A preparation method of high-purity dobutamine hydrochloride

Abstract

The invention discloses a preparation method of high-purity dobutamine hydrochloride. By heating and pulping the crude dobutamine hydrochloride in a mixed system of a common organic solvent and a small amount of hydrochloric acid, due to the dissolution and crystallization equilibrium process, impurities gradually dissolve into the solvent and are completely removed by filtration. This method is simple to operate, the obtained product has a purity of ≥99.5%, the maximum single impurity is ≤0.05%, the product quality is better, and it is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a preparation method of high-purity dobutamine hydrochloride. Background Art

[0002] Dobutamine hydrochloride, chemical name: 4-[2-[[1-methyl-3-(4-hydroxyphenyl)propyl]amino]ethyl]-1,2-benzenediol hydrochloride, English name: Dobutamine Hydrochloride, molecular formula: C 18 H 23 NO3·HCl, and the structural formula is shown as follows:

[0003]

[0004] Dobutamine hydrochloride is a homologue of dopamine and is an important anti-shock drug. Its main effects are to stimulate β-adrenergic receptors, enhance cardiac contraction, increase heart rate, raise blood pressure, and dilate blood vessels. As a short-term therapeutic drug, it has a good market prospect.

[0005] There are mainly three industrial synthesis methods of dobutamine hydrochloride.

[0006] US Patent No. US5442120 uses dopamine hydrochloride and 4-(4-hydroxyphenyl)-2-butanone as raw materials, and under the catalysis of Pt / C, dobutamine is obtained through reductive amination reaction, and then dobutamine hydrochloride is obtained by salification.

[0007] US Patent No. US3987200 uses 4-(4-methoxyphenyl)-3-buten-2-one as the starting material, and Raney nickel is used for catalytic hydrogenation reduction to obtain 4-(4-methoxyphenyl)-2-butanone. It further undergoes reductive amination reaction with 3,4-dimethoxybenzeneethylamine under the catalysis of palladium carbon to obtain the intermediate dobutamine trimethyl ether. The intermediate is demethylated in hydrobromic acid / acetic acid to obtain dobutamine hydrobromide, and then it is salted in hydrochloric acid to obtain dobutamine hydrochloride.

[0008] Chinese Patent No. CN108707079 uses 3,4-dimethoxybenzeneethylamine and 4-(4-methoxyphenyl)-2-butanone as starting materials. Under the action of the catalyst p-toluenesulfonic acid, it undergoes dehydration to form an imine structure condensate, and then potassium borohydride is used for hydrogenation reduction to obtain the intermediate dobutamine trimethyl ether. It is demethylated in hydrobromic acid to obtain dobutamine hydrobromide, and then it is salted in hydrochloric acid to obtain dobutamine hydrochloride. All the reactions involved in this route are conventional reactions, without high temperature and high pressure, with low requirements for equipment, simple operation, and suitable for industrial production. Currently, most domestic manufacturers use this route for the production of dobutamine hydrochloride.

[0009] The crude dobutamine hydrochloride obtained by the prior art mainly contains the following impurities: phenolic hydroxyl group oxidized to generate subquinone or quinone impurities, polymerized impurities, and various process impurities remaining from the previous step reaction. The properties of these impurities are similar to those of dobutamine hydrochloride, and they are difficult to separate and difficult to remove during production, which has a significant impact on the quality of the product.

[0010] The maximum daily dose of dobutamine hydrochloride is greater than 2 g. According to the requirements of ICH Q3A, the limit of unknown impurities should not be greater than 0.05%. However, the unknown impurity content of dobutamine hydrochloride currently available on the market is generally higher than 0.05%.

[0011] Impurities in drugs are the main factor affecting purity. If the drugs contain impurities exceeding the limit, it is possible to cause changes in physical and chemical constants, variations in appearance properties, and affect the stability of the drugs. Increased impurities will also cause the content to be significantly lower or the activity to decrease, and significantly increase toxic and side effects, thereby causing a series of adverse reactions and affecting the safety of clinical drug use.

[0012] The study found that during the synthesis of dobutamine hydrochloride, impurity 24 and impurity dimers can be produced.

[0013]

[0014] However, these two impurities are very difficult to remove, and it is difficult to reduce the concentration to less than 0.05% according to conventional purification methods. For example, the method of US Pat. No. 5,442,120 using purified water for recrystallization and the method of US Pat. No. 3,987,200 using 4N hydrochloric acid for recrystallization cannot remove these impurities.

[0015] Therefore, how to purify crude dobutamine hydrochloride to obtain high-purity dobutamine hydrochloride is a new issue to be solved urgently. Summary of the invention

[0016] The purpose of the present invention is to provide a method for preparing high-purity dobutamine hydrochloride. Compared with the prior art, the method is simple to operate, has a high yield, causes little environmental pollution, and is suitable for industrial production. Most importantly, the finished dobutamine hydrochloride product synthesized by the method has a purity of ≥99.5%, a maximum single impurity of ≤0.05%, and a better product quality.

[0017] The method for preparing high-purity dobutamine hydrochloride provided by the present invention comprises the following steps:

[0018] (1) mixing crude dobutamine hydrochloride, solvent A and hydrochloric acid, heating, stirring and beating;

[0019] (2) cooling, keeping the temperature to crystallize, filtering, washing, controlling the temperature to ≤45°C and drying under reduced pressure to obtain the finished product of dobutamine hydrochloride.

[0020] In the above method step (1), the solvent A is any one of acetone, methyl ethyl ketone, methanol, absolute ethanol and isopropyl alcohol, preferably acetone or absolute ethanol;

[0021] The volume-mass ratio of the solvent A to the crude dobutamine hydrochloride can be 2-8 mL:1 g, specifically 3-6 mL:1 g, and more specifically 4 mL:1 g;

[0022] The hydrochloric acid refers to hydrochloric acid with a concentration of 37%;

[0023] The mass ratio of the hydrochloric acid to the crude dobutamine hydrochloride can be 0.3-0.7:1, specifically 0.5-0.6:1, and more specifically 0.5:1;

[0024] When the solvent A is acetone, the ratio of the solvent A to the crude dobutamine hydrochloride and the hydrochloric acid can be 4-6 mL:1 g:0.5-0.6 g in sequence; preferably 4 mL:1 g:0.5 g or 6 mL:1 g:0.6 g;

[0025] When the solvent A is absolute ethanol, the ratio of the solvent A to the crude dobutamine hydrochloride and the hydrochloric acid can be 3-5 mL:1 g:0.5-0.6 g in sequence; preferably 3 mL:1 g:0.5 g or 5 mL:1 g:0.6 g;

[0026] The temperature of the said pulping can be 40-80 °C, preferably 55-65 °C, and the time can be 1-4 hours;

[0027] In step (2), the temperature of the said crystallization can be 0-20 °C, preferably 5-10 °C;

[0028] The time of the said crystallization can be 2-8 hours, preferably 2 or 4 hours.

[0029] The high-purity dobutamine hydrochloride prepared by the above method also belongs to the protection scope of the present invention.

[0030] The purity of the said dobutamine hydrochloride finished product ≥ 99.5%, and the maximum single impurity ≤ 0.05%.

[0031] The advantages of the present invention are as follows: The crude dobutamine hydrochloride is heated and pulped in a mixed system of a common organic solvent (absolute ethanol, acetone, methanol or isopropyl alcohol) and a small amount of hydrochloric acid. Due to the existence of the dissolution-crystallization equilibrium process, the impurities are gradually dissolved into the solvent and are completely removed by filtration. This method is simple in operation, the obtained product has a purity ≥ 99.5%, the maximum single impurity ≤ 0.05%, the product quality is better, and it is suitable for industrial production. Description of the Drawings

[0032] Figure 1 It is the process flow chart of the preparation of the crude dobutamine hydrochloride in the present invention.

[0033] Figure 2 This is the liquid chromatogram of the crude dobutamine hydrochloride in the present invention.

[0034] Figure 3 This is the liquid chromatogram of the finished dobutamine hydrochloride prepared in Example 1.

[0035] Figure 4 This is the liquid chromatogram of the finished dobutamine hydrochloride prepared in Example 2.

[0036] Figure 5 This is the liquid chromatogram of the finished dobutamine hydrochloride prepared in Example 3.

[0037] Figure 6 This is the liquid chromatogram of the finished dobutamine hydrochloride prepared in Example 4.

[0038] Figure 7 This is the liquid chromatogram of the finished dobutamine hydrochloride prepared in Example 5.

[0039] Figure 8 This is the liquid chromatogram of the finished dobutamine hydrochloride prepared in Comparative Example 1.

[0040] Figure 9 This is the liquid chromatogram of the finished dobutamine hydrochloride prepared in Comparative Example 2.

[0041] Figure 10 This is the liquid chromatogram of the finished dobutamine hydrochloride prepared in Comparative Example 5.

[0042] Figure 11 This is the liquid chromatogram of the finished dobutamine hydrochloride prepared in Comparative Example 6. Detailed Embodiments

[0043] The present invention will be further described in detail below in conjunction with the detailed embodiments. The provided examples are only for clarifying the present invention and not for limiting the scope of the present invention. The following examples can be used as a guide for those of ordinary skill in the art to make further improvements and do not constitute any limitation to the present invention in any way.

[0044] The experimental methods in the following examples are all conventional methods unless otherwise specified, and are carried out according to the techniques or conditions described in the literature in this field or according to the product instructions. The materials, reagents, etc. used in the following examples can be obtained from commercial sources unless otherwise specified.

[0045] The crude dobutamine hydrochloride in the following examples is prepared according to Figure 1 the following process route, and the specific steps are as follows:

[0046] Step (1): Add 1.1 L of cyclohexane, 362.8 g (2.0 mol) of 3,4-dimethoxyphenethylamine, and 356.6 g (2.0 mol) of 4-(4-methoxyphenyl)-2-butanone into a 5-L reaction flask equipped with a thermometer and a water separator. Stir and heat up to reflux. Carry out the water-carrying reaction under reflux at 81 - 85 °C and hold the reaction for 4 hours. After the reaction is completed, control the temperature ≤ 50 °C, and concentrate cyclohexane under reduced pressure until almost no distillate flows out to obtain a concentrated solution of oily intermediate 1, about 715.8 g.

[0047] Step (2): Add 3 L of absolute ethanol into a 5-L reaction flask containing 715.8 g (2.0 mol) of the concentrated solution of intermediate 1, and start stirring. Cool down to 0 - 10 °C, and add 37.9 g (1.0 mol) of sodium borohydride in batches. After the addition is complete (about 30 min), continue to stir at the same temperature for 30 min, then warm up to about 30 °C and stir for 2 h. After the reaction is completed, cool the system to 0 - 5 °C, slowly add 1 L of purified water, and dropwise add about 500 ml of concentrated hydrochloric acid. After the addition is complete, stir and crystallize for 2 h. Filter, wash with ethanol, control the temperature ≤ 45 °C, and dry under reduced pressure to obtain about 575.7 g of white solid intermediate 2. The total yield of the two steps is about 75.8%.

[0048] Step (3): Add about 571.8 g (1.5 mol) of intermediate 2 and 1.7 L of 48% hydrobromic acid into a 5-L four-necked reaction flask equipped with a thermometer. Stir and heat up to 120 °C and hold the reaction for 6 h. After the reaction is completed, cool down to 0 - 5 °C and stir and crystallize for 2 h. Filter, wash with purified water, and drain to obtain about 657.4 g of wet product of intermediate 3.

[0049] Step (4): Add 657.4 g of the wet product of intermediate 3 into a 5-L four-necked reaction flask equipped with a thermometer, add 3 L of purified water, stir, and slowly add about 660 ml of concentrated hydrochloric acid. Heat up to 90 °C until the system becomes clear. Then slowly cool down and crystallize, cool down to 0 - 5 °C, and stir and crystallize for 2 h. Filter, wash with purified water, control the temperature ≤ 45 °C, and dry under reduced pressure to obtain about 438.2 g of crude white dobutamine hydrochloride. The total yield of the two steps is about 86.5%.

[0050] Its HPLC purity is 99.51%, the content of dimer impurity is 0.28%, and the content of impurity 24 is 0.08%. The detection spectrum is shown in Figure 2 .

[0051] Example 1

[0052] Into a 500 ml four-necked reaction flask equipped with a thermometer, add 40 g of the crude dobutamine hydrochloride prepared above, 160 ml of acetone, and 20 g of concentrated hydrochloric acid. Stir and heat to reflux (about 60 °C) and slurry for 2 h. After the reaction is completed, slowly cool to 5 - 10 °C, keep warm and crystallize for 2 h, filter, wash with 40 ml of acetone, and drain to obtain the product. Control the temperature ≤ 45 °C, dry under reduced pressure to obtain 36 g of dobutamine hydrochloride finished product. The yield is 90%. (The HPLC purity is 99.79%, the maximum single impurity is 0.03%, and the detection spectrogram is shown in Figure 3 ).

[0053] Example 2

[0054] Into a 500 ml four-necked reaction flask equipped with a thermometer, add 40 g of the crude dobutamine hydrochloride prepared above, 120 ml of absolute ethanol, and 20 g of concentrated hydrochloric acid. Stir and heat to 55 - 65 °C, keep warm and slurry for 3 h. After the reaction is completed, slowly cool to 0 - 5 °C, keep warm and crystallize for 2 h, filter, wash with absolute ethanol. Drain to obtain the product, control the temperature ≤ 45 °C, dry under reduced pressure to obtain 34 g of dobutamine hydrochloride finished product. The yield is 85%. (The HPLC purity is 99.71%, the maximum single impurity is 0.04%, and the detection spectrogram is shown in Figure 4 ).

[0055] Example 3

[0056] Into a 500 ml four-necked reaction flask equipped with a thermometer, add 40 g of the crude dobutamine hydrochloride prepared above, 200 ml of isopropanol, and 24 g of concentrated hydrochloric acid. Stir and heat to 65 - 75 °C, keep warm and slurry for 4 h. After the reaction is completed, slowly cool to 0 - 5 °C, keep warm and crystallize for 2 h, filter, wash with absolute ethanol. Drain to obtain the product, control the temperature ≤ 45 °C, dry under reduced pressure to obtain 34.8 g of dobutamine hydrochloride finished product. The yield is 87%. (The HPLC purity is 99.79%, the maximum single impurity is 0.04%, and the detection spectrogram is shown in Figure 5 ).

[0057] Example 4

[0058] Into a 500 ml four-necked reaction flask equipped with a thermometer, add 20 g of the crude dobutamine hydrochloride prepared above, 120 ml of acetone, and 12 g of concentrated hydrochloric acid. Stir and heat to reflux (about 60 °C) and slurry for 2 h. After the reaction is completed, slowly cool to 5 - 10 °C, keep warm and crystallize for 2 h, filter, wash with 20 ml of acetone, and drain to obtain the product. Control the temperature ≤ 45 °C, dry under reduced pressure to obtain 18.4 g of dobutamine hydrochloride finished product. The yield is 92%. (The HPLC purity is 99.81%, the maximum single impurity is 0.03%, and the detection spectrogram is shown in Figure 6 ).

[0059] Example 5

[0060] Into a 500 ml four-necked reaction flask equipped with a thermometer, add 20 g of the crude dobutamine hydrochloride prepared above, 100 ml of absolute ethanol, and 12 g of concentrated hydrochloric acid. Stir and heat up to 55 - 65 °C, and keep stirring and pulping for 3 h. After the reaction is completed, slowly cool down to 0 - 5 °C, keep the temperature for crystal precipitation for 2 h, filter, and wash with absolute ethanol. Drain and discharge, control the temperature ≤ 45 °C, and dry under reduced pressure to obtain 17 g of the finished product of dobutamine hydrochloride. The yield is 84%. (The HPLC purity is 99.81%, the maximum single impurity is 0.04%, and the detection spectrogram is shown in Figure 7 ).

[0061] Comparative Example 1

[0062] Into a 250 ml four-necked reaction flask equipped with a thermometer, add 10 g of the crude dobutamine hydrochloride prepared above (the HPLC purity is 99.51%, the content of dimer impurity is 0.28%, the content of impurity 24 is 0.08%, and the detection spectrogram is shown in Figure 1 ), 100 g of purified water, and 20 g of concentrated hydrochloric acid. Stir and heat up to 90 - 95 °C until all are dissolved, and reflux for 3 h. After the reaction is completed, slowly cool down to 0 - 5 °C, keep the temperature for crystal precipitation for 2 h, filter, and wash with purified water. Drain and discharge, control the temperature ≤ 45 °C, and dry under reduced pressure to obtain 9.1 g of the finished product of dobutamine hydrochloride. The yield is 91%. (The content of dimer impurity is 0.28%, the content of impurity 24 is 0.06%, and the HPLC detection spectrogram is shown in Figure 8 ). It shows that recrystallization with dilute hydrochloric acid has basically no impurity removal effect.

[0063] Comparative Example 2

[0064] Into a 100 ml four-necked reaction flask equipped with a thermometer, add 10 g of the crude dobutamine hydrochloride prepared above, 50 ml of absolute ethanol, and 5 g of purified water. Stir and heat up to reflux until all are dissolved, and reflux for 3 h. After the reaction is completed, slowly cool down to 0 - 5 °C, keep the temperature for crystal precipitation for 2 h, filter, and wash with absolute ethanol. Drain and discharge, control the temperature ≤ 45 °C, and dry under reduced pressure to obtain 5.2 g of the finished product of dobutamine hydrochloride. The yield is 52%. (The content of dimer impurity is 0.24%, the content of impurity 24 is 0.06%, and the HPLC detection spectrogram is shown in Figure 9 ). It shows that recrystallization with an ethanol / water system has basically no impurity removal effect, and the yield is low, which is not suitable for industrial production.

[0065] Comparative Example 3

[0066] Into a 500 ml four-necked reaction flask equipped with a thermometer, add 10 g of the crude dobutamine hydrochloride prepared above, 50 ml of acetone, and 5 g of purified water. Stir and heat up to reflux until all are dissolved, and reflux for 2 h. After the reaction is completed, slowly cool down to 0 - 5 °C, keep the temperature for crystallization for 2 h, filter, and wash with acetone. Drain and discharge, control the temperature ≤ 45 °C, and dry under reduced pressure to obtain 3.2 g of the finished product of dobutamine hydrochloride. The yield is 32%. It shows that the recrystallization yield using the acetone / water system is low and not suitable for industrial production.

[0067] Comparative Example 4

[0068] Into a 250 ml four-necked reaction flask equipped with a thermometer, add 20 g of the crude dobutamine hydrochloride prepared above, 20 ml of acetone, and 20 g of concentrated hydrochloric acid. Stir and heat up to reflux (about 60 °C) and slurry for 2 h. After the reaction is completed, slowly cool down to 5 - 10 °C, keep the temperature for crystallization for 2 h, filter, wash with 20 ml of acetone, drain and discharge. Control the temperature ≤ 45 °C, and dry under reduced pressure to obtain 13.0 g of the finished product of dobutamine hydrochloride. The yield is 65%. The data shows that the impurity removal effect of this system is obvious, but the yield is too low and not suitable for industrial production.

[0069] Comparative Example 5

[0070] Into a 500 ml four-necked reaction flask equipped with a thermometer, add 20 g of the crude dobutamine hydrochloride prepared above, 200 ml of acetone, and 2 g of concentrated hydrochloric acid. Stir and heat up to reflux (about 60 °C) and slurry for 2 h. After the reaction is completed, slowly cool down to 5 - 10 °C, keep the temperature for crystallization for 2 h, filter, wash with 20 ml of acetone, drain and discharge. Control the temperature ≤ 45 °C, and dry under reduced pressure to obtain 19.1 g of the finished product of dobutamine hydrochloride. The yield is 95.5%. (The content of dimer impurity is 0.20%, the content of impurity 24 is 0.05%, and the HPLC detection spectrum is shown in Figure 10 . It shows that this system has no impurity removal effect and is not suitable for industrial production.

[0071] Comparative Example 6

[0072] Into a 250 ml four-necked reaction flask equipped with a thermometer, add 20 g of the crude dobutamine hydrochloride prepared above, 20 ml of acetone, and 2 g of concentrated hydrochloric acid. Stir and heat up to reflux (about 60 °C) and slurry for 2 h. After the reaction is completed, slowly cool down to 5 - 10 °C, keep the temperature for crystallization for 2 h, filter, wash with 20 ml of acetone, drain and discharge. Control the temperature ≤ 45 °C, and dry under reduced pressure to obtain 19.6 g of the finished product of dobutamine hydrochloride. The yield is 98%. (The content of dimer impurity is 0.23%, the content of impurity 24 is 0.05%, and the HPLC detection spectrum is shown in Figure 11 ). It shows that this system has no impurity removal effect and is not suitable for industrial production.

[0073] The present invention has been described in detail above. For those skilled in the art, without departing from the spirit and scope of the present invention and without unnecessary experiments, the present invention can be implemented within a relatively wide range under equivalent parameters, concentrations, and conditions. Although specific embodiments of the present invention are given, it should be understood that the present invention can be further improved. In short, according to the principle of the present invention, this application intends to cover any modifications, uses, or improvements to the present invention, including changes made using conventional techniques known in the art that depart from the scope disclosed in this application.

Claims

1. A preparation method of high-purity dobutamine hydrochloride, comprising the following steps: (1) Mix the crude dobutamine hydrochloride, solvent A, and hydrochloric acid, heat and stir, and perform pulping; (2) Lower the temperature, keep the temperature for crystal precipitation, filter, wash, and control the temperature ≤ 45 °C for drying under reduced pressure to obtain the finished product of dobutamine hydrochloride; In step (1), solvent A is any one of acetone, methyl ethyl ketone, methanol, absolute ethanol, and isopropyl alcohol; The volume-mass ratio of solvent A to the crude dobutamine hydrochloride is 2-8 mL:1 g; The mass ratio of hydrochloric acid to the crude dobutamine hydrochloride is 0.3-0.7:

1.

2. The method according to claim 1, wherein: The temperature of the pulping is 40-80 °C, and the time is 1-4 hours.

3. The method according to claim 1, wherein: In step (2), the temperature of the crystal precipitation is 0-20 °C, and the time of the crystal precipitation is 2-8 hours.

4. The method according to claim 1, characterized in that: The purity of the obtained finished product of dobutamine hydrochloride is ≥ 99.5%, and the maximum single impurity is ≤ 0.05%.

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