A kind of industrial production process of droperidol

Abstract

The invention discloses an industrial production process of droperidol, and belongs to the technical field of drug synthesis. The process is characterized in that SMⅠ: 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone and SMⅡ: 4-chloro-4′-fluorophenylbutyronitrile are used as starting materials, a microchannel reactor is used, a segmented flow addition feeding mode is provided, and non-equidistant and non-equidistant flow addition is used to prepare droperidol. The process has the following beneficial effects: the microchannel reactor is used to replace the existing kettle reactor, so that the problem of impurity E generated by the side reaction of the reaction product droperidol and the raw material SMⅠ can be alleviated to a certain extent; and the segmented flow addition feeding mode is provided, and non-equidistant and non-equidistant flow addition is used to control the content of impurity E to be below 0.25%, so as to directly meet the requirement that the impurity E is not higher than 0.25% as stipulated in the pharmacopoeia.

Description

Technical field:

[0001] The invention belongs to the technical field of drug synthesis, and more specifically relates to an industrial production process of droperidol. Background technology:

[0002] Droperidol (also known as haloperidol) is a commonly used butyrophenone drug in clinical anesthesia. It mainly blocks dopamine receptors in the central nervous system, hypothalamus, substantia nigra and striatum. It has strong sedative and antiemetic effects when used in clinical anesthesia. It has good effects on preventing PONV after various surgeries, especially nausea and vomiting caused by opioid receptor agonists such as morphine. It is often used in anesthesia induction and anesthesia-assisted medication to effectively prevent nausea and vomiting in patients after surgery.

[0003] Referring to the description of the original patent US3936468A, the route for industrial production of droperidol is as follows Figure 1 . Using 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolidinone (raw material: SM1) and 4-chloro-4′-fluorophenylbutyrophenone (raw material: SM2) as starting materials, the principle is as follows.

[0004]

[0005] Inevitably, this process will produce process impurity E (named according to the European Pharmacopoeia, EP11.0). Due to the influence of the amplification effect, the generation of this impurity is more obvious during industrial production.

[0006]

[0007] According to the Pharmacopoeia, impurity E should not exceed 0.25%. In industrial production, this impurity exceeds 2.0%, or even 3.0%, which results in many steps and a long cycle in the subsequent refining process, greatly increasing the production cost.

[0008] In actual production, in order to reduce the generation of impurities as much as possible, the process control includes: changing the ratio of raw materials and auxiliary materials, lowering the reaction temperature, changing the use of auxiliary materials, etc. However, this method controls the size of impurities to a certain extent, but it undoubtedly brings many undesirable results such as increased costs, prolonged reaction time, and increased operational complexity. Therefore, a production process with strong versatility and easy industrialization becomes the key. Summary of the invention:

[0009] In order to solve the above problems and overcome the shortcomings of the prior art, the present invention provides an industrial production process of droperidol, which can effectively solve the problem that the process impurity E generated in the industrial reaction process is too high, resulting in many refining steps and a long cycle in the subsequent process, which greatly increases the production cost.

[0010] The specific technical solution of the present invention to solve the above technical problems is: an industrial production process of droperidol, using SMⅠ: 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone and SMⅡ: 4-chloro-4′-fluorophenylbutyric acid as starting materials to prepare droperidol, comprising:

[0011] (1) preparing SMⅠ solution: adding alkaline reagent and starting material SMⅠ: 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolidinone into solvent Ⅰ, mixing and stirring until the system is dissolved for use;

[0012] (2) preparing SMⅡ solution: adding iodide and starting material SMⅡ: 4-chloro-4′-fluorophenylbutyrophenone to solvent Ⅱ, mixing and stirring until the system is dissolved for later use;

[0013] (3) The reactor is a microchannel reactor, and the microchannel reactor is provided with an SMⅠ liquid inlet and an SMⅡ liquid inlet. The SMⅠ solution and the SMⅡ solution are connected to the SMⅠ liquid inlet and the SMⅡ liquid inlet respectively through a feeding pump, the microchannel reactor is turned on to increase the temperature, the feeding pump is turned on, the flow rate of the SMⅠ and SMⅡ pipelines is set, and the feeding pump is allowed to contact and react in the mixer, and stay to keep warm;

[0014] (4) After the heat preservation is completed, the feed liquid is added into purified water to terminate the reaction, and then the reaction is carried out by cooling, filtering, dissolving, crystallizing and filtering to obtain droperidol.

[0015] Furthermore, the alkaline reagent is one of pyridine, DBU, triethylamine, and potassium carbonate powder.

[0016] Furthermore, the iodide is potassium iodide or sodium iodide powder.

[0017] Furthermore, the solvent I and the solvent II are of the same solvent type, which is one of DMF, DMSO, THF, and ethanol.

[0018] Furthermore, in the SMⅠ solution: the preparation ratio of 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone, alkaline reagent, and solvent Ⅰ is 1g: 0.5-1g: 8-10g;

[0019] In the SMⅡ solution, the ratio of 4-chloro-4′-fluorophenylbutyric acid ketone, iodide, and solvent Ⅱ is 1g: 0.1-0.3g: 8-10g, and the SMⅡ solution is equal in weight to the SMⅠ solution;

[0020] Furthermore, the microchannel reactor is provided with an SMⅠ liquid inlet and an SMⅡ liquid inlet, and the SMⅠ liquid inlets are arranged in 3 numbers, the distance between the first SMⅠ liquid inlet and the second SMⅠ liquid inlet is S1: the distance between the second SMⅠ liquid inlet and the third SMⅠ liquid inlet is S2: the total pipe length of the microchannel reactor is S, S1:S2:S=(2.5-3.5):(0.5-1.5):10.

[0021] Furthermore, the molar ratio of 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone in the total liquid inlet of SMⅠ to 4-chloro-4′-fluorophenylbutyrophenone in the liquid inlet of SMⅡ is 1 mol:1.05-1.15 mol.

[0022] Furthermore, the total flow rate of SMⅠ and the total flow rate of SMⅡ are consistent, both of which are 0.02-0.06 L / min, the temperature of the microreactor is set at 65-75°C, and the residence time of the feed liquid mixture in the reactor is 5-7 minutes.

[0023] Furthermore, the total flow rate of the SMⅠ and SMⅡ solutions is consistent, wherein the pipeline flow rate of the first SMⅠ inlet: the pipeline flow rate of the second SMⅠ inlet: the pipeline flow rate of the third SMⅠ inlet: the pipeline flow rate of the SMⅡ inlet is (80-90):(5-15):(3-6):100.

[0024] The beneficial effects of the present invention are:

[0025] (1) The present invention creatively uses a microreactor to replace the existing autoclave reactor, significantly alleviating the problem of the side reaction between the reaction product droperidol and the raw material SMⅠ, resulting in the generation of impurity E;

[0026] (2) The present invention creatively utilizes a microchannel reactor and sets up a segmented flow feeding method, combined with non-uniform spacing and non-uniform flow feeding, to control the impurity E content below 0.25%, directly meeting the requirement of the pharmacopoeia that the impurity E content should not be higher than 0.25%. Description of the drawings:

[0027] Attached Figure 1 It is the detection chromatogram of Example 1 of the present invention;

[0028] Attached Figure 2 It is the detection chromatogram of Example 2 of the present invention;

[0029] Attached Figure 3 It is the detection chromatogram of Example 3 of the present invention;

[0030] Attached Figure 4 It is the detection chromatogram of Example 4 of the present invention;

[0031] Attached Figure 5It is the detection chromatogram of Comparative Example 1 of the present invention;

[0032] Attached Figure 6 It is the detection chromatogram of Comparative Example 2 of the present invention;

[0033] Attached Figure 7 It is the detection chromatogram of Comparative Example 3 of the present invention;

[0034] Attached Figure 8 This is a chromatogram of the refined product detection of Example 4 of the present invention; in the accompanying drawings: Specific implementation method:

[0035] In the description of the present invention, specific details are only for a full understanding of the embodiments of the present invention, but those skilled in the art should know that the implementation of the present invention is not limited to these details. In addition, well-known structures and functions are not described or shown in detail to avoid blurring the key points of the embodiments of the present invention. For those of ordinary skill in the art, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0036] Specific implementation of the present invention:

[0037] (1) Preparation of SMⅠ solution: Add the starting material SMⅠ, i.e. 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolidinone, an alkaline reagent, and solvent Ⅰ into a container; after the addition of the materials is completed, stir until the system is uniformly dissolved, and after stirring uniformly, take out (80-90)%: (5-15)%: (3-6)% of the total amount of liquid and put them into container A1, container A2, and container A3 in sequence.

[0038] Wherein: the alkaline reagent is one of pyridine, DBU, triethylamine, and potassium carbonate powder;

[0039] In the SMⅠ solution, the ratio of 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone, alkaline reagent and solvent Ⅰ is 1g: 0.5-1g: 8-10g;

[0040] (2) Preparation of SMⅡ solution: Add the starting material SMⅡ (49.0 g of 4-chloro-4′-fluorophenylbutyric acid ketone), 5.0 g of iodide, and solvent Ⅱ into container B; after the addition of the materials is completed, stir until the system is uniform;

[0041] Wherein: in the SMⅡ solution: the preparation ratio of 4-chloro-4′-fluorophenylbutyric acid ketone, iodide, and solvent Ⅱ is 1g: 0.1-0.3g: 8-10g, and the balance is solvent Ⅱ;

[0042] The iodide is potassium iodide or sodium iodide powder.

[0043] The solvent I and the solvent II are of the same solvent type, which is one of DMF, DMSO, THF, and ethanol, and the SMⅡ solution is equal in weight to the SMⅠ solution;

[0044] (3) Inject 2000g of purified water into the liquid collector P with a stirring device in advance, and control the purified water temperature to 20-30°C. The total flow rates of SMⅡ and SMⅠ solutions are consistent, both 0.02-0.06L / min, among which the pipeline flow rate of the first SMⅠ inlet: the pipeline flow rate of the second SMⅠ inlet: the pipeline flow rate of the third SMⅠ inlet 1ml / min: the pipeline flow rate of the SMⅡ inlet is (80-90):(5-15):(3-6):100; the microreactor is set to a feed liquid insulation temperature of 65-75°C and a residence time of 5-7min.

[0045] (4) After all settings are completed, start the corresponding feed pump to enter the microreactor at the set flow rate, the mixed liquid is fully mixed, and after the residence time is over, the feed liquid flows into the collector P for quenching. No liquid flows out of the direct collector P, and the process ends.

[0046] (5) After quenching, the feed liquid is directly filtered, and the filter cake is rinsed with a small amount of ethanol. The filter cake is transferred to a flask, anhydrous ethanol is added, the temperature is raised to 70-80°C until reflux occurs, and the mixture is stirred and refluxed for 1 hour, then the temperature is slowly lowered, stirred and crystallized, and suction filtered. The wet filter cake is crystallized with ethyl acetate, and finally the temperature is controlled at 40-50°C to be dried to obtain the finished product of droperidol.

[0047] In order to better understand the present invention, a specific embodiment is used for illustration. It is worth emphasizing that the effect of this embodiment is not substantially different from the various embodiments within the protection scope of the present invention, including the respective reagents and the content ratio of the reagents, and all of them can achieve the effects described in the present invention and solve the above-mentioned problems. Other combinations are not described here.

[0048] Embodiment 1:

[0049] Prepare SMⅠ solution: Add the starting material SMⅠ: 50.0g of 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone, 25.0g of DBU, and 400.0g of solvent Ⅰ: N,N-dimethylformamide (DMF) to the preparation flask. After the addition of the materials is completed, stir until the system is evenly dissolved. After stirring evenly, take out 85%, 10%, and 5% of the total amount of liquid in the flask and put them into flask A1, flask A2, and flask A3 in turn.

[0050] Prepare SMⅡ solution: add starting material SMⅡ: 49.0g 4-chloro-4′-fluorophenylbutyric acid ketone, 5.0g potassium iodide powder, and 421.0g solvent Ⅱ: N,N-dimethylformamide (DMF) to flask B with stirring device. After the addition of materials is completed, start stirring until the system is uniform;

[0051] Inject 2000g of purified water into the liquid collector P with a stirring device in advance, and control the purified water temperature to 20-30°C. The total flow rates of SMⅠ and SMⅡ solutions are consistent, both 0.02L / min, wherein the SMⅠ inlet is set to 3, the distance between the first SMⅠ inlet A1 and the second SMⅠ inlet A2 is S1: the distance between the second SMⅠ inlet A2 and the third SMⅠ inlet A3 is S2: the total length of the microchannel reactor is S, S1: S2: S = (2.5-3.5): (0.5-1.5): 10;

[0052] The flow rate of pipeline A1 is 17 ml / min, the flow rate of pipeline A2 is 2 ml / min, and the flow rate of pipeline A3 is 1 ml / min. The microreactor is set with a liquid insulation temperature of 65°C and a residence time of 5 min.

[0053] After all settings are completed, start the corresponding feed pump to enter the microreactor at the set flow rate, the mixed liquid is fully mixed, and after the residence time is over, the feed liquid flows into the collector P for quenching. No liquid flows out of the direct collector P, and the process ends.

[0054] After quenching, the feed liquid is directly filtered, and the filter cake is rinsed with a small amount of ethanol. The filter cake is transferred to a flask, 30.0g of anhydrous ethanol is added, the temperature is raised to 70-80°C until reflux occurs, stirred and refluxed for 1h, then the temperature is slowly lowered, stirred and crystallized for 4h, and filtered. The wet product filter cake is heated with ethyl acetate to completely dissolve it, stirred and crystallized for 30min, cooled to 10°C, stirred and crystallized for 4h, filtered, and the wet product is dried at 40-50°C to obtain 73g of droperidol finished product, with a yield of 83%, a finished product purity of 98.23%, and an impurity E of 0.20%.

[0055] Embodiment 2:

[0056] Prepare SMⅠ solution: Add the starting material SMⅠ: 50.0g 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone, 50g pyridine, and 500.0g DMSO to the preparation flask. After the addition of the materials is completed, stir until the system is evenly dissolved. After stirring evenly, take out 86.7%, 7.5%, and 5.8% of the total amount of liquid in the flask and put them into flask A1, flask A2, and flask A3 in turn.

[0057] Prepare SMⅡ solution: add the starting material SMⅡ: 49.0g of 4-chloro-4′-fluorophenylbutyric acid ketone, 1.2g of sodium iodide powder, and 550.0g of DMSO as solvent Ⅱ to flask B with a stirring device. After the addition of materials is completed, start stirring until the system is uniform;

[0058] Inject 2000g of purified water into the liquid collector P with a stirring device in advance, and control the purified water temperature to 20-30°C. The total flow rate of SMⅠ and SMⅡ solutions is the same, both 0.06L / min, where

[0059] The number of the SMI liquid inlets is 3, the distance between the first SMI liquid inlet A1 and the second SMI liquid inlet A2 is S1: the distance between the second SMI liquid inlet A2 and the third SMI liquid inlet A3 is S2: the total pipe length of the microchannel reactor is S, S1:S2:S=(2.5-3.5):(0.5-1.5):10; the flow rate of the A1 pipeline is 52ml / min, the flow rate of the A2 pipeline is 4.5ml / min, and the flow rate of the A3 pipeline is 3.5ml / min; the microreactor is set to a liquid insulation temperature of 75°C and a residence time of 7min.

[0060] After all settings are completed, start the corresponding feed pump to enter the microreactor at the set flow rate, the mixed liquid is fully mixed, and after the residence time is over, the feed liquid flows into the collector P for quenching. No liquid flows out of the direct collector P, and the process ends.

[0061] After quenching, the feed liquid is directly filtered, and the filter cake is rinsed with a small amount of ethanol. The filter cake is transferred to a flask, 30.0g of anhydrous ethanol is added, the temperature is raised to 70-80°C until reflux occurs, stirred and refluxed for 1h, then the temperature is slowly lowered, stirred and crystallized for 4h, and filtered. The wet product filter cake is heated with ethyl acetate to completely dissolve it, stirred and crystallized for 30min, cooled to 10°C, stirred and crystallized for 4h, filtered, and the wet product is dried at 40-50°C to obtain 70.9g of droperidol finished product, with a yield of 80.4%, a finished product purity of 97.9%, and an impurity E of 0.25%.

[0062] Embodiment 3:

[0063] Prepare SMⅠ solution: Add the starting material SMⅠ: 50.0g of 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone, 25.0g of DBU, and 400.0g of THF as solvent Ⅰ to the preparation flask. After the addition of the materials is completed, stir until the system is evenly dissolved. After stirring evenly, take out 85%, 10%, and 5% of the total amount of liquid in the flask and put them into flask A1, flask A2, and flask A3 in turn.

[0064] Prepare SMⅡ solution: add the starting material SMⅡ: 49.0g of 4-chloro-4′-fluorophenylbutyric acid, 5.0g of potassium iodide powder, and 421.0g of THF to the flask B equipped with a stirring device. After the addition of the materials is completed, start stirring until the system is uniform;

[0065] Inject 2000g of purified water into the liquid collector P with a stirring device in advance, and control the purified water temperature to 20-30°C. The total flow rate of SM1 and SM2 solutions is the same, both 0.02L / min, where

[0066] The microchannel reactor is provided with an SMⅠ liquid inlet and an SMⅡ liquid inlet, wherein the SMⅠ liquid inlets are arranged in three numbers, the distance between the first SMⅠ liquid inlet A1 and the second SMⅠA2 liquid inlet is S1: the distance between the second SMⅠ liquid inlet A2 and the third SMⅠ liquid inlet A3 is S2: the total pipe length of the microchannel reactor is S, and the above is S1:S2:S=(2.5-3.5):(0.5-1.5):10.

[0067] The flow rate of pipeline A1 is 17 ml / min, the flow rate of pipeline A2 is 2 ml / min, and the flow rate of pipeline A3 is 1 ml / min; the microreactor is set with a feed liquid insulation temperature of 65°C and a residence time of 5 min.

[0068] After all settings are completed, start the corresponding feed pump to enter the microreactor at the set flow rate, the mixed liquid is fully mixed, and after the residence time is over, the feed liquid flows into the collector P for quenching. No liquid flows out of the direct collector P, and the process ends.

[0069] After quenching, the feed liquid is directly filtered, and the filter cake is rinsed with a small amount of ethanol. The filter cake is transferred to a flask, 30.0g of anhydrous ethanol is added, the temperature is raised to 70-80°C until reflux occurs, stirred and refluxed for 1h, then the temperature is slowly lowered, stirred and crystallized for 4h, and filtered. The wet product filter cake is heated with ethyl acetate to completely dissolve it, stirred and crystallized for 30min, cooled to 10°C, stirred and crystallized for 4h, filtered, and the wet product is dried at 40-50°C to obtain 74g of droperidol finished product, with a yield of 84.0%, a finished product purity of 98.07%, and an impurity E of 0.22%.

[0070] Embodiment 4:

[0071] The preparation method is the same as that of Example 1, except that: in the preparation process of this comparative example, the SMⅠ liquid inlet is set to 1; the flow rate of SMⅠ and the flow rate of SMⅡ are consistent, the temperature of the microreactor is set to 65-75°C, and the residence time of the feed liquid mixture in the reactor is 5-7min;

[0072] In order to more intuitively demonstrate the process advantages of the present invention, the same process is compared using an equivalent replacement method.

[0073] Comparative Example 1:

[0074] The industrial process based on patent No. US3936468A is adopted by way of reference to prepare droperidol, except that in the preparation process of this comparative example, the reactor is a kettle reactor, and the material is added in a one-pot method.

[0075] Comparative Example 2:

[0076] The preparation method is the same as that in Example 1, except that: in the preparation process of this comparative example, the reactor is a kettle reactor, the material is added in a staged flow addition manner, and the order of flow addition is the pipeline flow rate of the first SMⅠ liquid inlet: the pipeline flow rate of the first SMⅠ liquid inlet: the pipeline flow rate of the first SMⅠ liquid inlet: the pipeline flow rate of the first SMⅠ liquid inlet: the pipeline flow rate of the SMⅡ liquid inlet is (80-90):(5-15):(3-6):100.

[0077] Comparative Example 3:

[0078] The preparation method is the same as that in Example 1, and three SMⅠ liquid inlets are provided, and the distance between the first SMⅠ liquid inlet A1 and the second SMⅠ liquid inlet A2 is S1: the distance between the second SMⅠ liquid inlet A2 and the third SMⅠ liquid inlet A3 is S2; the difference is that: in the preparation process of this comparative example, S1:S2:S=2.5:2.5:10, and the flow rate of the A1 pipeline, the flow rate of the A2 pipeline, and the flow rate of the A3 pipeline are the same, and the total feed flow rate is 0.02L / min;

[0079] Each embodiment and comparative example was tested according to a unified standard, and the testing method is as follows:

[0080] Take 0.25g of this product, accurately weigh it, put it in a 100ml volumetric flask, dilute it to the mark with N,N-dimethylformamide, shake it well, and use it as the test solution; accurately measure 1ml, put it in a 100ml volumetric flask, dilute it to the mark with N,N-dimethylformamide, shake it well, and use it as the control solution. According to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512), use octadecylsilane bonded silica gel as the filler (BDS or equivalent column is applicable, 4.6*250mm, 3μm); use acetonitrile as mobile phase A, 10g / L tetrabutylammonium hydrogen sulfate solution as mobile phase B, and perform gradient elution according to the table below; the flow rate is 1.0ml per minute; the detection wavelength is 275nm. Take 6.25 mg of impurity E and droperidol reference substance, place them in the same 50 ml volumetric flask, dissolve and dilute to scale with N, N-dimethylformamide, shake well; then accurately measure 1 ml, place it in a 10 ml volumetric flask, dilute to scale with N, N-dimethylformamide, shake well, and use it as the system suitability solution. Take 10 μl of the system suitability solution and record the chromatogram. The separation degree of droperidol peak and droperidol peak should be no less than 1.5.

[0081]

[0082] Accurately measure 10 μl of the test solution and the control solution, respectively, and inject them into the liquid chromatograph to record the chromatogram. If there are impurity peaks in the chromatogram of the test solution, after correction according to the corresponding correction factor, the peak area of ​​impurity E shall not be greater than 0.25 times (0.25%) the main peak area of ​​the control solution. Any chromatographic peak in the test solution that is less than 0.05 times the main peak area of ​​the control solution can be ignored.

[0083] Table 1: Comparison of total yield and impurity E content of droperidol in different embodiments and comparative examples

[0084]

[0085]

[0086] From the data analysis in Table 1, we can see that:

[0087] (1) In Examples 1-3, the content of impurity E in the finished product of droperidol is maintained at 0.20-0.25%, which meets the requirement of the pharmacopoeia that the peak area of ​​impurity E shall not be greater than 0.25 times the main peak area of ​​the control solution (i.e., the impurity is not higher than 0.25% after normalization by area);

[0088] (2) Compared with Comparative Example 1 and Examples 1-3, the content of impurity E is 2.74%, which is much greater than the requirement that impurity E is not higher than 0.25%. This may be due to the fact that the reaction product droperidol is in the autoclave reactor, and the autoclave reactor cannot timely separate the generated reaction product droperidol from the reaction system, resulting in a side reaction between the reaction product droperidol and the raw materials;

[0089] (3) Compared with Comparative Example 1, although the content of impurity E in Comparative Example 2 is reduced from 2.74% to 1.06%, it is still much greater than the requirement that impurity E is not higher than 0.25%. The reason for the reduction may be that the addition of SMⅠ can make the raw material SMⅡ in a slightly excessive state, which can alleviate the side reaction between the reaction product droperidol and the raw material SMⅠ to a certain extent. However, the content of impurity E in the finished droperidol product is still higher than the requirement that impurity E is not higher than 0.25% as stipulated in the Pharmacopoeia, and it needs to be refined.

[0090] (4) The content of impurity E in Example 4 is 0.54%, which is higher than the requirement of Pharmacopoeia that the impurity E should not be higher than 0.25%. This may be because Example 4 uses a microchannel reactor. Although the microchannel reactor can timely separate the generated reaction product droperidol from the reaction system compared with the autoclave reactor, it uses a non-segmented flow feeding method. The non-segmented flow feeding method is to feed the raw material SMⅠ and the raw material SMⅡ in equal moles, and the reaction requires a period of time. The raw material SMⅠ that does not participate in the reaction produces a side reaction with the reaction product droperidol to generate impurity E.

[0091] (5) Comparative Example 3 Compared with Examples 1-3, although Comparative Example 3 also adopts a microchannel reactor and also adopts segmented flow feeding, in the preparation process of this comparative example, S1:S2:S=2.5:2.5:10, and the flow rates of the A1 pipeline, the A2 pipeline, and the A3 pipeline are the same, and the total feed flow rate is 0.02L / min, the inventors creatively found that when a microchannel reactor is used to prepare droperidol, the reaction progress in the entire reaction tube of the microchannel reactor is different. At this time, if equal intervals and equal flow rates are used for feeding, the raw material SMI will still be in an excessive state in the reaction tube of the microchannel reactor for feeding in the rear stage, resulting in a side reaction between the raw material SMI and the reaction product droperidol, resulting in the content of impurity E being 0.29%, which still does not meet the requirement of not more than 0.25% stipulated in the Pharmacopoeia, and still needs to be purified.

[0092] As a further illustration of the present invention, Example 4 is subjected to a refining treatment, and the specific steps are as follows:

[0093] Take out 10g of the finished product of droperidol obtained in Example 4 and put it in a flask, add ethyl acetate and ethanol into the flask. Control the temperature at 70-80°C to make it completely dissolved, then add medicinal charcoal, control the temperature and stir for 30 minutes to filter, transfer the filtrate to another flask, cool to 10°C, stir and crystallize for 4 hours, and filter until no obvious liquid flows out. The wet product filter cake is decolorized twice according to the above process, and the filter cake after the second decolorization is refined again by adding 15 times the weight of dichloromethane. After drying, 8g of the refined droperidol is obtained; the final calculated total yield is 69%, and the impurity E is reduced from 0.54% before refining to 0.27%,

[0094] Table 2: Comparative data before and after refining of Example 4

[0095]

[0096] From the data analysis in Table 2, we can see that:

[0097] Although the purification treatment in Example 4 can meet the requirement of the Pharmacopoeia that the impurity E is not higher than 0.25%, the total yield of droperidol is reduced from 82% to 69%, and the subsequent purification process has many steps and a long cycle, which greatly increases the production cost.

[0098] In summary:

[0099] (1) The present invention creatively uses a microreactor to replace the existing autoclave reactor, significantly alleviating the problem of the side reaction between the reaction product droperidol and the raw material SMⅠ, resulting in the generation of impurity E;

[0100] (2) The present invention creatively utilizes a microchannel reactor and sets up a segmented flow feeding method, combined with non-uniform spacing and non-uniform flow feeding, to control the impurity E content below 0.25%, directly meeting the requirement of the pharmacopoeia that the impurity E content should not be higher than 0.25%.

Claims

1. An industrial production process of droperidol, using SMⅠ: 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone and SMⅡ: 4-chloro-4′-fluorophenylbutyrophenone as starting materials to prepare droperidol, characterized in that Technology include: (1) preparing SMⅠ solution: adding an alkaline reagent and a starting material SMⅠ: 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolidinone to solvent Ⅰ, mixing and stirring until the system is dissolved for use; the alkaline reagent is one of pyridine, DBU, triethylamine, and potassium carbonate powder; (2) preparing SMⅡ solution: adding iodide and starting material SMⅡ: 4-chloro-4′-fluorophenylbutyric acid to solvent Ⅱ, mixing and stirring until the system is dissolved for later use; the iodide is potassium iodide or sodium iodide powder; (3) The reactor is a microchannel reactor, and the microchannel reactor is provided with an SMⅠ liquid inlet and an SMⅡ liquid inlet. The SMⅠ solution and the SMⅡ solution are connected to the SMⅠ liquid inlet and the SMⅡ liquid inlet respectively through a feeding pump, the microchannel reactor is turned on to increase the temperature, the feeding pump is turned on, the flow rate of the SMⅠ and SMⅡ pipelines is set, and the feeding pump is allowed to contact and react in the mixer, and the temperature is kept; (4) After the heat preservation is completed, the feed liquid is added into purified water to terminate the reaction, and then the reaction is performed by cooling, filtering, dissolving, crystallizing and filtering to obtain droperidol; The solvent I and the solvent II are of the same solvent type, which is one of DMF, DMSO and THF.

2. The industrial production process of droperidol according to claim 1, characterized in that: In the SMⅠ solution, the ratio of 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone, alkaline reagent and solvent Ⅰ is 1g: 0.5-1g: 8-10g; In the SMⅡ solution, the preparation ratio of 4-chloro-4′-fluorophenylbutyric acid ketone, iodide and solvent Ⅱ is 1g: 0.1-0.3g: 8-10g, and the SMⅡ solution is equal in weight to the SMⅠ solution.

3. The industrialized production process of droperidol according to claim 1, characterized in that The microchannel reactor is provided with an SMⅠ liquid inlet and an SMⅡ liquid inlet, wherein the SMⅠ liquid inlets are arranged in three numbers, the distance between the first SMⅠ liquid inlet and the second SMⅠ liquid inlet is S1: the distance between the second SMⅠ liquid inlet and the third SMⅠ liquid inlet is S2: the total pipe length of the microchannel reactor is S, S1:S2:S=(2.5-3.5):(0.5-1.5):

10.

4. The industrial production process of droperidol according to claim 3, characterized in that The molar ratio of 1-(1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone in the total liquid inlet of SMⅠ to 4-chloro-4′-fluorophenylbutyrophenone in the liquid inlet of SMⅡ is 1 mol:1.05-1.15 mol.

5. The industrial production process of droperidol according to claim 4, characterized in that The total flow rate of SMⅠ solution is consistent with that of SMⅡ solution, both of which are 0.02-0.06 L / min. The temperature of the microreactor is set at 65-75°C, and the residence time of the feed-liquid mixture in the reactor is 5-7 min.

6. The industrial production process of droperidol according to claim 5, characterized in that The total flow rates of the SMⅠ solution and SMⅡ solution are consistent, wherein the pipeline flow rate of the first SMⅠ liquid inlet: the pipeline flow rate of the second SMⅠ liquid inlet: the pipeline flow rate of the third SMⅠ liquid inlet: the pipeline flow rate of the SMⅡ liquid inlet is (80-90):(5-15):(3-6):100.

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