Production method of dobutamine hydrochloride

Abstract

The invention relates to a production method of dobutamine hydrochloride. The preparation method comprises the following steps: taking 3, 4-dimethoxybenzaldehyde as an initial raw material, carrying out Henry reaction on the initial raw material and nitromethane, carrying out reduction through concentrated hydrochloric acid zinc powder, carrying out Borch reductive amination under the catalysis of sodium triacetoxyborohydride, carrying out demethylation and salt conversion under strong acid (48wt% HBr) to obtain dobutamine hydrochloride, and mixing the dobutamine hydrochloride with a gallic acid derivative, mannitol and water to obtain a finished product. The method provided by the invention can effectively avoid the phenomenon of impurity increase caused by easy oxidation of the dobutamine hydrochloride, thereby obtaining a stable and high-quality dobutamine hydrochloride finished product.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to a production method of dobutamine hydrochloride. Background Art

[0002] Dobutamine hydrochloride, with the chemical name 4-[2-[[1-methyl-3-(4-hydroxyphenyl)propyl]amino]ethyl]-1,2-benzenediol hydrochloride, is a β-adrenergic receptor agonist and belongs to a selective myocardial stimulant. This drug mainly acts on the β1 receptor and also has slight α-receptor and β2-receptor agonist effects. Dobutamine hydrochloride was initially synthesized and developed by Eli Lilly and Company in the United States in 1978. Dobutamine hydrochloride mainly enhances myocardial contractility and improves the heart's pumping ability, that is, increases cardiac output, by activating cardiac β1 adrenergic receptors. This effect is particularly important for treating heart failure patients as it helps improve blood circulation and oxygen delivery. In addition to enhancing myocardial contractility, dobutamine hydrochloride also has a mild vasodilatory effect, especially at high doses. This vasodilatory effect helps reduce the heart's afterload (i.e., the resistance that the heart needs to overcome when pumping blood), thus reducing the heart's workload. By increasing cardiac output and reducing vascular resistance, dobutamine hydrochloride can improve blood perfusion of all organs in the body, especially for heart failure patients, it can improve blood flow to the kidneys and brain. Due to the improved blood perfusion of the kidneys, dobutamine hydrochloride can increase the filtration rate of the kidneys, thus increasing urine output and helping to relieve the edema symptoms of heart failure patients. Dobutamine hydrochloride can increase heart rate, and this effect is more obvious at low doses, which helps increase the heart's pumping frequency. In a cardiac stress test, dobutamine hydrochloride can be used to evaluate the heart's response to stress, as well as diagnose and evaluate patients with coronary heart disease. In the case of acute heart failure, dobutamine hydrochloride can rapidly improve symptoms and increase the survival rate of patients. In cardiac surgery or certain high-risk surgeries, dobutamine hydrochloride can be used to maintain cardiac function and blood pressure.

[0003] CN102085180A relates to a dobutamine hydrochloride aqueous injection, which contains the following components: 10.0 - 30.0 g of dobutamine hydrochloride; 0.4 - 1.2 mg of cysteine hydrochloride; 10.0 - 30.0 g of mannitol; and water for injection is added to 2000 mL. The invention also relates to a preparation method of the dobutamine hydrochloride aqueous injection. This method has a simple process, and the prepared product has good quality stability and high clinical safety.

[0004] CN104706572A discloses a preparation method of an injection containing sodium metabisulfite, methionine, sodium chloride, dilute hydrochloric acid and dobutamine hydrochloride. Among them, sodium metabisulfite and methionine are antioxidants, sodium chloride is an isotonic regulator and stabilizer, and dilute hydrochloric acid is a pH regulator. The quality of the dobutamine hydrochloride injection prepared by applying this invention meets the requirements of the Chinese Pharmacopoeia (2010 Edition), and the quality is stable in the accelerated test and long-term stability investigation.

[0005] Dobutamine hydrochloride has low solubility in water, but is more easily soluble in an acidic environment. Therefore, dilute hydrochloric acid needs to be added to adjust the pH value during the preparation process. However, it is found during the production process that dobutamine hydrochloride is relatively sensitive to light and high-temperature conditions. Its aqueous solution will gradually turn red at room temperature, and the change in pH value has a great influence on the stability of the drug, especially on visible foreign matters. To ensure the stability of the injection, the current dobutamine hydrochloride preparations usually add sodium bisulfite as an antioxidant and disodium edetate as a metal ion chelating agent. Sodium bisulfite has potential toxicity and irritation, may cause irritation to the skin, eyes and respiratory tract, and may trigger allergic reactions. In severe cases, it may even cause corneal damage and blindness. In the formulation process, when sodium bisulfite is added as an antioxidant and the pH value is adjusted with a strong acid, sulfurous acid and sulfur dioxide may be generated. If the liquid preparation temperature is too high, sodium bisulfite may decompose to release sulfur dioxide, thus affecting the product quality. On the other hand, after disodium edetate enters the human body, it can form a chelate with calcium ions in the body, posing a risk of reducing the calcium concentration in the blood. Summary of the Invention

[0006] In view of the above-mentioned defects of the prior art, the technical problem to be solved by this invention is to provide a production method of dobutamine hydrochloride.

[0007] Due to the poor stability caused by the easy oxidation of multiple phenolic hydroxyl groups in the dobutamine hydrochloride molecule, the stability will affect the related substances of the finished product, thereby affecting the impurity level. The introduction of impurities has a certain impact on the quality of the finished product, and the current antioxidants pose certain risk challenges to the safety of clinical medication. Therefore, this invention provides a production method of dobutamine hydrochloride, using 3,4-dimethoxybenzaldehyde as the starting material, carrying out a Henry reaction with nitromethane, then reducing with concentrated hydrochloric acid and zinc powder, carrying out a Borch reductive amination under the catalysis of sodium triacetoxyborohydride, then demethylating under strong acid (48wt% HBr), and converting to salt to obtain dobutamine hydrochloride, which is prepared into the finished product by mixing with a gallic acid derivative, mannitol and water.

[0008] Gallic acid has a strong antioxidant capacity, mainly due to multiple hydroxyl (-OH) groups in its molecular structure. These groups can provide hydrogen atoms or electrons to neutralize free radicals, while the carboxylic acid group results in its weak acidity. Therefore, it is not only a good antioxidant but also can be used as a pH regulator. However, gallic acid is soluble in hot water, ether, ethanol, acetone and other solvents, but insoluble in cold water, chloroform and petroleum ether. This is because gallic acid is extremely prone to π–π stacking due to its aromatic ring structure, leading to intermolecular aggregation and thus affecting its water solubility. In the present invention, gallic acid derivatives are obtained by modifying gallic acid, improving its water solubility. Adding gallic acid derivatives to the production of finished dobutamine hydrochloride can not only have antioxidant effect but also play a role in adjusting pH, thereby enhancing the stability of the finished dobutamine hydrochloride. After the modifier reacts with gallic acid, since the sulfonic acid group not only has acidity but also is a good hydrophilic group, it can not only play a role in adjusting pH but also improve water solubility. In addition, the modification can also affect the π–π stacking between benzene rings by increasing steric hindrance, so the water solubility is further improved.

[0009] To achieve the above object, the present invention provides a production method of dobutamine hydrochloride, which comprises the following steps:

[0010] S1. Add 3,4-dimethoxybenzaldehyde (structural formula DBF00), ammonium acetate, and methylamine hydrochloride into a solvent, stir evenly at 15 - 25 °C, then add nitromethane, stir until the peak area ratio of 3,4-dimethoxybenzaldehyde is lower than 5%, that is, reach the reaction end point, dilute, cool down to 15 - 25 °C, stir, centrifuge to dryness, wash the filter cake and then centrifuge to dryness, dry until the water content ≤ 0.4%, discharge to obtain a compound with structural formula DBF01;

[0011]

[0012] S2. Add concentrated hydrochloric acid into a solvent and mix evenly with the compound with structural formula DBF01, add zinc powder in batches at -20 - -10 °C, control the temperature < 10 °C. After adding, raise the temperature to 5 - 15 °C and keep stirring for 1 - 2 h, then raise the temperature to 15 - 25 °C and keep stirring for 1 - 2 h, then raise the temperature to 35 - 45 °C and keep stirring for 2 - 3 h. When the peak area ratio of the compound with structural formula DBF01 is lower than 0.5%, that is, reach the reaction end point, let the reaction solution stand, draw out the supernatant, wash the solid and then draw out the supernatant, combine the supernatants, after extraction, adjust the pH of the aqueous phase to 5 - 6 and then centrifuge, filter to obtain a filtrate. After adjusting the pH of the filtrate > 11, extract, separate and then concentrate to obtain a compound with structural formula DBF02;

[0013]

[0015] S3. Add sodium triacetoxyborohydride to a solvent, cool down to 15 - 25°C under a nitrogen atmosphere, and dropwise add a 2-methyltetrahydrofuran solution containing 4-(4-methoxyphenyl)-2-butanone and the compound of structural formula DBF02, controlling the internal temperature < 40°C. After the addition is complete, raise the temperature of the system to 25 - 35°C for reaction. When the peak area of the compound of structural formula DBF02 is lower than 2.0%, it is regarded as the end point of the reaction. Cool down to 15 - 25°C, wash with alkali, brine, and concentrated hydrochloric acid respectively, then crystallize, and after centrifugation, wash the filter cake and dry it until the water content ≤ 0.4%, and discharge to obtain the compound of structural formula DBF03;

[0016] S4. Under nitrogen protection, heat the compound of structural formula DBF03, 48 wt% hydrobromic acid, sodium metabisulfite, and sodium bisulfite to 100 - 110°C and react for 6 - 10 h. Cool down to 65 - 75°C and keep warm for crystallization, then cool down to 20 - 30°C and keep warm for crystallization. Wash the filter cake obtained by centrifugation and centrifuge until dry. Stir the crude product obtained with concentrated hydrochloric acid, then crystallize, centrifuge, and wash. After centrifugation, wash the filter cake and dry it until the water content ≤ 0.4%, and discharge to obtain the crude product of dobutamine hydrochloride with structural formula DBF04;

[0017]

[0018] Wash the filter cake obtained by centrifugation and centrifuge until dry. Stir the crude product obtained with concentrated hydrochloric acid, then crystallize, centrifuge, and wash. After centrifugation, wash the filter cake and dry it until the water content ≤ 0.4%, and discharge to obtain the crude product of dobutamine hydrochloride with structural formula DBF04;

[0019] S5. Add the crude product of dobutamine hydrochloride with structural formula DBF04 to methanol, heat it to 55 - 65°C under a nitrogen atmosphere, keep warm and stir, then cool down to 45 - 55°C, filter. Add concentrated hydrochloric acid to the filtrate, stir, then crystallize, centrifuge, and wash. After centrifugation, wash the filter cake and dry it until the water content ≤ 0.2%, sieve, and pulverize to obtain dobutamine hydrochloride;

[0020]

[0021] S6. Add dobutamine hydrochloride, mannitol, and gallic acid derivative to water, stir until dissolved, then filter, fill, and sterilize to obtain the product.

[0022] S6. Add dobutamine hydrochloride, mannitol, and gallic acid derivative to water, stir until dissolved, then filter, fill, and sterilize to obtain the product.

[0023] Furthermore, in step S1, the mass ratio of 3,4-dimethoxybenzaldehyde with structural formula DBF00, nitromethane, ammonium acetate, and methylamine hydrochloride is 1:0.86 - 0.90:0.12 - 0.16:0.11 - 0.13.

[0024] Furthermore, in step S2, the mass ratio of the compound of structural formula DBF01, concentrated hydrochloric acid, and zinc powder is 1:11.62 - 12.01:4.9 - 5.1.

[0025] Further, the mass ratio of the compound of structural formula DBF02 described in step S3 to sodium triacetoxyborohydride and 4-(4-methoxyphenyl)-2-butanone is 1:1.6 to 1.68:0.95 to 1.01.

[0026] Further, the mass ratio of the compound of structural formula DBF03 described in step S4 to 48 wt% hydrobromic acid, sodium metabisulfite and sodium bisulfite is 1:11.81 to 12.01:0.01:0.01.

[0027] Further, the mass ratio of the compound of structural formula DBF04 described in step S5 to methanol is 1:2.66 to 2.86.

[0028] Further, the dosage of dobutamine hydrochloride in step S6 is 10 - 20 g / L based on water.

[0029] Further, the dosage of mannitol in step S6 is 10 - 20 g / L based on water.

[0030] Further, the dosage of the gallic acid derivative in step S6 is 0.5 - 1.5 g / L based on water.

[0031] The preparation method of the gallic acid derivative includes the following steps:

[0032] Add gallic acid into a medium and mix it with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide. Cool down and add a modifier and triethylamine. After the reaction is completed, carry out post-treatment and purification to obtain the product.

[0033] Further, the mass ratio of gallic acid to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N-hydroxysuccinimide, the modifier, and triethylamine is 1:1.35 to 1.7:0.6 to 1:0.8 to 2:1.5 to 2.

[0034] Further, the preparation method of the gallic acid derivative includes the following steps:

[0035] Add gallic acid into a medium and mix it with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide. Cool down to 0 - 5°C and add the modifier and triethylamine. Stir at 30 - 40°C for 12 - 24 h. After the reaction is completed, concentrate and purify by column chromatography to obtain the product.

[0036] Preferably, the modifier is one of ammonium 2-aminoethane-1,1-disulfonate, 2-(aminomethylamino)ethanesulfonic acid, or taurine.

[0037] The beneficial effects of the present invention:

[0038] 1. The present invention uses 3,4-dimethoxybenzaldehyde as the starting material, undergoes a Henry reaction with nitromethane, followed by reduction with concentrated hydrochloric acid and zinc powder, Borch reductive amination under the catalysis of sodium triacetoxyborohydride, and then demethylation under strong acid (48 wt% HBr), and the salt is converted to dobutamine hydrochloride. The finished product is prepared by mixing it with a gallic acid derivative, mannitol, and water. The present invention can effectively avoid the phenomenon that dobutamine hydrochloride is easily oxidized to increase impurities, thereby obtaining a stable and high-quality dobutamine hydrochloride finished product.

[0039] 2. The present invention modifies gallic acid to obtain a gallic acid derivative, improves its water solubility, and adds the gallic acid derivative to the production of the dobutamine hydrochloride finished product, which can not only antioxidize but also play a role in adjusting the pH, thereby improving the stability of the dobutamine hydrochloride finished product. Detailed implementation mode

[0040] 2-Aminoethane-1,1-disulfonic acid ammonium, CAS: 1235825-84-9.

[0041] 2-(Aminomethylamino)ethanesulfonic acid, CAS: 87163-48-2.

[0042] Saturated brine refers to a saturated aqueous solution of sodium chloride at 20°C.

[0043] Example 1

[0044] A production method of dobutamine hydrochloride includes the following steps:

[0045] S1. Add 0.5 kg of 3,4-dimethoxybenzaldehyde (structural formula DBF007), 1.04 kg of ammonium acetate, and 0.91 kg of methylamine hydrochloride to 35.6 kg of absolute ethanol, stir evenly at 20°C, then add 6.61 kg of nitromethane, stir until the peak area of 3,4-dimethoxybenzaldehyde reaches 3.8%, reach the reaction end point, add 22.5 kg of water for dilution, cool down to 15°C, stir, centrifuge to dryness, wash the filter cake and then centrifuge to dryness, dry until the water content is ≤ 0.4%, discharge to obtain a compound with structural formula DBF01;

[0046] S2. Add 49.6 kg of 36 wt% concentrated hydrochloric acid to a mixture of 13.3 kg of absolute ethanol, 16.8 kg of water and 4.2 kg of the compound with structural formula DBF01, and mix them evenly. Add 21 kg of zinc powder in batches at -15°C, control the temperature < 10°C. After adding, raise the temperature to 10°C and stir for 2 h, then raise the temperature to 20°C and stir for 2 h, and then raise the temperature to 40°C and stir for 3 h. The peak area ratio of the compound with structural formula DBF01 is 0.03%, reaching the reaction end point. Let the reaction solution stand, draw out the supernatant, wash the solid and draw out the supernatant, combine the supernatants, adjust the pH of the aqueous phase to 6 after extraction and then centrifuge, filter to obtain the filtrate. After adjusting the pH of the filtrate to 12, concentrate it after extraction and liquid separation to obtain the compound with structural formula DBF02;

[0047] S3. Add 11.92 kg of sodium triacetoxyborohydride to 36.4 kg of 2-methyltetrahydrofuran, cool down to 20°C under a nitrogen atmosphere, and dropwise add a 2-methyltetrahydrofuran solution containing 7.16 kg of 4-(4-methoxyphenyl)-2-butanone and 7.28 kg of the compound with structural formula DBF02. The amount of 2-methyltetrahydrofuran is 36.4 kg. Control the internal temperature < 40°C. After dropping, raise the temperature of the system to 30°C for reaction. The peak area of the compound with structural formula DBF02 is 0.4%, reaching the reaction end point. Cool down to 20°C, wash with 2 mol / L sodium hydroxide aqueous solution, saturated brine, and 36 wt% concentrated hydrochloric acid respectively, then crystallize for 1 h, wash the centrifuged filter cake and dry it until the water content ≤ 0.4%, and discharge to obtain the compound with structural formula DBF03;

[0048] S4. Add 7 kg of the compound with structural formula DBF03, 83.4 kg of 48 wt% hydrobromic acid, 0.07 kg of sodium metabisulfite, and 0.07 kg of sodium bisulfite under nitrogen protection, raise the temperature to 102°C, react for 8 h, cool down to 70°C, keep the temperature for crystallization for 2 h, and then cool down to 25°C and keep the temperature for crystallization for 2 h. Wash the centrifuged filter cake and centrifuge until dry. Stir the obtained crude product with 36 wt% concentrated hydrochloric acid, then crystallize, centrifuge, and wash. Wash the centrifuged filter cake and dry it until the water content ≤ 0.4%, and discharge to obtain the compound with structural formula DBF04;

[0049] S5. Add 5.4 kg of the compound with structural formula DBF04 to 14.9 kg of methanol, raise the temperature to 55°C under a nitrogen atmosphere and stir for 1 h, then cool down to 50°C, filter. Stir the filtrate with 18 wt% concentrated hydrochloric acid, then crystallize for 2 h, centrifuge, and wash. Wash the centrifuged filter cake and dry it until the water content ≤ 0.2%, sieve and crush to obtain dobutamine hydrochloride.

[0050] Example 2

[0051] A production method of dobutamine hydrochloride, comprising the following steps:

[0052] S1. Add 0.5 kg of 3,4-dimethoxybenzaldehyde (structural formula DBF007), 1.04 kg of ammonium acetate, and 0.91 kg of methylamine hydrochloride to 35.6 kg of absolute ethanol. Stir evenly at 20 °C, then add 6.61 kg of nitromethane. Stir until the peak area of 3,4-dimethoxybenzaldehyde reaches 3.8%, reaching the reaction end point. Add 22.5 kg of water for dilution, cool down to 15 °C, stir, centrifuge until dry. The filter cake is washed and then centrifuged until dry, and dried until the water content is ≤0.4%. Discharge to obtain the compound with structural formula DBF01;

[0053] S2. Add 49.6 kg of 36 wt% concentrated hydrochloric acid to a mixture of 13.3 kg of absolute ethanol, 16.8 kg of water, and 4.2 kg of the compound with structural formula DBF01. Mix evenly, and add 21 kg of zinc powder in batches at -15 °C, controlling the temperature <10 °C. After adding, raise the temperature to 10 °C and stir for 2 h, then raise the temperature to 20 °C and stir for 2 h, and then raise the temperature to 40 °C and stir for 3 h. When the peak area ratio of the compound with structural formula DBF01 reaches 0.03%, reaching the reaction end point, let the reaction solution stand, draw out the supernatant. After the solid is washed, draw out the supernatant again. Combine the supernatants, adjust the pH of the aqueous phase to 6 after extraction and then centrifuge, filter to obtain the filtrate. After adjusting the pH of the filtrate to 12, concentrate after extraction and liquid separation to obtain the compound with structural formula DBF02;

[0054] S3. Add 11.92 kg of sodium triacetoxyborohydride to 36.4 kg of 2-methyltetrahydrofuran. Cool down to 20 °C under a nitrogen atmosphere, and dropwise add a 2-methyltetrahydrofuran solution containing 7.16 kg of 4-(4-methoxyphenyl)-2-butanone and 7.28 kg of the compound with structural formula DBF02. The amount of 2-methyltetrahydrofuran is 36.4 kg, controlling the internal temperature <40 °C. After dropping, raise the temperature of the system to 30 °C for reaction. When the peak area of the compound with structural formula DBF02 reaches 0.4%, reaching the reaction end point, cool down to 20 °C, wash with 2 mol / L sodium hydroxide aqueous solution, saturated brine, and 36 wt% concentrated hydrochloric acid respectively, then crystallize for 1 h. The filter cake after centrifugation is washed and then dried until the water content is ≤0.4%. Discharge to obtain the compound with structural formula DBF03;

[0055] S4. Under nitrogen protection, add 7 kg of the compound with structural formula DBF03, 83.4 kg of 48 wt% hydrobromic acid, 0.07 kg of sodium metabisulfite, and 0.07 kg of sodium bisulfite. Raise the temperature to 102 °C and react for 8 h, then cool down to 70 °C and crystallize for 2 h, and then cool down to 25 °C and crystallize for 2 h. The filter cake obtained by centrifugation is washed and then centrifuged until dry. The obtained crude product is stirred with 36 wt% concentrated hydrochloric acid, then crystallized, centrifuged, and washed. The filter cake after centrifugation is washed and then dried until the water content is ≤0.4%. Discharge to obtain the compound with structural formula DBF04;

[0056] S5. Add 5.4 kg of the compound of structural formula DBF04 to 14.9 kg of methanol. Under a nitrogen atmosphere, heat the mixture to 55 °C, keep it warm and stir for 1 h, then cool it to 50 °C, filter. Add 18 wt% concentrated hydrochloric acid to the filtrate, stir, crystallize for 2 h, centrifuge, and wash. After washing, dry the filter cake obtained by centrifugation until the water content is ≤ 0.2%, sieve, and crush to obtain dobutamine hydrochloride.

[0057] S6. Add 20 g of dobutamine hydrochloride, 20 g of mannitol, and 2 g of gallic acid derivative to water, make up the volume to 2 L, stir until dissolved, filter, fill, and sterilize to obtain the product.

[0058] The preparation method of the gallic acid derivative includes the following steps:

[0059] Add 2 g of gallic acid to 200 mL of ethanol, mix with 3.1 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1.6 g of N-hydroxysuccinimide, cool to 0 °C, add 2.8 g of 2-(aminomethylamino)ethanesulfonic acid and 3.5 g of triethylamine, stir at 35 °C for 18 h. After the reaction is completed, concentrate and purify by column chromatography to obtain the product.

[0060] Example 3

[0061] It is basically the same as Example 2, and the only difference is that 2-(aminomethylamino)ethanesulfonic acid is replaced by taurine.

[0062] Example 4

[0063] It is basically the same as Example 2, and the only difference is that 2-(aminomethylamino)ethanesulfonic acid is replaced by 2-aminoethane-1,1-disulfonic acid ammonium.

[0064] Example 5

[0065] It is basically the same as Example 3, and the only difference is that the addition amount of the gallic acid derivative is 1.25 g.

[0066] Example 6

[0067] It is basically the same as Example 3, and the only difference is that the addition amount of the gallic acid derivative is 1.5 g.

[0068] Example 7

[0069] It is basically the same as Example 4, and the only difference is that the addition amount of the gallic acid derivative is 1.25 g.

[0070] Example 8

[0071] It is basically the same as Example 4, and the only difference is that the addition amount of the gallic acid derivative is 1.5 g.

[0072] Control Example 1

[0073] It is basically the same as Example 2, and the only difference is that no gallic acid derivative is added.

[0074] Control Example 2

[0075] It is basically the same as Example 2, and the only difference is that the gallic acid derivative is replaced with gallic acid.

[0076] Test Example 1

[0077] The stability tests were carried out on the dobutamine hydrochloride prepared in the examples and control examples, including accelerated tests and long-term tests. For the accelerated test, the samples were placed in a constant temperature and humidity chamber at a temperature of 45°C and a relative humidity of 80% for 6 months, and samples were taken at the 1st, 2nd, 3rd, and 6th months respectively to test the performance of the samples. For the long-term test, the samples were placed under intermediate conditions of a temperature of 25°C and a relative humidity of 60%, and samples were taken at the 3rd, 6th, 9th, and 12th months respectively to test the performance of the samples.

[0078] Table 1 Results of the stability test of dobutamine hydrochloride

[0079]

[0080]

[0081]

[0082]

[0083] Since dobutamine hydrochloride is slightly soluble in water and soluble in acidic solutions, pH regulators need to be added for adjustment. However, it was found during the preparation process that the product is unstable to strong light and high temperatures, its aqueous solution will change color when placed at room temperature, and the pH range also has a great impact on the product's stability. From the pH values of the samples prepared in the examples and control examples, it can be seen that when gallic acid or its derivatives are not added, the pH of the finished product is relatively high. As time prolongs, the content of related substances in the finished product increases, while the content of dobutamine hydrochloride continuously decreases. This indicates that pH has a certain impact on the stability of dobutamine hydrochloride. In control example 1, since no gallic acid or gallic acid derivatives were added, the stability performance is the worst. In control example 2, gallic acid was added, but due to the relatively weak acidity of gallic acid, the pH of the finished product is relatively high, which also has a certain impact on stability. The gallic acid derivatives in the examples have stronger acidity than gallic acid due to the grafting of sulfonic acid groups. Therefore, the pH of the finished product in the examples is lower, and the stability performance is also better. The multiple hydroxyl (-OH) groups in the molecular structure of gallic acid derivatives can provide hydrogen atoms or electrons to neutralize free radicals, thus playing an antioxidant role. The sulfonic acid group not only has acidity but also is a good hydrophilic group. Therefore, it can not only play a role in adjusting the pH but also improve water solubility. In addition, the modification can also affect the π–π stacking interaction between benzene rings by increasing steric hindrance, thus further improving water solubility. Compared with examples 2 - 3 and 5 - 8, 2-aminoethane-1,1-disulfonic acid ammonium in example 4 has more sulfonic acid groups. Therefore, it has a better effect on adjusting the pH and can reach a lower pH value with a smaller addition amount. Therefore, the modifier in example 4 plays a greater role in improving the final stability.

[0084] The preferred specific embodiments of the present invention have been described in detail above. It should be understood that those of ordinary skill in the art can make many modifications and variations based on the concept of the present invention without creative efforts. Therefore, all technical solutions that can be obtained by those skilled in the art in the technical field of the present invention based on the concept of the present invention through logical analysis, reasoning, or limited experiments on the basis of the prior art shall fall within the protection scope determined by the claims.

Claims

1. A method for producing dobutamine hydrochloride, characterized in that: The steps include: S1. Add 3,4-dimethoxybenzaldehyde of structural formula DBF00, ammonium acetate and methylamine hydrochloride to a solvent and stir evenly at 15-25° C., then add nitromethane and stir until the peak area ratio of 3,4-dimethoxybenzaldehyde is less than 5%, i.e., the reaction end point is reached, dilute, cool to 15-25° C., stir, centrifuge to dryness, wash the filter cake and centrifuge to dryness, dry to a moisture content of ≤0.4%, and discharge to obtain a compound of structural formula DBF01; S2. Add concentrated hydrochloric acid to the solvent and mix evenly with the compound of structural formula DBF01, add zinc powder in batches at -20 to -10°C, control the temperature to <10°C, after the addition, heat to 5 to 15°C and keep stirring for 1 to 2 hours, heat to 15 to 25°C and keep stirring for 1 to 2 hours, heat to 35 to 45°C and keep stirring for 2 to 3 hours, the peak area ratio of the compound of structural formula DBF01 is less than 0.5%, that is, the reaction end point is reached, the reaction solution is allowed to stand, the supernatant is extracted, the supernatant is extracted after the solid is eluted, the supernatant is combined, the aqueous phase is adjusted to pH 5 to 6 after extraction, centrifuged, filtered to obtain a filtrate, the filtrate is adjusted to pH>11, extracted, separated and concentrated to obtain a compound of structural formula DBF02; S3, adding sodium triacetoxyborohydride to the solvent, cooling to 15-25°C under nitrogen atmosphere, dripping 2-methyltetrahydrofuran solution containing 4-(4-methoxyphenyl)-2-butanone and the compound of structural formula DBF02, controlling the internal temperature to <40°C, after the dripping is completed, heating the system to 25-35°C for reaction, and the peak area of ​​the compound of structural formula DBF02 is less than 2.0%, which is regarded as the end point of the reaction, cooling to 15-25°C, washing with alkali, brine and concentrated hydrochloric acid respectively, and crystallizing, washing the filter cake after centrifugation, and drying to a moisture content of ≤0.4%, discharging, and obtaining a compound of structural formula DBF03; S4, the compound of structural formula DBF03 and 48wt% hydrobromic acid, sodium pyrosulfite, sodium bisulfite are heated to 100-110°C under nitrogen protection, react for 6-10h, cool to 65-75°C, keep warm for crystallization, cool to 20-30°C for crystallization, wash the filter cake obtained by centrifugation and centrifuge to dryness, add concentrated hydrochloric acid to the obtained crude product, stir, crystallize, centrifuge, wash, wash the filter cake after centrifugation, dry to a moisture content of ≤0.4%, and discharge to obtain a crude dobutamine hydrochloride product with structural formula DBF04; S5. Add crude dobutamine hydrochloride product with structural formula DBF04 into methanol, and nitrogen The mixture was heated to 55-65°C in an atmosphere, kept warm and stirred, then cooled to 45-55°C, filtered, the filtrate was stirred with concentrated hydrochloric acid, crystallized, centrifuged and rinsed, the filter cake after centrifugation was rinsed, dried to a moisture content of ≤0.2%, sieved and crushed to obtain dobutamine hydrochloride; S6. Add dobutamine hydrochloride, mannitol and gallic acid derivative into water, stir until dissolved, filter, fill and sterilize.

2. The method for producing dobutamine hydrochloride according to claim 1, wherein: The mass ratio of 3,4-dimethoxybenzaldehyde structural formula DBF00, nitromethane, ammonium acetate and methylamine hydrochloride in step S1 is 1:0.86-0.90:0.12-0.16:0.11-0.

13.

3. The method for producing dobutamine hydrochloride according to claim 1, wherein: The mass ratio of the compound of structural formula DBF01 to concentrated hydrochloric acid and zinc powder in step S2 is 1:11.62-12.01:4.9-5.

1.

4. The method for producing dobutamine hydrochloride according to claim 1, wherein: The mass ratio of the compound of structural formula DBF02, sodium triacetoxyborohydride and 4-(4-methoxyphenyl)-2-butanone in step S3 is 1:1.6-1.68:0.95-1.

01.

5. The method for producing dobutamine hydrochloride according to claim 1, characterized in that: In step S4, the mass ratio of the compound of structural formula DBF03 to 48wt% hydrobromic acid, sodium pyrosulfite and sodium bisulfite is 1:11.81-12.01:0.01:0.

01.

6. The method for producing dobutamine hydrochloride according to claim 1, characterized in that: The mass ratio of the compound of structural formula DBF04 to methanol in step S5 is 1:2.66-2.

86.

7. The method for producing dobutamine hydrochloride according to claim 1, characterized in that: The dosage of dobutamine hydrochloride in step S6 is 10-20 g / L, based on water.

8. The method for producing dobutamine hydrochloride according to claim 1, characterized in that: The dosage of mannitol in step S6 is 10-20 g / L; the dosage of gallic acid derivative is 0.5-1.5 g / mL, based on water.

9. The method for producing dobutamine hydrochloride according to claim 1, characterized in that: The preparation method of the gallic acid derivative comprises the following steps: Gallic acid is mixed with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide in a medium, and a modifier and triethylamine are added after cooling. After the reaction is completed, the product is post-treated and purified to obtain the product; the mass ratio of the gallic acid to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N-hydroxysuccinimide, modifier and triethylamine is 1:1.35-1.7:0.6-1:0.8-2:1.5-2.

10. The method for producing dobutamine hydrochloride according to claim 9, characterized in that: The modifier is one of 2-aminoethane-1,1-disulfonic acid ammonium, 2-(aminomethylamino)ethanesulfonic acid or taurine.

Images