water to the reactant, stir at 75°C to wash and separate the layers, discard the water layer, and add 40 ml of water to the obtained organic layer to wash once to obtain a toluene layer, and cool to 40°C;

[0087] Add concentrated hydrochloric acid dropwise to the toluene layer to adjust the pH to 1-2, add 40 ml of toluene, raise the temperature to 75°C, evaporate part of the solvent under reduced pressure until material precipitates, stop distillation, slowly cool to 10°C, filter, and dry the wet product under reduced pressure at 60°C for 8 hours.

[0088] The method according to the second aspect of the present invention comprises the following steps:

[0089] Stir 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran, methanol and toluene until dissolved, add diethylamine, heat the reactants and stir until the reaction is complete;

[0090] Add cyclohexane and acetone to the reactants, stir evenly, then add water, wash and separate the layers with water while keeping warm and stirring, discard the water layer, continue to wash the obtained organic layer with water to obtain a toluene layer, and cool;

[0091] Add concentrated hydrochloric acid to the toluene layer to adjust the pH to 1-2, add toluene, cyclohexane and acetone, raise the temperature again, evaporate part of the solvent under reduced pressure until material precipitates, stop distillation, slowly cool down, filter and dry to obtain.

[0092] The method according to the second aspect of the present invention comprises the following steps:

[0093] Add 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran, methanol and toluene to the reaction bottle at room temperature, stir to dissolve, add diethylamine, heat the reactant to 75°C, stir and react for 6 hours;

[0094] Add cyclohexane and acetone to the reactants, stir evenly, then add water, stir at 75°C to wash and separate the layers, discard the water layer, continue to wash the obtained organic layer with water to obtain a toluene layer, and cool to 40°C;

[0095] Add concentrated hydrochloric acid to the toluene layer to adjust the pH to 1-2, add toluene, cyclohexane and acetone, then raise the temperature to 75°C, evaporate part of the solvent under reduced pressure until material precipitates, stop distillation, slowly cool to 10°C, filter and dry to obtain.

[0096] The method according to the second aspect of the present invention comprises the following steps:

[0097] Add 4.8 g of 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran, 5 ml of methanol, and 40 ml of toluene to a reaction flask at room temperature, stir to dissolve, add 2.3 g of diethylamine, heat the reactant to 75°C, stir and react for 6 hours;

[0098] Add 15 ml of cyclohexane and 15 ml of acetone to the reactant, stir evenly, then add 40 ml of water, stir at 75°C to wash and separate the layers, discard the water layer, add 40 ml of water to the obtained organic layer, wash it once more, obtain the toluene layer, and cool it to 40°C;

[0099] Concentrated hydrochloric acid was added dropwise to the toluene layer to adjust the pH value to 1-2, and 40 ml of toluene, 15 ml of cyclohexane and 15 ml of acetone were added. The temperature was raised to 75°C, and part of the solvent was evaporated under reduced pressure until material precipitated. The distillation was stopped, and the temperature was slowly lowered to 10°C. The product was filtered and dried under reduced pressure at 60°C for 8 hours.

[0100] According to the method of the second aspect of the present invention, the 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran is prepared by a method comprising the following steps:

[0101] Step 1: Preparation of methyl 3,5-diiodo-4-hydroxybenzoate

[0102] Add 5 g of methyl p-hydroxybenzoate and 40 ml of methanol to a reaction bottle at room temperature, stir to dissolve, add 5.65 g of sodium acetate and 3.5 ml of water, stir to dissolve, then add 15 g of iodine, heat to 75°C and react for 2 hours;

[0103] Add sodium hydroxide solution (2.8 g of sodium hydroxide and 100 ml of water) to the reaction solution, and keep the temperature at 75°C to react for 2 hours;

[0104] Slowly cool to room temperature, add 5.3 g of 25% sodium bisulfite solution dropwise until the color of the liquid fades, stir and crystallize for 1 hour, filter, and dry the wet product at 50°C with hot air for 8 hours to obtain the title compound;

[0105] Step 2: Preparation of 3,5-diiodo-4-(2-hydroxyethoxy)-benzoic acid methyl ester

[0106] Add 12 g of methyl 3,5-diiodo-4-hydroxybenzoate and 50 ml of DMF to a reaction bottle at room temperature, stir to dissolve, add 12.5 g of potassium carbonate, raise the temperature to 80°C, add 9.7 g of 2-chloroethanol dropwise within 1.2 hours, continue to heat and react for 1 hour, and remove potassium carbonate by hot filtration;

[0107] DMF was evaporated under reduced pressure in a water bath at 75°C, and then 100 ml of toluene and 80 ml of water were added, stirred evenly, allowed to stand to separate into layers, and the aqueous layer was discarded;

[0108] Add 80 ml of 1% potassium carbonate solution to the toluene layer, wash three times at 50°C, and discard the potassium carbonate washing solution;

[0109] Add 80 ml of water to the toluene layer, wash twice at 50°C, and discard the water layer;

[0110] Toluene was evaporated under reduced pressure at 60°C in a water bath until the concentrate solidified, then 50ml of methanol was added, dissolved at 50°C, 60ml of water was added dropwise, and crystallization was carried out for 12 hours;

[0111] After stirring for 2 hours, the crystals were filtered and the wet product was dried in hot air at 50°C for 6 hours to obtain the title compound;

[0112] Step 3: Preparation of 3,5-diiodo-4-(2-hydroxyethoxy)-benzoic acid

[0113] Add 10 g of methyl 3,5-diiodo-4-(2-hydroxyethoxy)benzoate, 100 ml of methanol, and a sodium hydroxide solution (2.2 g of sodium hydroxide + 50 ml of water) to a reaction flask at room temperature, heat the reactants to 55°C, and hydrolyze for 3 hours;

[0114] The water bath temperature was controlled at 55°C, methanol and part of the water were evaporated under reduced pressure, 120 ml of water was added, and the mixture was stirred and dissolved at room temperature. A 10% hydrochloric acid solution was added to adjust the pH to about 2.0, and a solid was precipitated. The solid was filtered and the wet product was dried at 50°C with hot air for 8 hours to obtain the title compound.

[0115] Step 4: Preparation of 3,5-diiodo-4-(2-chloroethoxy)-benzoyl chloride

[0116] 6.5 g of 3,5-diiodo-4-(2-hydroxyethoxy)-benzoic acid, 80 ml of toluene, and 2 drops of DMF were added to the reaction flask at room temperature, and the reaction mixture was heated to 117°C and the toluene was refluxed for 1 hour to remove moisture;

[0117] Under nitrogen protection, the reactants were slowly cooled to 80°C, 9 g of thionyl chloride was added, and then the reactants were kept at 85°C for 15 hours;

[0118] Remove toluene and excess thionyl chloride by vacuum distillation in a 70°C water bath. After almost all distillation is completed, add 50 ml of dichloromethane and mix well. Continue to remove dichloromethane by vacuum distillation to obtain the title compound.

[0119] Step 5: Preparation of 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran

[0120] Add 50 ml of dichloromethane to the 3,5-diiodo-4-(2-chloroethoxy)-benzoyl chloride obtained in the previous step to obtain a dichloromethane solution of 3,5-diiodo-4-(2-chloroethoxy)-benzoyl chloride for standby use;

[0121] Under nitrogen protection, add 2.8 g of anhydrous aluminum chloride and 40 ml of dichloromethane to another dry reaction bottle, slowly cool to -5°C, add the dichloromethane solution of the compound dropwise within 20 minutes, maintain -5°C and allow the reaction to proceed for 1 hour;

[0122] Under the condition of maintaining the temperature at -5°C, 2.7 g of 2-butylbenzofuran was added dropwise within 40 minutes. After the addition was completed, the reaction was continued at -5°C for 12 hours;

[0123] Add 50 ml of 1% hydrochloric acid solution to the reactant at room temperature, stir and separate the layers, wash the dichloromethane layer once with 50 ml of 1% hydrochloric acid solution, wash the dichloromethane layer once with 50 ml of water, and separate the layers to obtain the dichloromethane layer;

[0124] Add 50 ml of 2% sodium bicarbonate solution to the dichloromethane layer and wash it twice. Add 50 ml of water to the separated dichloromethane layer and wash it twice. Separate the layers to obtain the dichloromethane layer. Remove the dichloromethane by distillation under reduced pressure to obtain the title compound.

[0125] According to the method of the second aspect of the present invention, the compound has a melting point of 181-185°C, for example, it has a melting point of 182-184°C.

[0126] According to the method of the second aspect of the present invention, the compound uses Cu-Kα radiation, and in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 7.03°±0.20°, 11.31°±0.20°, 15.07°±0.20°, 16.88°±0.20°, 17.62°±0.20°, 18.77°±0.20°, 21.73°±0.20°, 21.94°±0.20°, 22.63°±0.20°, 23.42°±0.20°, 24.78°±0.20°, and 27.42°±0.20°.

[0127] According to the method of the second aspect of the present invention, the compound uses Cu-Kα radiation, and in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 7.03°±0.10°, 11.31°±0.10°, 15.07°±0.10°, 16.88°±0.10°, 17.62°±0.10°, 18.77°±0.10°, 21.73°±0.10°, 21.94°±0.10°, 22.63°±0.10°, 23.42°±0.10°, 24.78°±0.10°, and 27.42°±0.10°.

[0128] According to the method of the second aspect of the present invention, the compound uses Cu-Kα radiation, and in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 7.03°, 11.31°, 15.07°, 16.88°, 17.62°, 18.77°, 21.73°, 21.94°, 22.63°, 23.42°, 24.78°, and 27.42°.

[0129] Furthermore, the third aspect of the present invention provides the use of any of the compounds described in the first aspect of the present invention in the preparation of drugs for treating heart diseases, especially for treating severe arrhythmias, and is particularly suitable for drugs for heart diseases such as atrial arrhythmias with rapid ventricular rhythms, tachycardia of WPW syndrome, severe ventricular arrhythmias, and cardiopulmonary resuscitation of ventricular fibrillation-related cardiac arrest that is resistant to external defibrillation.

[0130] Furthermore, the fourth aspect of the present invention provides an amiodarone hydrochloride injection, which comprises 50 mg of amiodarone hydrochloride, 18-22 mg of benzyl alcohol, for example 20 mg, 95-105 mg, for example 100 mg of Tween-80, and an appropriate amount of water for injection added to 2-3 ml, for example 3 ml.

[0131] The amiodarone hydrochloride injection according to the fourth aspect of the present invention further comprises 20-30 mg of propylene glycol, for example, 25 mg of propylene glycol.

[0132] According to the fourth aspect of the present invention, the amiodarone hydrochloride injection has a pH value of 2.5 to 4.0, for example, a pH value of 3.0 to 4.0.

[0133] The amiodarone hydrochloride injection according to the fourth aspect of the present invention is prepared according to a method comprising the following steps:

[0134] Dissolve benzyl alcohol with an appropriate amount of water for injection and set aside;

[0135] Mix amiodarone hydrochloride, Tween-80 and propylene glycol evenly, heat, and add water for injection while keeping warm and stirring to dissolve the materials;

[0136] Slowly add the benzyl alcohol solution to the amiodarone hydrochloride solution while keeping warm and stirring, add water for injection to the full amount, and adjust the pH of the solution to 3-3.2;

[0137] Fill nitrogen into the drug solution under continuous stirring and allow the drug solution to cool naturally, filter with a microporous filter membrane, and then fill the drug solution into an ampoule bottle under nitrogen filling conditions, and seal it by melting to obtain the product.

[0138] The amiodarone hydrochloride injection according to the fourth aspect of the present invention is prepared according to a method comprising the following steps:

[0139] Dissolve benzyl alcohol in about 10 times the amount of 65°C injection water and set aside;

[0140] Mix amiodarone hydrochloride, Tween-80 and propylene glycol evenly, heat to 65°C, and add 65°C water for injection (the amount is about 10 times the amount of amiodarone hydrochloride) to dissolve the materials while keeping warm and stirring;

[0141] Slowly add the benzyl alcohol solution to the amiodarone hydrochloride solution while keeping warm and stirring, add 65°C water for injection to the full amount, and adjust the pH of the solution to 3-3.2 with 1M hydrochloric acid solution (or 1M sodium hydroxide solution if necessary);

[0142] With continuous stirring, nitrogen is introduced into the drug solution and the drug solution is naturally cooled to 25-30°C. The drug solution is filtered twice with 0.45 μm and 0.22 μm microporous filter membranes respectively. Then, the drug solution is filled into ampoule bottles (3 ml / bottle) under nitrogen filling conditions and sealed by melting.

[0143] According to the amiodarone hydrochloride injection of the fourth aspect of the present invention, the amiodarone hydrochloride is as described in any one of the first aspect of the present invention.

[0144] Furthermore, the fifth aspect of the present invention provides a method for preparing amiodarone hydrochloride injection, comprising the following steps:

[0145] Dissolve benzyl alcohol with an appropriate amount of water for injection and set aside;

[0146] Mix amiodarone hydrochloride, Tween-80 and propylene glycol evenly, heat, and add water for injection while keeping warm and stirring to dissolve the materials;

[0147] Slowly add the benzyl alcohol solution to the amiodarone hydrochloride solution while keeping warm and stirring, add water for injection to the full amount, and adjust the pH of the solution to 3-3.2;

[0148] Fill nitrogen into the drug solution under continuous stirring and allow the drug solution to cool naturally, filter with a microporous filter membrane, and then fill the drug solution into an ampoule bottle under nitrogen filling conditions, and seal it by melting to obtain the product.

[0149] The method according to the fifth aspect of the present invention comprises the following steps:

[0150] Dissolve benzyl alcohol in about 10 times the amount of 65°C water for injection and set aside;

[0151] Mix amiodarone hydrochloride, Tween-80 and propylene glycol evenly, heat to 65°C, and add 65°C water for injection (the amount is about 10 times the amount of amiodarone hydrochloride) to dissolve the materials while keeping warm and stirring;

[0152] Slowly add the benzyl alcohol solution to the amiodarone hydrochloride solution while keeping warm and stirring, add 65°C water for injection to the full amount, and adjust the pH of the solution to 3-3.2 with 1M hydrochloric acid solution (or 1M sodium hydroxide solution if necessary);

[0153] With continuous stirring, nitrogen is introduced into the drug solution and the drug solution is naturally cooled to 25-30°C. The drug solution is filtered twice with 0.45 μm and 0.22 μm microporous filter membranes respectively. Then, the drug solution is filled into ampoule bottles (3 ml / bottle) under nitrogen filling conditions and sealed by melting.

[0154] According to the method of the fifth aspect of the present invention, the amiodarone hydrochloride injection contains 50 mg of amiodarone hydrochloride, 18-22 mg of benzyl alcohol, for example 20 mg, 95-105 mg, for example 100 mg of Tween-80, and an appropriate amount of water for injection added to 2-3 ml, for example 3 ml.

[0155] According to the method of the fifth aspect of the present invention, the amiodarone hydrochloride injection further comprises 20-30 mg of propylene glycol, for example, 25 mg of propylene glycol.

[0156] According to the method of the fifth aspect of the present invention, the pH of the amiodarone hydrochloride injection is 2.5-4.0, for example, the pH is 3.0-4.0.

[0157] Furthermore, the sixth aspect of the present invention provides the use of the injection described in any one of the fourth aspects of the present invention in the preparation of drugs for treating heart diseases, especially for treating severe arrhythmias, and is particularly suitable for drugs for heart diseases such as atrial arrhythmias with rapid ventricular rhythms, tachycardia of WPW syndrome, severe ventricular arrhythmias, and cardiopulmonary resuscitation of ventricular fibrillation-related cardiac arrest that is resistant to external defibrillation.

[0158] In the steps of the above-mentioned preparation method of the present invention, although the specific steps described therein are different from the steps described in the preparation examples in the specific implementation mode part below in some details or language descriptions, those skilled in the art can fully summarize the above-mentioned method steps based on the detailed disclosure of the full text of the present invention.

[0159] Any embodiment of any aspect of the present invention can be combined with other embodiments, as long as they do not conflict. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical features in other embodiments, as long as they do not conflict.

[0160] The present invention is further described below.

[0161] All documents cited in the present invention are incorporated herein by reference in their entirety, and if the meanings expressed in these documents are inconsistent with the present invention, the description of the present invention shall prevail. In addition, the various terms and phrases used in the present invention have the general meanings known to those skilled in the art. Even so, the present invention still hopes to provide a more detailed description and explanation of these terms and phrases. If the terms and phrases mentioned are inconsistent with the known meanings, the meanings expressed in the present invention shall prevail.

[0162] The amiodarone hydrochloride and the injection thereof of the present invention are clinically applicable to treating severe arrhythmias when oral administration is not suitable, and are particularly applicable to the following situations: atrial arrhythmias with rapid ventricular rhythms, tachycardia of WPW syndrome, severe ventricular arrhythmias, and cardiopulmonary resuscitation of ventricular fibrillation-related cardiac arrest in which external electric defibrillation is ineffective.

[0163] The amiodarone hydrochloride injection prepared by the present invention can be administered by intravenous drip after being diluted with an isotonic glucose solution. After injection, the blood concentration of amiodarone decreases rapidly and tissue penetration occurs. The effect reaches a maximum about 15 minutes after injection and disappears within 4 hours.

[0164] The antiarrhythmic properties of amiodarone hydrochloride mainly include: prolonging the phase 3 action potential of myocardial cells, but not affecting the height and decay rate of the action potential (VaughanWlilams classification class III); simply prolonging the phase 3 action potential of myocardial cells is due to the reduction of potassium ion outflow, while the outflow of sodium ions and calcium ions remains unchanged; reducing the automaticity of the sinoatrial node, and this effect cannot be reversed by atropine; non-competitive α and β adrenergic inhibition; slowing down the conduction of the sinoatrial, atrium and node areas, which is more obvious when the heart rate is fast; not changing the intraventricular conduction; prolonging the refractory period, reducing the myocardial excitability of the atria, node areas and ventricles; slowing down the conduction of the atrioventricular bypass pathway and prolonging its refractory period; no negative inotropic effect.

[0165] Regarding clinical trials of cardiopulmonary resuscitation for ventricular fibrillation-related cardiac arrest that is resistant to external defibrillation, there are literature reports that researchers studied the effectiveness and safety of intravenous amiodarone in performing cardiopulmonary resuscitation in patients with out-of-hospital ventricular fibrillation-related cardiac arrest that is resistant to external shock in two double-blind studies: the ARREST study comparing amiodarone injection with placebo and the ALIVE study comparing amiodarone injection with lidocaine. The primary endpoint of both studies was the proportion of patients who survived to hospital. In the ARREST study, 504 patients with out-of-hospital cardiac arrest due to at least 3 defibrillation shocks and adrenaline-resistant ventricular fibrillation or pulseless ventricular tachycardia were randomly divided into 2 groups and received 300 mg of amiodarone diluted in 20 mL of 5% glucose solution and injected rapidly through a peripheral intravenous route (246 patients) or received placebo (258 patients). Among the 197 patients who survived to hospital admission (39%), amiodarone significantly increased the likelihood of resuscitation and survival to hospital admission: 44% in the amiodarone group and 34% in the placebo group (p = 0.03). After adjustment for other predictors of outcome, the adjusted odds ratio for survival to hospital admission was 1.6 (95% confidence interval, 1.1 to 2.4; p = 0.02) in the amiodarone group versus the placebo group. More patients in the amiodarone group than in the placebo group experienced hypotension (59% vs 48%, p = 0.04) or bradycardia (41% vs 25%, p -0.004). In the ALIVE study, 347 patients with VF resistant to 3 defibrillation shocks, epinephrine, and further defibrillation shocks or with recurrence of VF after initial successful defibrillation were randomized to receive amiodarone (5 mg / kg estimated body weight diluted in 30 mL of 5% dextrose solution) and lidocaine-matched placebo or lidocaine (1.5 mg / kg at a concentration of 10 mg / mL) and amiodarone-matched placebo in the same diluent (polysorbate 80).Among the 347 patients enrolled in the study, amiodarone significantly increased the likelihood ratio of resuscitation and hospital admission, with 22.8% of patients in the amiodarone group (417 / 180) surviving to hospital admission, compared with 12% of patients in the lidocaine group (20 / 167) surviving to hospital admission (p=0.009). The adjusted odds ratio for survival to hospital admission was 2.49 (95% confidence interval 1.28 to 4.85, p = 0.007) for patients in the amiodarone group versus the placebo group after adjustment for other factors that are likely to affect the likelihood of survival. There was no difference between the 2 treatment groups in the number of patients who required atropine for bradycardia or dopamine for blood pressure increases, or in the number of patients who received lidocaine (in addition to study treatment). A higher number of patients who experienced cardiac arrest after defibrillation and study treatment were those who received lidocaine (28.9%) compared with those who received amiodarone (18.4%) (p = 0.04).

[0166] As described in the context of the present invention, the amiodarone hydrochloride and its injection obtained in the present invention have excellent properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0167] Figure 1 : DSC chart of amiodarone hydrochloride.

[0168] Figure 2 :X-ray powder diffraction (XRPD) pattern of amiodarone hydrochloride DETAILED DESCRIPTION

[0169] The present invention can be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be appreciated by those skilled in the art that various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention. The present invention provides general and / or specific descriptions of the materials and test methods used in the test. Although many materials and operating methods used to achieve the purpose of the present invention are well known in the art, the present invention is still described in as much detail as possible at this point.

[0170] Example 1: Preparation of Amiodarone Hydrochloride

[0171] The following steps 1 to 6 of this embodiment are carried out with reference to Examples 1 to 7 of CN109988132B to prepare amiodarone hydrochloride, and the material feed amount is reduced by about half.

[0172] Step 1: Preparation of methyl 3,5-diiodo-4-hydroxybenzoate (I)

[0173]

[0174] Add 5 g (32.8 mmol) of methyl p-hydroxybenzoate and 40 ml of methanol to a reaction bottle at room temperature, stir to dissolve, add 5.65 g of sodium acetate and 3.5 ml of water, stir to dissolve, then add 15 g (59.2 mmol) of iodine, heat to 75°C and react for 2 hours;

[0175] Sodium hydroxide solution (2.8 g (70 mmol) of sodium hydroxide and 100 ml of water) was added to the reaction solution, and the temperature was maintained at 75° C. to react for 2 hours;

[0176] The mixture was slowly cooled to room temperature, 5.3 g of 25% sodium bisulfite solution was added dropwise until the color of the solution faded, and then stirred for crystallization for 1 hour. The mixture was filtered and the wet product was dried at 50°C for 8 hours to obtain 13.5 g of off-white crystalline powder, which was compound (I).

[0177] Step 2: Preparation of 3,5-diiodo-4-(2-hydroxyethoxy)-benzoic acid methyl ester (II)

[0178]

[0179] Add 12 g (about 30 mmol) of methyl 3,5-diiodo-4-hydroxybenzoate (I) and 50 ml of DMF to a reaction flask at room temperature, stir to dissolve, add 12.5 g (about 90 mmol) of potassium carbonate, raise the temperature to 80°C, add 9.7 g (120 mmol) of 2-chloroethanol dropwise within 1.2 hours, continue to heat and react for 1 hour, and remove potassium carbonate by hot filtration;

[0180] DMF was evaporated under reduced pressure in a water bath at 75°C, and then 100 ml of toluene and 80 ml of water were added, stirred evenly, allowed to stand to separate into layers, and the aqueous layer was discarded;

[0181] Add 80 ml of 1% potassium carbonate solution to the toluene layer, wash three times at 50°C, and discard the potassium carbonate washing solution;

[0182] Add 80 ml of water to the toluene layer, wash twice at 50°C, and discard the water layer;

[0183] Toluene was evaporated under reduced pressure at 60°C in a water bath until the concentrate solidified, then 50ml of methanol was added, dissolved at 50°C, 60ml of water was added dropwise, and crystallization was carried out for 12 hours;

[0184] After stirring for 2 hours, the crystals were filtered and the wet product was dried in hot air at 50°C for 6 hours to obtain 11.2 g of yellow-brown powder, which was compound (II).

[0185] Step 3: Preparation of 3,5-diiodo-4-(2-hydroxyethoxy)-benzoic acid (III)

[0186]

[0187] Add 10 g (22.3 mmol) of 3,5-diiodo-4-(2-hydroxyethoxy)-benzoic acid methyl ester (II), 100 ml of methanol, and a sodium hydroxide solution (2.2 g (55 mmol) of sodium hydroxide + 50 ml of water) to a reaction flask at room temperature, heat the reactants to 55°C, and hydrolyze for 3 hours;

[0188] The water bath temperature was controlled at 55°C, methanol and part of the water were evaporated under reduced pressure, 120 ml of water was added, and the mixture was stirred and dissolved at room temperature. 10% hydrochloric acid solution was added to adjust the pH to about 2.0, solid was precipitated, and the solid was filtered. The wet product was dried at 50°C with hot air for 8 hours to obtain 9.8 g of white powder, which was compound (III).

[0189] Step 4: Preparation of 3,5-diiodo-4-(2-chloroethoxy)-benzoyl chloride (IV)

[0190]

[0191] 6.5 g (15 mmol) of 3,5-diiodo-4-(2-hydroxyethoxy)-benzoic acid (III), 80 ml of toluene, and 2 drops of DMF were added to the reaction flask at room temperature. The reaction mixture was heated to 117°C and toluene was refluxed for 1 hour to remove moisture.

[0192] Under nitrogen protection, the reactant was slowly cooled to 80°C, 9 g (75.6 mmol) of thionyl chloride was added, and then the reactant was kept at 85°C for 15 hours;

[0193] Toluene and excess thionyl chloride were removed by vacuum distillation in a 70°C water bath. After almost all distillation was completed, 50 ml of dichloromethane was added and mixed. The dichloromethane was then removed by vacuum distillation to obtain 3,5-diiodo-4-(2-chloroethoxy)-benzoyl chloride (IV) (containing 6.6 g, 14.6 mmol).

[0194] Step 5: Preparation of 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran (VI)

[0195]

[0196] Add 50 ml of dichloromethane to the 3,5-diiodo-4-(2-chloroethoxy)-benzoyl chloride (IV) obtained in the previous step to obtain a dichloromethane solution of 3,5-diiodo-4-(2-chloroethoxy)-benzoyl chloride (IV) for standby use;

[0197] Under nitrogen protection, add 2.8 g (21 mmol) of anhydrous aluminum chloride and 40 ml of dichloromethane to another dry reaction bottle, slowly cool to -5°C, add the dichloromethane solution of compound (IV) dropwise within 20 minutes, maintain -5°C and allow the reaction to proceed for 1 hour;

[0198] Add 2.7 g (15.5 mmol) of 2-butylbenzofuran (V) dropwise within 40 min while maintaining the temperature at -5 °C. After the addition is complete, continue to keep the temperature at -5 °C for 12 hours;

[0199] Add 50 ml of 1% hydrochloric acid solution to the reactant at room temperature, stir and separate the layers, wash the dichloromethane layer once with 50 ml of 1% hydrochloric acid solution, wash the dichloromethane layer once with 50 ml of water, and separate the layers to obtain the dichloromethane layer;

[0200] The dichloromethane layer was washed twice with 50 ml of 2% sodium bicarbonate solution. The separated dichloromethane layer was washed twice with 50 ml of water. The dichloromethane layer was separated and the dichloromethane layer was removed by distillation under reduced pressure to obtain 8.1 g (13.3 mmol) of a concentrate, which was 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran (VI).

[0201] Step 6: Preparation of amiodarone hydrochloride (VII)

[0202]

[0203] Add 4.8 g (7.9 mmol) of 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran (VI), 5 ml of methanol, and 40 ml of toluene to a reaction flask at room temperature, stir to dissolve, add 2.3 g (31.5 mmol) of diethylamine, heat the reactant to 75°C, stir and react for 6 hours;

[0204] Add 40 ml of water to the reactant, stir at 75°C to wash and separate the layers, discard the water layer, and add 40 ml of water to the obtained organic layer to wash once to obtain a toluene layer, and cool to 40°C;

[0205] Concentrated hydrochloric acid was added dropwise to the toluene layer to adjust the pH value to 1-2, and 40 ml of toluene was added. The temperature was raised to 75°C, and a part of the solvent was evaporated under reduced pressure until the material precipitated. The distillation was stopped, and the temperature was slowly lowered to 10°C. The wet product was filtered and dried under reduced pressure at 60°C for 8 hours to obtain 4.9 g of white powder, which was amiodarone hydrochloride (VII).

[0206] The feed amount of each operation in the above steps 1 to 6 is about half of that in the literature method, and the yield of each step is basically the same as that in the literature. Some parameters of the obtained amiodarone hydrochloride were measured, and the results were:

[0207] 1 H NMR (400 MHz, CDCl3) δ8.232 (s, 2H), 7.494-7.456 (d, 1H), 7.387-7.344 (m, 1H), 7.324-7.304 (dd, 1H), 7.274-7.253 (m, 1H), 4.612-4.593 (t, 2H), 3.788-3.654 (m, 2H), 3.473-3.467 (q, 4H), 2.885-2.863 (t, 2H), 1.787-1.712 (m, 2H), 1.587-1.574 (t, 6H), 1.413-1.346 (m, 2H), 0.932-0.906 (t, 3H); the NMR data were consistent with those of amiodarone hydrochloride.

[0208] Melting point: 158.7~160.2℃;

[0209] Acidity: 0.5g → 10ml, dissolved at 80℃ and cooled, pH = 3.63;

[0210] Content: The content was determined by potentiometric titration under the item of amiodarone hydrochloride on page 1279 of Part II of the 2020 edition of the Chinese Pharmacopoeia. Calculated on the basis of the dry product, it contained 99.36% C25H29I2NO3·HCl. The remaining items were determined in accordance with the pharmacopoeia methods and were in compliance with the regulations.

[0211] Example 2: Preparation of Amiodarone Hydrochloride

[0212] According to the operations described in steps 1 to 5 of the embodiment of the present invention, 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran (VI) is prepared, and then the conditions are changed in step 6 to prepare amiodarone hydrochloride (VII) according to the following operations:

[0213] Add 4.8 g (7.9 mmol) of 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran (VI), 5 ml of methanol, and 40 ml of toluene to a reaction flask at room temperature, stir to dissolve, add 2.3 g (31.5 mmol) of diethylamine, heat the reactant to 75°C, stir and react for 6 hours;

[0214] Add 15 ml of cyclohexane and 15 ml of acetone to the reactant, stir evenly, then add 40 ml of water, stir at 75°C to wash and separate the layers, discard the water layer, add 40 ml of water to the obtained organic layer, wash it once more, obtain the toluene layer, and cool it to 40°C;

[0215] Concentrated hydrochloric acid was added dropwise to the toluene layer to adjust the pH value to 1-2. 40 ml of toluene, 15 ml of cyclohexane and 15 ml of acetone were added, and the temperature was raised to 75°C. A portion of the solvent was evaporated under reduced pressure until material precipitated. The distillation was stopped, and the temperature was slowly lowered to 10°C. The wet product was dried under reduced pressure at 60°C for 8 hours to obtain 4.6 g of white powder with a yield of 85.4%, which was amiodarone hydrochloride (VII).

[0216] Some parameters of amiodarone hydrochloride obtained in Example 2 were measured, and the results were:

[0217] 1 H NMR (400 MHz, CDCl3) δ8.227 (s, 2H), 7.498-7.463 (d, 1H), 7.377-7.345 (m, 1H), 7.336-7.309 (dd, 1H), 7.278-7.259 (m, 1H), 4.607-4.586 (t, 2H), 3.794-3.652 (m, 2H), 3.478-3.469 (q, 4H), 2.881-2.867 (t, 2H), 1.783-1.726 (m, 2H), 1.589-1.567 (t, 6H), 1.424-1.347 (m, 2H), 0.927-0.911 (t, 3H); the NMR data were consistent with those of amiodarone hydrochloride.

[0218] DSC: measured using a DSC-3 differential scanning calorimeter (METTLER TOLEDO), with a sample size of 5 mg, a wetting rate of 10°C / min, and calibration using an indium standard. The DSC thermal analysis diagram is shown in 1, which is consistent with the melting point determination result.

[0219] Determination of X-ray powder diffraction (XRPD) characteristic pattern: The XRPD pattern of amiodarone hydrochloride was determined using Cu-Kα rays on a Shimadzu XRD-6000 X-ray powder diffractometer. The instrument was equipped with a fine focus X-ray tube, and the tube voltage and current were set to 40 kV and 40 mA, respectively. The emission slit and scattering slit were 1°, and the receiving slit was 0.15 mm. The diffraction lines were detected by a NaI scintillation detector. The 2θ angle was continuously scanned from θ to 2θ from 2° to 40° at 3° / min (0.4 seconds / 0.02° steps). It is well known that fluctuations of + / -0.2° or + / -0.1° at the 2θ position are completely acceptable and recognized. The XRPD pattern of amiodarone hydrochloride obtained in this Example 2 is shown in FIG. Figure 2 , where the 2θ and relative intensity of typical diffraction peaks are as follows:

[0220] No. 2θ(°) Relative strength (%) 1 7.03 31.6 2 11.31 26.3 3 15.07 72.4 4 16.88 26.1 5 17.62 29.5 6 18.77 100.0 7 21.73 57.7 8 21.94 21.1 9 22.63 31.3 10 23.42 66.3 11 24.78 23.2 12 27.42 37.9

[0221] Test Example 1: Quality Testing of Amiodarone Hydrochloride

[0222] In this test example 1, according to the various indicators under amiodarone hydrochloride on page 1279 of Part II of the 2020 edition of the Chinese Pharmacopoeia, the various indicators of amiodarone hydrochloride obtained in Example 2 after being placed at 0 month and 40°C for 6 months were measured. The results are as shown in the following table.

[0223]

[0224]

[0225] *Note: The content is determined by potentiometric titration and is calculated based on the dry product.

[0226] It can be seen from the results in the above table that the amiodarone hydrochloride prepared by the method of Example 2 of the present invention has excellent performance and can fully meet the requirements of the pharmacopoeia.

[0227] Example 3: Preparation of Amiodarone Hydrochloride

[0228] According to the operations described in steps 1 to 5 of the embodiment of the present invention, 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran (VI) is prepared, and then in step 6, amiodarone hydrochloride (VII) is prepared according to the following operation:

[0229] Add 4.8 g (7.9 mmol) of 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran (VI), 5 ml of methanol, and 40 ml of toluene to a reaction flask at room temperature, stir to dissolve, add 2.3 g (31.5 mmol) of diethylamine, heat the reactant to 75°C, stir and react for 6 hours;

[0230] Add 15 ml of cyclohexane to the reactant, stir evenly, then add 40 ml of water, stir at 75°C to wash and separate the layers, discard the water layer, add 40 ml of water to the obtained organic layer, wash it once more, obtain a toluene layer, and cool it to 40°C;

[0231] Concentrated hydrochloric acid was added dropwise to the toluene layer to adjust the pH value to 1-2, and 40 ml of toluene and 15 ml of cyclohexane were added. The temperature was raised to 75°C, and part of the solvent was evaporated under reduced pressure until the material precipitated. The distillation was stopped, and the temperature was slowly lowered to 10°C. The wet product was filtered and dried under reduced pressure at 60°C for 8 hours to obtain 4.8 g of white powder, which was amiodarone hydrochloride (VII).

[0232] Example 4: Preparation of Amiodarone Hydrochloride

[0233] According to the operations described in steps 1 to 5 of the embodiment of the present invention, 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran (VI) is prepared, and then in step 6, amiodarone hydrochloride (VII) is prepared according to the following operation:

[0234] Add 4.8 g (7.9 mmol) of 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran (VI), 5 ml of methanol, and 40 ml of toluene to a reaction flask at room temperature, stir to dissolve, add 2.3 g (31.5 mmol) of diethylamine, heat the reactant to 75°C, stir and react for 6 hours;

[0235] Add 15 ml of acetone to the reactant, stir evenly, then add 40 ml of water, stir at 75°C to wash and separate the layers, discard the water layer, add 40 ml of water to the obtained organic layer, wash it once more, obtain the toluene layer, and cool it to 40°C;

[0236] Concentrated hydrochloric acid was added dropwise to the toluene layer to adjust the pH value to 1-2, and 40 ml of toluene and 15 ml of acetone were added. The temperature was raised to 75°C, and part of the solvent was evaporated under reduced pressure until material precipitated. The distillation was stopped, and the temperature was slowly lowered to 10°C. The wet product was filtered and dried under reduced pressure at 60°C for 8 hours to obtain 4.5 g of white powder, which was amiodarone hydrochloride (VII).

[0237] Example 5: Preparation of Amiodarone Hydrochloride

[0238] According to the operations described in steps 1 to 5 of the embodiment of the present invention, 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran (VI) is prepared, and then in step 6, amiodarone hydrochloride (VII) is prepared according to the following operation:

[0239] Add 4.8 g (7.9 mmol) of 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran (VI), 5 ml of methanol, and 40 ml of toluene to a reaction flask at room temperature, stir to dissolve, add 2.3 g (31.5 mmol) of diethylamine, heat the reactant to 75°C, stir and react for 6 hours;

[0240] Add 15 ml of cycloheptane and 15 ml of acetone to the reactant, stir evenly, then add 40 ml of water, stir at 75°C to wash and separate the layers, discard the water layer, add 40 ml of water to the obtained organic layer, wash it once more, obtain the toluene layer, and cool to 40°C;

[0241] Concentrated hydrochloric acid was added dropwise to the toluene layer to adjust the pH value to 1-2. 40 ml of toluene, 15 ml of cycloheptane and 15 ml of acetone were added. The temperature was raised to 75°C and a portion of the solvent was evaporated under reduced pressure until material precipitated. The distillation was stopped and the temperature was slowly lowered to 10°C. The wet product was filtered and dried under reduced pressure at 60°C for 8 hours to obtain 4.1 g of white powder, which was amiodarone hydrochloride (VII).

[0242] Example 6: Preparation of Amiodarone Hydrochloride

[0243] According to the operations described in steps 1 to 5 of the embodiment of the present invention, 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran (VI) is prepared, and then in step 6, amiodarone hydrochloride (VII) is prepared according to the following operation:

[0244] Add 4.8 g (7.9 mmol) of 2-butyl-3-[3,5-diiodo-4-(2-chloroethoxy)benzoyl]benzofuran (VI), 5 ml of methanol, and 40 ml of toluene to a reaction flask at room temperature, stir to dissolve, add 2.3 g (31.5 mmol) of diethylamine, heat the reactant to 75°C, stir and react for 6 hours;

[0245] Add 15 ml of cyclohexane and 15 ml of methyl ethyl ketone to the reactant, stir evenly, then add 40 ml of water, stir at 75°C to wash and separate the layers, discard the water layer, add 40 ml of water to the obtained organic layer, wash it once more, obtain the toluene layer, and cool to 40°C;

[0246] Concentrated hydrochloric acid was added dropwise to the toluene layer to adjust the pH value to 1-2. 40 ml of toluene, 15 ml of cyclohexane and 15 ml of methyl ethyl ketone were added, and the temperature was raised to 75°C. A portion of the solvent was evaporated under reduced pressure until material precipitated. The distillation was stopped, and the temperature was slowly lowered to 10°C. The wet product was filtered and dried under reduced pressure at 60°C for 8 hours to obtain 4.3 g of white powder, which was amiodarone hydrochloride (VII).

[0247] Test Example 2: Method for determining the content of amiodarone hydrochloride (HPLC-A method):

[0248] The HPLC-A method provided in this test example can be used to determine the content of the active substance, i.e., the main component, amiodarone hydrochloride, in the amiodarone hydrochloride raw material. The specific details of the HPLC-A method are as follows:

[0249] Buffer solution: Dissolve 6.80 g potassium dihydrogen phosphate in 900 mL water, add 1.0 mL triethylamine, adjust the pH to 6.00 ± 0.05 with phosphoric acid, and dilute to 1000 mL with water;

[0250] Diluent: acetonitrile and water (1:1);

[0251] Mobile phase: acetonitrile and buffer (1:1);

[0252] Standard stock solution: Use methanol as solvent to prepare a 0.5 mg / mL concentration of amiodarone hydrochloride reference solution;

[0253] Standard solution: dilute the standard stock solution with diluent to prepare a 0.1 mg / mL amiodarone hydrochloride reference solution;

[0254] Sample stock solution: 0.5 mg / mL amiodarone hydrochloride methanol solution;

[0255] Sample solution: dilute the sample stock solution with diluent to prepare a 0.1 mg / mL amiodarone hydrochloride sample solution;

[0256] Liquid chromatography detector: UV 240nm;

[0257] Chromatographic column: 150 mm × 3.9 mm, 5 μm, Ultra C4 column (filler type L26);

[0258] Flow rate: 1.5 mL / min;

[0259] Injection volume: 10 μL;

[0260] System suitability: using standard solution, the theoretical plates are greater than 1000, the tailing factor is less than 2.0, and the relative standard deviation does not exceed 1.0%;

[0261] Sample determination: Use the standard solution and sample solution to calculate the percentage of amiodarone hydrochloride (C25H29I2NO3·HCl) according to the following formula:

[0262] Result = (rU / rS) × (CS / CU) × 100

[0263] rU = peak response of amiodarone in sample solution,

[0264] rS = peak response of amiodarone in standard solution,

[0265] CS = concentration of amiodarone hydrochloride in the standard solution (mg / mL),

[0266] CU = nominal concentration of amiodarone hydrochloride in the sample solution (mg / mL).

[0267] Generally speaking, the content of amiodarone hydrochloride as a pharmaceutical raw material determined by the above-mentioned HPLC-A method should be within the range of 98.5% to 101.0% calculated on a dry basis.

[0268] Using the above HPLC-A method, the contents of amiodarone hydrochloride in Examples 1 to 6 were all within the range of 99.1% to 100.2%, for example, the contents in Example 1 and Example 2 were 99.4% and 99.7%, respectively.

[0269] Test Example 3: Performance test of amiodarone hydrochloride

[0270] This test example performs a performance test on the amiodarone hydrochloride prepared in Examples 1 to 6.

[0271] Melting point: The melting points of amiodarone hydrochloride in Examples 1 to 6 are 158.7 to 160.2°C, 182.3 to 183.7°C, 157.7 to 159.1°C, 159.3 to 160.8°C, 163.2 to 164.8°C, and 164.6 to 166.1°C, respectively. It can be seen that only the amiodarone hydrochloride obtained by the process of adding cyclohexane and acetone in step 6 of Example 2 shows significantly different melting points, while the melting points of the products of Examples 5 to 6 slightly increase but not significantly when the alkane and ketone solvents used are changed, and the yields of the two are slightly reduced.

[0272] Content change A: The six kinds of amiodarone hydrochloride raw materials of Examples 1 to 6 were placed in a sealed, light-proof environment at 60°C for 15 days, and their contents were determined by HPLC-A method. For each batch of samples, the quotient obtained by dividing the content on day 15 by the content on day 0 and then multiplying the quotient by 100% was used as the percentage obtained by the residual rate of the amiodarone hydrochloride raw material after treatment at 60°C for 15 days (which can be recorded as the residual rate a). As a result, the residual rate of amiodarone hydrochloride in Example 2 was a=98.7%, and the residual rates of amiodarone hydrochloride in Example 1 and Examples 3 to 6 were a=90.3% to 92.6%. For example, the residual rate of amiodarone hydrochloride in Example 1 was a=90.8%.

[0273] Content change B: Accurately weigh appropriate amounts of the six amiodarone hydrochloride raw materials of Examples 1 to 6, heat them at a heating rate of 5°C / min to a temperature 3°C higher than the upper limit of the respective measured melting points (for example, the amiodarone hydrochloride in Examples 1 to 2 was heated to 163.2°C and 186.7°C, respectively), keep at this temperature for 15 minutes and then cool, and then determine the content of amiodarone hydrochloride therein by HPLC-A method, and divide this content by the content at 0 (the same as the content at 0 days measured in content change A) and multiply the quotient by 100% to obtain the percentage as the residual rate of the amiodarone hydrochloride raw material after treatment at the high melting point - 15 minutes (which can be recorded as the residual rate b); as a result, the residual rate of amiodarone hydrochloride in Example 2 is b=92.3%, and the residual rates of amiodarone hydrochloride in Example 1 and Examples 3 to 6 are b=71% to 77%, for example, the residual rate of amiodarone hydrochloride in Example 1 is b=73.1%.

[0274] According to the above results, it can be seen that the amiodarone hydrochloride obtained by the method of Example 2 of the present invention exhibits significantly better performance.

[0275] In the specific example of preparing amiodarone hydrochloride injection in this article, its formula and preparation method are explained in a ratio of 1 ml total volume, and it is actually prepared in a volume of 10 L.

[0276] Example 11: Preparation of Amiodarone Hydrochloride Injection

[0277] Formula: amiodarone hydrochloride (prepared in Example 2, and all items tested according to the 2020 edition of the Pharmacopoeia standards meet the requirements) 50 mg, benzyl alcohol 20 mg, Tween-80 100 mg, propylene glycol 25 mg, water for injection q.s. to 1 ml, pH 3-3.2.

[0278] Preparation method:

[0279] Dissolve benzyl alcohol in about 10 times the amount of 65°C injection water and set aside;

[0280] Mix amiodarone hydrochloride, Tween-80 and propylene glycol evenly, heat to 65°C, and add 65°C water for injection (the amount is about 10 times the amount of amiodarone hydrochloride) to dissolve the materials while keeping warm and stirring;

[0281] Slowly add the benzyl alcohol solution to the amiodarone hydrochloride solution while keeping warm and stirring, add 65°C water for injection to the full amount, and adjust the pH of the solution to 3-3.2 with 1M hydrochloric acid solution (or 1M sodium hydroxide solution if necessary);

[0282] With continuous stirring, nitrogen is introduced into the drug solution and the drug solution is naturally cooled to 25-30°C. The drug solution is filtered twice with 0.45 μm and 0.22 μm microporous filter membranes respectively. Then, the drug solution is filled into ampoule bottles (3 ml / bottle) under nitrogen filling conditions and sealed by melting.

[0283] Example 12: Preparation of Amiodarone Hydrochloride Injection

[0284] Formula: amiodarone hydrochloride (prepared in Example 2, and all items tested according to the 2020 edition of the Pharmacopoeia standards meet the requirements) 50 mg, benzyl alcohol 22 mg, Tween-80 95 mg, propylene glycol 30 mg, water for injection q.s. to 1 ml, pH 3-3.2.

[0285] Preparation method:

[0286] Dissolve benzyl alcohol in about 10 times the amount of 65°C water for injection and set aside;

[0287] Mix amiodarone hydrochloride, Tween-80 and propylene glycol evenly, heat to 65°C, and add 65°C water for injection (the amount is about 10 times the amount of amiodarone hydrochloride) to dissolve the materials while keeping warm and stirring;

[0288] Slowly add the benzyl alcohol solution to the amiodarone hydrochloride solution while keeping warm and stirring, add 65°C water for injection to the full amount, and adjust the pH of the solution to 3-3.2 with 1M hydrochloric acid solution (or 1M sodium hydroxide solution if necessary);

[0289] With continuous stirring, nitrogen is introduced into the drug solution and the drug solution is naturally cooled to 25-30°C. The drug solution is filtered twice with 0.45 μm and 0.22 μm microporous filter membranes respectively. Then, the drug solution is filled into ampoule bottles (3 ml / bottle) under nitrogen filling conditions and sealed by melting.

[0290] Example 13: Preparation of Amiodarone Hydrochloride Injection

[0291] Formula: amiodarone hydrochloride (prepared in Example 2, and all items tested according to the 2020 edition of the Pharmacopoeia standards meet the requirements) 50 mg, benzyl alcohol 18 mg, Tween-80 105 mg, propylene glycol 20 mg, water for injection q.s. to 1 ml, pH 3-3.2.

[0292] Preparation method:

[0293] Dissolve benzyl alcohol in about 10 times the amount of 65°C water for injection and set aside;

[0294] Mix amiodarone hydrochloride, Tween-80 and propylene glycol evenly, heat to 65°C, and add 65°C water for injection (the amount is about 10 times the amount of amiodarone hydrochloride) to dissolve the materials while keeping warm and stirring;

[0295] Slowly add the benzyl alcohol solution to the amiodarone hydrochloride solution while keeping warm and stirring, add 65°C water for injection to the full amount, and adjust the pH of the solution to 3-3.2 with 1M hydrochloric acid solution (or 1M sodium hydroxide solution if necessary);

[0296] With continuous stirring, nitrogen is introduced into the drug solution and the drug solution is naturally cooled to 25-30°C. The drug solution is filtered twice with 0.45 μm and 0.22 μm microporous filter membranes respectively. Then, the drug solution is filled into ampoule bottles (3 ml / bottle) under nitrogen filling conditions and sealed by melting.

[0297] Example 14: Preparation of Amiodarone Hydrochloride Injection

[0298] Formula: amiodarone hydrochloride (prepared in Example 1, tested according to the 2020 edition of the Pharmacopoeia standards and found to be in compliance with the regulations) 50 mg, benzyl alcohol 20 mg, Tween-80 100 mg, propylene glycol 25 mg, water for injection q.s. to 1 ml, pH 3-3.2.

[0299] Preparation method:

[0300] Dissolve benzyl alcohol in about 10 times the amount of 65°C water for injection and set aside;

[0301] Mix amiodarone hydrochloride, Tween-80 and propylene glycol evenly, heat to 65°C, and add 65°C water for injection (the amount is about 10 times the amount of amiodarone hydrochloride) to dissolve the materials while keeping warm and stirring;

[0302] Slowly add the benzyl alcohol solution to the amiodarone hydrochloride solution while keeping warm and stirring, add 65°C water for injection to the full amount, and adjust the pH of the solution to 3-3.2 with 1M hydrochloric acid solution (or 1M sodium hydroxide solution if necessary);

[0303] With continuous stirring, nitrogen is introduced into the drug solution and the drug solution is naturally cooled to 25-30°C. The drug solution is filtered twice with 0.45 μm and 0.22 μm microporous filter membranes respectively. Then, the drug solution is filled into ampoule bottles (3 ml / bottle) under nitrogen filling conditions and sealed by melting.

[0304] Example 15: Preparation of Amiodarone Hydrochloride Injection

[0305] Formula: Amiodarone hydrochloride (commercially available H20083090, all items tested according to the 2020 edition of the Pharmacopoeia standards meet the requirements) 50 mg, benzyl alcohol 20 mg, Tween-80 100 mg, propylene glycol 25 mg, water for injection up to 1 ml, pH 3-3.2.

[0306] Preparation method:

[0307] Dissolve benzyl alcohol in about 10 times the amount of 65°C water for injection and set aside;

[0308] Mix amiodarone hydrochloride, Tween-80 and propylene glycol evenly, heat to 65°C, and add 65°C water for injection (the amount is about 10 times the amount of amiodarone hydrochloride) to dissolve the materials while keeping warm and stirring;

[0309] Slowly add the benzyl alcohol solution to the amiodarone hydrochloride solution while keeping warm and stirring, add 65°C water for injection to the full amount, and adjust the pH of the solution to 3-3.2 with 1M hydrochloric acid solution (or 1M sodium hydroxide solution if necessary);

[0310] With continuous stirring, nitrogen is introduced into the drug solution and the drug solution is naturally cooled to 25-30°C. The drug solution is filtered twice with 0.45 μm and 0.22 μm microporous filter membranes respectively. Then, the drug solution is filled into ampoule bottles (3 ml / bottle) under nitrogen filling conditions and sealed by melting.

[0311] Example 16: Preparation of Amiodarone Hydrochloride Injection

[0312] Formula: amiodarone hydrochloride (prepared in Example 2, and all items tested according to the 2020 edition of the Pharmacopoeia standards meet the requirements) 50 mg, benzyl alcohol 20 mg, Tween-80 100 mg, water for injection q.s. to 1 ml, pH 3-3.2.

[0313] Preparation method:

[0314] Dissolve benzyl alcohol in about 10 times the amount of 65°C water for injection and set aside;

[0315] Mix amiodarone hydrochloride and Tween-80 evenly, heat to 65°C, and add 65°C injection water (about 10 times the amount of amiodarone hydrochloride) to dissolve the materials while keeping warm and stirring;

[0316] Slowly add the benzyl alcohol solution to the amiodarone hydrochloride solution while keeping warm and stirring, add 65°C water for injection to the full amount, and adjust the pH of the solution to 3-3.2 with 1M hydrochloric acid solution (or 1M sodium hydroxide solution if necessary);

[0317] With continuous stirring, nitrogen is introduced into the drug solution and the drug solution is naturally cooled to 25-30°C. The drug solution is filtered twice with 0.45 μm and 0.22 μm microporous filter membranes respectively. Then, the drug solution is filled into ampoule bottles (3 ml / bottle) under nitrogen filling conditions and sealed by melting.

[0318] Example 17: Preparation of Amiodarone Hydrochloride Injection

[0319] Amiodarone hydrochloride prepared in Example 2 of the present invention was used as the raw material drug and prepared according to the formula and preparation method of Example 1 of CN114917187A (202210651954.3), with a total liquid volume of 10L.

[0320] Example 18: Preparation of Amiodarone Hydrochloride Injection

[0321] Amiodarone hydrochloride prepared in Example 2 of the present invention is used as the raw material, and is prepared according to the formula and preparation method of Example 1 of CN112472668A (202011207802.1), with a total liquid volume of 10L.

[0322] When preparing injections in the above Examples 11 to 18, it has been found that Examples 17 to 18 both need to appropriately increase the amount of feed so that the content of active drugs in the obtained injections can match the desired drug concentration. This may be due to the loss of active drugs in the preparation process. The actual amount of active ingredients in the injection of Example 17 is 94.7% of the actual amount of feed added (equivalent to a loss of about 5.3%), and the actual amount of active ingredients in the injection of Example 17 is 95.4% of the actual amount of feed added. However, there is basically no loss of active drugs in the preparation process in Examples 11 to 16. The actual amount of active ingredients in the injection of Examples 11 to 16 is 98.8 to 99.6% of the actual amount of feed added, for example, 99.2% in Example 11, which shows that the methods of Examples 11 to 16 can avoid the loss of active drugs in the preparation process.

[0323] Test Example 4: Performance test of amiodarone hydrochloride injection

[0324] The related substances measured in the amiodarone hydrochloride injection included in the 2021 edition of the United States Pharmacopoeia involve impurity D (its chemical name is (2-butylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)methanone), and the related substances measured in the amiodarone hydrochloride injection included in the 2020 edition of the Chinese Pharmacopoeia involve impurity II. The above impurity D and impurity II are the same substance. The Chinese Pharmacopoeia stipulates that its limit should be less than 1.6%, and the US Pharmacopoeia stipulates that the limit of this impurity is less than 3%; while the total impurities detected in the amiodarone hydrochloride raw material contained in the Chinese Pharmacopoeia should be less than 0.5%, and the impurity D in the amiodarone hydrochloride raw material contained in the US Pharmacopoeia should be less than 0.2%; in the two solid preparations of amiodarone hydrochloride tablets and capsules contained in the Chinese Pharmacopoeia, it is stipulated that the total impurities detected should be less than 0.5%. This information shows that the impurity II (i.e., impurity D) of amiodarone hydrochloride in aqueous solution will increase, so the attention to impurity II in the injection will help understand the quality status of the injection.

[0325] This test example follows the determination method under "Related Substances" in the amiodarone hydrochloride injection (Part II, page 1281) in the 2020 edition of the Chinese Pharmacopoeia to determine the content of impurity II in (a) the raw material amiodarone hydrochloride used to prepare the injection, (b) the prepared injection, and (c) the injection after being placed at 45°C for 4 months. For each injection,

[0326] The following formula is used to calculate the growth rate (%) of impurity II in the preparation of injection:

[0327]

[0328] The following formula is used to calculate the growth rate (%) of high temperature impurity II in injection:

[0329]

[0330] In addition, each injection was placed at 4-8°C for 15 days, and samples were taken at 0 days and 15 days respectively (avoid shaking the 15-day sample during sampling and take the supernatant to avoid touching the sediment that may exist at the bottom of the bottle). Then, the content of amiodarone hydrochloride in each injection at 0 days and 15 days was determined according to the determination method under "Content Determination" in Amiodarone Hydrochloride Injection (Part II, page 1281) included in the 2020 edition of the Chinese Pharmacopoeia. The quotient obtained by dividing the 15-day content by the 0-day content and multiplying it by 100% is the percentage of the active ingredient residual rate (%).

[0331] In addition, each injection was placed at 4-8°C for 15 days, and samples were taken at 0 days and 15 days respectively (the 15-day sample was shaken to mix the drug solution and then sampled), and then the amiodarone hydrochloride content of each injection at 0 days and 15 days was determined according to the determination method under "Content Determination" in the amiodarone hydrochloride injection (Part II, page 1281) included in the 2020 edition of the Chinese Pharmacopoeia. The quotient obtained by dividing the 15-day content by the 0-day content and multiplying it by 100% is the percentage obtained by correcting the residual rate (%) of the active ingredient.

[0332] The above experiments obtained the results of the growth rate (%) of impurity II in the preparation of injection and the growth rate (%) of impurity II in the high temperature of injection, as well as the residual rate of active ingredients after the injection was subjected to low temperature for 15 days, as shown in the following table.

[0333]

[0334]

[0335] According to the above results, the growth rate of impurity II in the injection prepared by using the raw material with a unique melting point in Example 2 was significantly lower than that in the injection obtained by the commercially available raw material or the raw material in Example 1 after being placed at a high temperature of 45°C for 4 months, indicating that the stability of the injection obtained by using the raw material in Example 2 is significantly more ideal; in addition, the growth rate of impurity II in the preparation process of the injection prepared by adding propylene glycol in Examples 11 to 15 was significantly lower than that in Examples 16 to 18 where propylene glycol was not added, indicating that the addition of propylene glycol during the preparation process of the injection was beneficial to inhibiting the growth of impurity II. The results of the corrected residual rate of active ingredients at low temperature for 15 days showed that the content of active ingredients was basically unchanged regardless of whether propylene glycol was added to the prescription, but the content of the supernatant in the injection without propylene glycol was reduced after the low temperature treatment, which was obviously caused by the possibility that the drug was precipitated due to the low temperature. From the perspective of avoiding the formation of precipitation, it is obviously the effect of the solubilizer, but compared with Tween 80, the solubilization ability of propylene glycol is negligible, so it can be inferred that propylene glycol does not prevent the precipitation of the injection by the solubilization principle. In addition, considering that propylene glycol is a commonly used pharmaceutical excipient for injections, its safety is far better than that of Tween and benzyl alcohol, so the excellent safety of the injections such as Example 11 is obvious.

[0336] Test Example 5: Determination of quality indicators of amiodarone hydrochloride injection

[0337] In this test example, according to the various indicators under the amiodarone hydrochloride injection listed on page 1281 of Part II of the 2020 edition of the Chinese Pharmacopoeia, the various indicators of the injections of Examples 11 to 13 after being placed at 0 month and 40°C for 6 months were measured. The results of the injection of Example 11 are as shown in the following table.

[0338]

[0339] The results of the injections of Examples 12 to 13 are similar to those in the above table, and all indicators meet the requirements. It can be seen that the amiodarone hydrochloride injections prepared in Examples 11 to 13 of the present invention have excellent performance and can fully meet the requirements of the pharmacopoeia.

[0340] The above-described embodiments are only preferred embodiments for fully illustrating the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or changes made by those skilled in the art based on the present invention are within the protection scope of the present invention. The protection scope of the present invention shall be subject to the claims.

Claims

1. An amiodarone hydrochloride injection, comprising 50 mg of amiodarone hydrochloride, 18-22 mg of benzyl alcohol, 95-105 mg of Tween-80, and an appropriate amount of water for injection to 2-3 ml, wherein the pH of the injection is 2.5-4.0; wherein: The amiodarone hydrochloride has a melting point of 181-185°C; The amiodarone hydrochloride uses Cu-Kα radiation, and in the powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 7.03°±0.20°, 11.31°±0.20°, 15.07°±0.20°, 16.88°±0.20°, 17.62°±0.20°, 18.77°±0.20°, 21.73°±0.20°, 21.94°±0.20°, 22.63°±0.20°, 23.42°±0.20°, 24.78°±0.20°, and 27.42°±0.20°.

2. The amiodarone hydrochloride injection according to claim 1, comprising 50 mg amiodarone hydrochloride, 20 mg benzyl alcohol, 100 mg Tween-80, and an appropriate amount of water for injection added to 3 ml, and the pH of the injection is 3.0-4.

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3. The amiodarone hydrochloride injection according to claim 1, further comprising 20-30 mg of propylene glycol.

4. The amiodarone hydrochloride injection according to claim 1, further comprising 25 mg of propylene glycol.

5. The amiodarone hydrochloride injection according to claim 3 is prepared according to a method comprising the following steps: dissolving benzyl alcohol with an appropriate amount of water for injection for standby use; mixing amiodarone hydrochloride, Tween-80, and propylene glycol evenly, heating, and adding water for injection thereto while keeping warm and stirring to dissolve the materials; slowly adding the benzyl alcohol solution to the amiodarone hydrochloride solution while keeping warm and stirring, adding water for injection to the full amount, and adjusting the pH of the liquid to 3-3.2; filling the liquid with nitrogen under continuous stirring and allowing the liquid to cool naturally, filtering with a microporous filter membrane, and then filling the liquid into an ampoule under nitrogen filling conditions, sealing, and obtaining the product.

6. The amiodarone hydrochloride injection according to claim 5 is prepared according to a method comprising the following steps: dissolving benzyl alcohol with 10 times the amount of 65°C water for injection for standby use; uniformly mixing amiodarone hydrochloride, Tween-80, and propylene glycol, heating to 65°C, and adding 10 times the amount of amiodarone hydrochloride at 65°C water for injection thereto under insulation and stirring to dissolve the materials; slowly adding the benzyl alcohol solution to the amiodarone hydrochloride solution under insulation and stirring, adding 65°C water for injection to the full amount, and adjusting the pH value of the liquid to 3-3.2 with 1M hydrochloric acid solution; filling the liquid with nitrogen under continuous stirring and allowing the liquid to cool naturally to 25-30°C, filtering twice with 0.45µm and 0.22µm microporous filter membranes respectively, and then filling the liquid into an ampoule under nitrogen filling conditions, sealing, and obtaining the product.

7. The amiodarone hydrochloride injection according to claim 1, wherein the amiodarone hydrochloride has a melting point of 182-184°C.

8. The amiodarone hydrochloride injection according to claim 1, wherein the amiodarone hydrochloride uses Cu-Kα radiation, and in a powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 7.03°±0.10°, 11.31°±0.10°, 15.07°±0.10°, 16.88°±0.10°, 17.62°±0.10°, 18.77°±0.10°, 21.73°±0.10°, 21.94°±0.10°, 22.63°±0.10°, 23.42°±0.10°, 24.78°±0.10°, and 27.42°±0.10°.

9. The amiodarone hydrochloride injection according to claim 1, wherein the amiodarone hydrochloride uses Cu-Kα radiation, and in a powder X-ray diffraction pattern expressed in 2θ angles, there are diffraction peaks at 7.03°, 11.31°, 15.07°, 16.88°, 17.62°, 18.77°, 21.73°, 21.94°, 22.63°, 23.42°, 24.78°, and 27.42°.

10. Use of the amiodarone hydrochloride injection according to any one of claims 1 to 9 in the preparation of a medicament for treating severe arrhythmias.

11. Use of the amiodarone hydrochloride injection according to any one of claims 1 to 9 in the preparation of a medicament for the treatment of atrial arrhythmia with rapid ventricular rhythm, tachycardia of WPW syndrome, severe ventricular arrhythmia, and cardiopulmonary resuscitation of ventricular fibrillation-related cardiac arrest ineffective with external defibrillation.

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