A continuous process for the synthesis of a rocuronium bromide intermediate

Abstract

The application relates to a continuous synthesis method of a rocuronium bromide intermediate, which is prepared from rocuronium bromide sulfone, the raw material is dissolved into a clear solution by a solvent, and the reaction is carried out in a micro-channel reactor under the condition of high-temperature catalysis; the material after the reaction is completed is collected in a receiving kettle after heat exchange and temperature reduction, the continuous flow technology is used to reduce the liquid holding capacity of the reaction, steam heating is replaced by heat conduction oil heating, the back pressure is increased to increase the reaction temperature, the reaction time is shortened, the quality control impurities are effectively controlled, the production efficiency and the production safety are improved, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and specifically to a continuous synthesis method for rocuronium bromide intermediates. Background Technology

[0002] Rocuronium bromide is a non-depolarizing neuromuscular blocking skeletal muscle relaxant, primarily used during general anesthesia to assist in endotracheal intubation and maintain skeletal muscle relaxation during surgery. It achieves its muscle relaxation effect by competitively binding to acetylcholine receptors, preventing ion channel activation and cell membrane depolarization. Its structural formula is shown below:

[0003] .

[0004] 5α-Androst-2-en-17-one is an important intermediate in the synthesis of rocuronium bromide. Currently, epiandrostone is mostly used as a raw material, and it is prepared by a two-step method of sulfonation / elimination.

[0005] Chinese patent CN101225099 discloses a method for preparing 5α-androst-2-en-17-one. The method involves sulfonating epiandrostone to obtain epiandrostone p-toluenesulfonate, then adding N,N-dimethylformamide and diisopropylethanolamine, heating under reflux to remove p-toluenesulfonate, and post-treatment to obtain 5α-androst-2-en-17-one with a yield of 85%.

[0006] Chinese patent CN109678918A discloses a method for preparing 5α-androst-2-en-17-one. Using epiandrostone as raw material, a dehydration reaction is carried out under the co-catalysis of protic acid and trifluoromethanesulfonate. After post-treatment and recrystallization separation, 5α-androst-2-en-17-one is obtained with a yield of 88%.

[0007] Chinese patent CN113683655A discloses a method for preparing 5α-androst-2-en-17-one. Using epiandrostone as a raw material, a dehydration reaction is carried out under the catalysis of Eaton reagent (a mixture of methanesulfonic acid and phosphorus pentoxide). The resulting product is then washed, extracted, and concentrated to obtain 5α-androst-2-en-17-one. This preparation method lowers the reaction temperature to 40°C, but extends the reaction time to over 17 hours.

[0008] The Chinese Journal of Medicinal Chemistry, 2008, 18(1), 61-63, disclosed that epiandrolone sulfonate was dissolved in DMF and reacted at 120°C for 3 hours. After naturally cooling to room temperature, crystals precipitated. The product was filtered, the mother liquor was removed, the product was washed, dried, and then subjected to column chromatography to obtain 5α-androst-2-en-17-one.

[0009] Furthermore, the background technology disclosed in CN103360455 states that the batch reaction temperature of α-androst-2-en-17-one is affected by the vapor pressure. Existing batch equipment cannot be further heated with steam, and the heating and cooling times are relatively long, easily generating isomer impurities. Its structural formula is shown below:

[0010] .

[0011] Therefore, it is necessary to develop a new method for preparing rocuronium bromide intermediates. Summary of the Invention

[0012] One object of the present invention is to provide a method for preparing 5α-androst-2-en-17-one, comprising the following steps:

[0013] (1) Prepare a solution by mixing epiandrolone p-toluenesulfonate with an organic solvent;

[0014] (2) The liquid obtained in step 1 is pumped into the microchannel reactor through a feed pump;

[0015] .

[0016] In some embodiments of the present invention, the reaction temperature is 150~190°C and the pressure is 0.5~1 MPa; preferably, the temperature is 160°C~170°C and the pressure is 0.6~0.8 MPa.

[0017] The temperature of the reaction is controlled by adding an oil bath device outside the reactor, which uses heat transfer oil to conduct the heat.

[0018] In some embodiments, the organic solvent is selected from one or more of N,N-dimethylacetamide, N,N-dimethylformamide, or N-methylpyrrolidone. In some typical embodiments, the organic solvent is N,N-dimethylacetamide.

[0019] In some embodiments of the present invention, the organic solvent is dimethylacetamide, the reaction temperature is 160~170°C, for example 160°C, 165°C, 170°C or any value or range thereof, and the reaction pressure is 0.8~0.9 MPa.

[0020] In some embodiments, the mass ratio of epiandrolone p-toluenesulfonate to organic solvent is 1:2 to 5; in some typical embodiments, the mass ratio of epiandrolone p-toluenesulfonate to organic solvent is 1:3 to 5.

[0021] In some embodiments, the feed pump is selected from plunger pumps, diaphragm pumps, peristaltic pumps, injection pumps, and gear pumps.

[0022] In some embodiments, the microchannel reactor is a plate and / or tubular reactor with a pipe diameter of 10-20 mm and a pipe length of 50-100 m.

[0023] In some embodiments, the flow rate of the feed liquid is 2~10 mL / min, and the reaction time is 5~10 min.

[0024] In some embodiments, the preparation method further includes a step of cooling through a cooling section after the reaction is completed.

[0025] In some embodiments, a water bath device is added outside the cooling section for cooling, and the temperature of the cooling section is 40℃-90℃.

[0026] In some embodiments, the method further includes quenching the reaction solution in a receiving bottle containing water, wherein the amount of water is 6 to 10 times the amount of the collected solution, the water temperature is 40 to 90°C, the mixture is stirred and filtered, the filter cake is adjusted to pH 7 to 8 with water, and then dried to obtain 5α-androst-2-en-17-one.

[0027] A second aspect of the present invention is to provide a method for preparing rocuronium bromide, wherein 5α-androst-2-en-17-one obtained by the method of the present invention is subjected to acetylation, epoxidation, addition, esterification and propyleneation to obtain rocuronium bromide.

[0028] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0029] 1. This invention uses microchannel reactor technology to prepare 5α-androst-2-en-17-one. The product purity can reach over 97%, the isomer impurities are less than 1%, and the product yield is over 95%. The next step of the reaction can be carried out without further purification, making the operation simpler and suitable for industrial production.

[0030] 2. Employing microchannel continuous flow technology and using heat transfer oil for heating results in low heat loss and allows for precise temperature control and rapid heating and cooling within a short time. This effectively reduces the formation of isomers during the reaction process. While ensuring high yield and high-quality products, it enables automated and continuous production, significantly shortening the production cycle, saving energy and reducing consumption, and is environmentally friendly. Attached Figure Description

[0031] Figure 1 A diagram of the apparatus for preparing 5α-androst-2-en-17-one using the microchannel reactor of the present invention:

[0032] 1: Storage tank for a mixed solution of epiandrolone p-toluenesulfonate and dimethylacetamide;

[0033] 2: Feed pump;

[0034] 3: Microreactor;

[0035] 4: Cooling stage;

[0036] 5: Valves;

[0037] 6: Receiving tank;

[0038] The various devices are connected by metal pipes. Detailed Implementation

[0039] To further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims of the present invention.

[0040] Those skilled in the art will readily understand that the error range of the parameters listed in this invention also falls within the scope of protection of this invention. The error range includes, but is not limited to, the degree of expected experimental error, technical error, instrument error, and industrial operational error of the given technique used to measure the value. When the degree of error is not specified, all values ​​listed in this invention encompass a range of ±10% of the specified value.

[0041] In this embodiment of the invention, the HPLC measurement conditions for 5α-androst-2-en-17-one are as follows:

[0042] Instrument: High-performance liquid chromatograph equipped with an ultraviolet detector;

[0043] Chromatographic column: ACE Excel 3 CN-ES 150*4.6mm 3.0μm or equivalent column;

[0044] Mobile phase A: Water;

[0045] Mobile phase B: Acetonitrile;

[0046] Flow rate: 1.0 mL / min;

[0047] Injection volume: 10 μL;

[0048] Column temperature: 35℃;

[0049] Running time: 78 minutes;

[0050] Detection wavelength: 210nm;

[0051] Gradient table:

[0052] Time (min) Mobile phase A (%V / V) Mobile phase B (%V / V) 0 75 25 65 18 82 65.1 5 95 70 5 95 70.1 75 25 78 75 25

[0053] Example 1: Preparation method of epiandrolone p-toluenesulfonate

[0054] Take 40g of p-toluenesulfonyl chloride, dissolve it in 120g of pyridine, then add 40g of epiandrolone and stir to raise the temperature. The material temperature rises to 43℃ and reacts for 4 hours. During the reaction, solid material (pyridine salt) is precipitated. After the reaction is completed, cool down to 0~-5℃. The material has good fluidity. Add 0.5mL of water pre-cooled to 0-5℃. After the reaction temperature drops back to -5℃, add another 0.5mL of water. Then, after the reaction temperature drops back to -5℃, repeat the same operation 4 times. Then start to add the remaining water dropwise (a total of 800mL of water is added). After the addition is complete, stir at room temperature (15-30℃) for 1 hour, filter, and obtain epiandrolone p-toluenesulfonate.

[0055] Example 2: Preparation of 5α-androst-2-en-17-one

[0056]

[0057] 300g of epiandrolone p-toluenesulfonate and 600g of dimethylacetamide were added to a 1000mL volumetric flask and stirred until dissolved at 60℃. The solution was transferred to a silicon carbide plate reaction system using a plunger pump at a flow rate of 8mL / min. The plate reaction consisted of a reaction section and a cooling section. The reaction section was controlled at 165℃, with the pressure of the reaction system controlled at 0.8MPa via a back pressure valve, and the reaction time was 7.5min. The cooling section was controlled at 70℃. After the reaction, the solution was collected in a receiving bottle containing 7.5 times the volume of the solution at 60℃. The mixture was stirred and filtered. The filter cake was adjusted to pH 7-8 with water and dried to obtain 120g of 5α-androst-2-en-17-one with a purity of 97.3% and isomer impurities of 0.45%.

[0058] Example 3: Preparation of 5α-androst-2-en-17-one

[0059] 100g of epiandrolone p-toluenesulfonate and 200g of dimethylacetamide were added to a 500mL volumetric flask and stirred until dissolved at 60℃. The solution was transferred to a silicon carbide plate reaction system using a plunger pump at a flow rate of 2mL / min. The plate reaction consisted of a reaction section and a cooling section. The reaction section was controlled at 160℃, with the pressure of the reaction system controlled at 0.8MPa via a back pressure valve, and the reaction time was 10min. The cooling section was controlled at 70℃. After the reaction, the solution was collected in a receiving bottle containing 7.5 times the volume of the solution at 60℃. The mixture was stirred and filtered. The filter cake was adjusted to pH 7-8 with water and dried to obtain 58.8g of 5α-androst-2-en-17-one with a purity of 98.4% and isomer impurities of 0.96%.

[0060] Example 4: Preparation of 5α-androst-2-en-17-one

[0061] 150 g of epiandrolone p-toluenesulfonate and 300 g of dimethylacetamide were added to a 500 mL volumetric flask and stirred until dissolved at 60 °C. The solution was then transferred to a silicon carbide plate reaction system using a plunger pump at a flow rate of 5 mL / min. The plate reaction consisted of a reaction section and a cooling section. The reaction section was controlled at 170 °C, with the pressure of the reaction system controlled at 0.8 MPa via a back pressure valve, and the reaction time was 8 min. The cooling section was controlled at 70 °C. After the reaction was completed, the solution was collected in a receiving bottle containing 7.5 times the volume of the solution at 60 °C. The mixture was stirred and filtered. The filter cake was adjusted to neutral pH with water and dried to obtain 88.5 g of 5α-androst-2-en-17-one with a purity of 97.9% and isomer impurities of 0.58%.

[0062] Comparative Example 1

[0063] 40 g of dimethylacetamide and 20 g of epiandrolone p-toluenesulfonate were added to a 250 mL three-necked flask. The mixture was magnetically stirred and the temperature was monitored with a thermometer. The reaction solution was first heated from room temperature to 140 °C over 1 hour, and reacted at 140 °C for 30 minutes. Then the temperature was lowered to 60-70 °C and cooled for 1 hour. Subsequently, 100 mL of water was slowly added dropwise to the reaction vessel. During the dropwise addition, the reaction solution was observed to see if it became cloudy. If it became cloudy, the dropwise addition was stopped, and the mixture was stirred for 30 minutes. The dropwise addition was then continued slowly until the addition was complete. The mixture was stirred for 1 hour, filtered, and the pH of the filter cake was adjusted to neutral with water. After drying, 10.9 g of 5α-androst-2-en-17-one was obtained. The purity of the product obtained from the reaction solution was 94.15%, and the isomer impurity was 2.25%.

[0064] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A method for preparing 5α-androst-2-en-17-one, characterized in that, Includes the following steps: (1) Prepare a solution by mixing epiandrolone p-toluenesulfonate with an organic solvent; (2) The liquid obtained in step 1 is pumped into the microchannel reactor through a feed pump; 。 2. The preparation method according to claim 1, characterized in that, The reaction temperature is 150℃~190℃ and the pressure is 0.5~1 MPa; preferably, the temperature is 160℃~170℃ and the pressure is 0.6~0.8 MPa.

3. The preparation method according to claim 1, characterized in that, The temperature of the reaction is controlled by adding an oil bath device outside the reactor, which uses heat transfer oil to conduct the heat.

4. The preparation method according to claim 1, characterized in that, The organic solvent is selected from one or more of N,N-dimethylacetamide, N,N-dimethylformamide or N-methylpyrrolidone, preferably N,N-dimethylacetamide.

5. The preparation method according to claim 1, characterized in that, The mass ratio of the substrate epiandrolone p-toluenesulfonate to the organic solvent is 1:2~5; preferably 1:3~5.

6. The preparation method according to claim 1, characterized in that, The feed pump is selected from plunger pumps, diaphragm pumps, peristaltic pumps, injection pumps, and gear pumps.

7. The preparation method according to claim 1, characterized in that, The microchannel reactor is a plate and / or tubular reactor with a pipe diameter of 10-20 mm and a pipe length of 50-100 m.

8. The preparation method according to claim 1, characterized in that, The flow rate of the feed solution is 2~10 ml / min, and the reaction time is 5~10 min.

9. The preparation method according to claim 1, characterized in that, The preparation method also includes a step of cooling through a cooling section after the reaction is completed.

10. The preparation method according to claim 10, characterized in that, A water bath device is added outside the cooling section for cooling, and the temperature of the cooling section is 40℃-90℃.

11. The preparation method according to claim 1, characterized in that, The method also includes collecting the reaction solution in a receiving bottle filled with water for quenching, wherein the amount of water is 6 to 10 times the amount of the collected solution, the water temperature is 40 to 90°C, stirring and filtering, adding water to the filter cake to adjust the pH to 7 to 8, and drying to obtain 5α-androst-2-en-17-one.

12. A method for preparing rocuronium bromide, characterized in that, Rocuronium bromide was obtained by the preparation method described in claims 1 to 11 via acetylation, epoxidation, addition, esterification and propylene reactions of 5α-androst-2-en-17-one.

Images