Olmesartan medoxomil phosgene substitution type acylation reaction system

Abstract

The invention relates to the technical field of drug synthesis equipment, in particular to an olmesartan medoxomil phosgene substitution type acylation reaction system, which comprises a reaction container, a reaction kettle, a reaction kettle and a control system, the triphosgene adding device is connected with the reaction container and is used for quantitatively adding triphosgene into the reaction container; the solvent conveying unit is connected with the reaction container and is used for pumping a solvent into the reaction container; the mixed solution feeding unit is connected with the reaction container and is used for slowly adding a mixed solution of 3-hydroxybutanone and a solvent into the reaction container; the temperature control module is connected with the reaction container and is used for accurately controlling the reaction temperature in the reaction container; and the pH adjusting and quenching unit is connected with the reaction container. According to the invention, the triphosgene adding device and the closed system are adopted to completely replace highly toxic gas phosgene, so that major potential safety hazards in the production, storage and transportation processes are fundamentally solved.

Description

Olmesartan ester phosgene-alternative acylation reaction system Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis equipment technology, and in particular to an olmesartan medoxomil phosgene-substituted acylation reaction system. Background Technology

[0002] 4,5-Dimethyl-1,3-dioxacyclopenten-2-one (DMDO) is a key intermediate in the synthesis of olmesartan medoxomil, an angiotensin II receptor antagonist. Traditional DMDO preparation processes typically use 3-hydroxy-2-butanone as a starting material, undergoing an acylation reaction with highly toxic phosgene (carbonyl chloride). Phosgene is an extremely hazardous gas, posing significant safety risks and environmental pressures during storage, transportation, and use, and placing extremely stringent requirements on production equipment, severely limiting the industrial application and development of this process.

[0003] While some laboratory methods exist that use triphosgene (solid phosgene) instead of gaseous phosgene, applying these methods safely, efficiently, and controllably to industrial production remains a challenge. Industrial production requires not only solutions to the reaction itself but also a complete system solution to automate, continuously, and safely control key aspects such as solid phosgene addition, precise temperature control during the reaction, precise pH control during quenching, and efficient product separation and crystallization.

[0004] Therefore, there is an urgent need in this field to develop an acylation reaction system specifically for the synthesis of olmesartan medoxomil intermediates, capable of completely replacing highly toxic phosgene and achieving safe and efficient production. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to overcome the defects of poor safety, high equipment requirements and difficulty in industrialization of the production of olmesartan medoxomil intermediate using highly toxic phosgene in the prior art, and to provide an olmesartan medoxomil phosgene-substituted acylation reaction system that is safe to operate, precise to control and suitable for industrial production.

[0006] To achieve the above objectives, the present invention provides the following technical solution: an olmesartan medoxomil phosgene-substituted acylation reaction system, comprising:

[0007] Reaction vessel used for acylation reactions;

[0008] A solid phosgene dosing device is connected to the reaction vessel and is used to quantitatively add solid phosgene into the reaction vessel;

[0009] A solvent delivery unit, connected to the reaction vessel, is used to pump solvent into the reaction vessel;

[0010] A mixed solution feeding unit, connected to the reaction vessel, is used to slowly add a mixed solution of 3-hydroxybutanone and solvent into the reaction vessel;

[0011] A temperature control module, connected to the reaction vessel, is used to precisely control the reaction temperature inside the reaction vessel;

[0012] The pH adjustment and quenching unit is connected to the reaction vessel and is used to add an alkaline solution to the reaction material to neutralize residual acidic substances and adjust the pH value.

[0013] The stratification and separation module is used to receive materials from the reaction vessel and allow them to settle and separate the organic phase.

[0014] The unit includes a solvent recovery and crystallization unit for receiving the organic phase, performing solvent distillation recovery, and adding a mixed solvent for crystallization to obtain the 4,5-dimethyl-1,3-dioxacyclopenten-2-one product.

[0015] Furthermore, the solid phosgene dosing device adds solid phosgene to the reaction vessel under a slight negative pressure state, effectively preventing dust and vapor leakage.

[0016] Furthermore, the temperature control module can control the reaction process through multiple temperature control stages, including low-temperature feeding (approximately 0°C), low-temperature stirring, programmed heating to reflux, and programmed cooling to crystallization (to 0°C). The heating and cooling rates can be precisely set.

[0017] Furthermore, the pH adjustment and quenching unit includes an online pH detector, which is used to monitor the pH value of the system in real time and ensure that it is stable between 7 and 8. If the pH is too low, it can automatically prompt or add alkali solution.

[0018] Furthermore, the mixed solvent in the solvent recovery and crystallization unit is a mixture of isopropanol and cyclohexane.

[0019] The present invention also provides a method for preparing 4,5-dimethyl-1,3-dioxacyclopenten-2-one using the above system, comprising the following steps:

[0020] S1: Solid phosgene is added to the reaction vessel through a solid phosgene dosing device, and solvent is added through a solvent delivery unit to dissolve and form a reaction solution;

[0021] S2: The mixture of 3-hydroxybutanone and solvent is slowly added to the reaction vessel at a controllable rate through the mixed solution feeding unit, and the reaction temperature is controlled by the temperature control module to proceed under a predetermined program.

[0022] S3: After the reaction is completed, saturated sodium bicarbonate solution is added to the reaction vessel through the pH adjustment and quenching unit for quenching and pH adjustment to ensure that the system pH is 7-8.

[0023] S4: Transfer the material to the layering and separation module for static layering and separation to obtain the organic phase;

[0024] S5: The organic phase is transported to the solvent recovery and crystallization unit. After distillation to recover part of the solvent, a mixed solvent (isopropanol:cyclohexane = 1:1 v / v) is added while hot. Then, the mixture is subjected to programmed reflux, programmed cooling crystallization, and spun filtration to obtain crude 4,5-dimethyl-1,3-dioxacyclopenten-2-one.

[0025] Furthermore, after step S5, a purification step is also included: the crude product is dissolved in a mixed solvent of isopropanol and cyclohexane, heated to reflux to dissolve, then cooled to crystallize, filtered, and dried to obtain high-purity 4,5-dimethyl-1,3-dioxacyclopenten-2-one.

[0026] Compared with the prior art, the beneficial effects of the present invention are:

[0027] 1. This invention completely replaces the highly toxic gaseous phosgene by employing a solid phosgene dosing device and a closed system, fundamentally solving major safety hazards in the production, storage and transportation processes.

[0028] 2. This invention achieves precise automated control of key processes such as reaction, quenching, and crystallization by integrating a temperature control module and an online pH monitoring and adjustment unit, thereby improving the stability and reproducibility of product quality and significantly increasing product yield and purity compared to traditional manual control methods.

[0029] 3. The system is reasonably designed with smooth modular connections, making it very suitable for continuous or batch industrial production, which greatly reduces the occupational health risks and labor intensity of operators. Attached Figure Description

[0030] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0031] Figure 1 is a flowchart of the method for preparing 4,5-dimethyl-1,3-dioxacyclopenten-2-one according to the present invention. Detailed Implementation

[0032] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0033] Please refer to Figure 1. This invention provides a technical solution:

[0034] An olmesartan ester phosgene-substituted acylation reaction system, comprising:

[0035] Reaction vessel used for acylation reactions;

[0036] A solid phosgene dosing device is connected to the reaction vessel and is used to quantitatively add solid phosgene into the reaction vessel;

[0037] A solvent delivery unit, connected to the reaction vessel, is used to pump solvent into the reaction vessel;

[0038] A mixed solution feeding unit, connected to the reaction vessel, is used to slowly add a mixed solution of 3-hydroxybutanone and solvent into the reaction vessel;

[0039] A temperature control module, connected to the reaction vessel, is used to precisely control the reaction temperature inside the reaction vessel;

[0040] The pH adjustment and quenching unit is connected to the reaction vessel and is used to add an alkaline solution to the reaction material to neutralize residual acidic substances and adjust the pH value.

[0041] The stratification and separation module is used to receive materials from the reaction vessel and allow them to settle and separate the organic phase.

[0042] The unit includes a solvent recovery and crystallization unit for receiving the organic phase, performing solvent distillation recovery, and adding a mixed solvent for crystallization to obtain the 4,5-dimethyl-1,3-dioxacyclopenten-2-one product.

[0043] Furthermore, the solid phosgene dosing device adds solid phosgene to the reaction vessel under a slight negative pressure state, effectively preventing dust and vapor leakage.

[0044] Furthermore, the temperature control module can control the reaction process through multiple temperature control stages, including low-temperature feeding (approximately 0°C), low-temperature stirring, programmed heating to reflux, and programmed cooling to crystallization (to 0°C). The heating and cooling rates can be precisely set.

[0045] Furthermore, the pH adjustment and quenching unit includes an online pH detector, which is used to monitor the pH value of the system in real time and ensure that it is stable between 7 and 8. If the pH is too low, it can automatically prompt or add alkali solution.

[0046] Furthermore, the mixed solvent in the solvent recovery and crystallization unit is a mixture of isopropanol and cyclohexane.

[0047] The present invention also provides a method for preparing 4,5-dimethyl-1,3-dioxacyclopenten-2-one using the above system, comprising the following steps:

[0048] S1: Solid phosgene is added to the reaction vessel through a solid phosgene dosing device, and solvent is added through a solvent delivery unit to dissolve and form a reaction solution;

[0049] S2: The mixture of 3-hydroxybutanone and solvent is slowly added to the reaction vessel at a controllable rate through the mixed solution feeding unit, and the reaction temperature is controlled by the temperature control module to proceed under a predetermined program.

[0050] S3: After the reaction is completed, saturated sodium bicarbonate solution is added to the reaction vessel through the pH adjustment and quenching unit for quenching and pH adjustment to ensure that the system pH is 7-8.

[0051] S4: Transfer the material to the layering and separation module for static layering and separation to obtain the organic phase;

[0052] S5: The organic phase is transported to the solvent recovery and crystallization unit. After distillation to recover part of the solvent, a mixed solvent (isopropanol:cyclohexane = 1:1 v / v) is added while hot. Then, the mixture is subjected to programmed reflux, programmed cooling crystallization, and spun filtration to obtain crude 4,5-dimethyl-1,3-dioxacyclopenten-2-one.

[0053] Furthermore, after step S5, a purification step is also included: the crude product is dissolved in a mixed solvent of isopropanol and cyclohexane, heated to reflux to dissolve, then cooled to crystallize, filtered, and dried to obtain high-purity 4,5-dimethyl-1,3-dioxacyclopenten-2-one.

[0054] Example 1: Preparation of DMDO using this system

[0055] Start the system to bring the reaction vessel to a slightly negative pressure state. Add 250 kg of solid phosgene to the 2000 L enamel-lined reactor using the solid phosgene dosing device. Pump 1000 kg of dichloromethane into the reactor using the solvent delivery unit. Start the stirring and temperature control module, maintain the temperature at 0 °C, and stir for 1 hour until the solid phosgene is completely dissolved.

[0056] A mixed solution of 70 kg of 3-hydroxybutanone and 280 kg of dichloromethane was slowly added to the reactor at a rate of approximately 20 kg / min via the mixed solution feeding unit, taking about 3 hours to complete. During this period, the temperature control module maintained the reactor temperature at 0°C. After the addition was complete, stirring continued at 0°C for 1 hour.

[0057] Subsequently, the temperature was programmed to rise to the reflux temperature at a rate of 0.5℃ / min using the temperature control module, and the reaction continued under reflux conditions for 2 hours. After the reaction was completed, the temperature was then programmed to drop to 0℃.

[0058] The reactants were transferred to a 3000L layering and separation module. 700 kg of saturated sodium bicarbonate solution was added to the system via a pH adjustment and quenching unit. The mixture was stirred, and the pH was monitored using an online pH meter, stabilizing it between 7 and 8. The mixture was then allowed to settle and separate into layers, with the lower organic phase being separated.

[0059] The organic phase was transferred to the solvent recovery and crystallization unit. After distilling and recovering approximately 1200 kg of dichloromethane solvent, 500 kg of mixed solvent (isopropanol:cyclohexane = 1:1 v / v) was added while hot at a rate of 20 kg / min. After the addition was complete, the mixture was heated to reflux and held for 30 minutes.

[0060] Finally, the crystallization unit was programmed to cool to 0°C at a rate of 1°C / min using the temperature control module, and crystallization was carried out at this temperature for 2 hours. After filtration, 85 kg of crude 4,5-dimethyl-1,3-dioxacyclopenten-2-one was obtained.

[0061] The obtained 85 kg of crude product was transferred to the refining section, and 340 kg of mixed solvent (isopropanol:cyclohexane = 1:1 v / v) was added. After dissolving under reflux, the temperature was programmed to decrease to 0 °C at a rate of 1 °C / min, and allowed to stand for crystallization for 2 hours. After filtration and vacuum drying, 78 kg of high-purity 4,5-dimethyl-1,3-dioxacyclopenten-2-one product was obtained, with a purity of 99.5%.

[0062] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A phosgene-substituted acylation reaction system for olmesartan medoxomil, characterized in that, include: A reaction vessel is used for acylation reaction; a solid phosgene dosing device is connected to the reaction vessel for quantitatively adding solid phosgene to the reaction vessel; a solvent delivery unit is connected to the reaction vessel for pumping solvent into the reaction vessel; a mixed solution feeding unit is connected to the reaction vessel for slowly adding a mixed solution of 3-hydroxybutanone and solvent into the reaction vessel; a temperature control module is connected to the reaction vessel for precisely controlling the reaction temperature inside the reaction vessel; and a pH adjustment and quenching unit is connected to the reaction vessel for adding an alkaline solution to the reaction product to neutralize residual acidic substances and adjust the pH value. The layering and separation module is used to receive materials from the reaction vessel and allow them to stand and separate into layers, thus separating the organic phase; and the solvent recovery and crystallization unit is used to receive the organic phase, perform solvent distillation recovery, and add a mixed solvent to crystallize, thereby obtaining the 4,5-dimethyl-1,3-dioxacyclopenten-2-one product.

2. The olmesartan medoxomil phosgene-substituted acylation reaction system according to claim 1, characterized in that, The solid phosgene dosing device adds solid phosgene to the reaction vessel under a slightly negative pressure.

3. The olmesartan medoxomil phosgene-substituted acylation reaction system according to claim 1, characterized in that, The temperature control module controls the reaction process through multiple temperature control stages, including low-temperature feeding, low-temperature stirring, programmed heating and reflux, and programmed cooling and crystallization.

4. The olmesartan medoxomil phosgene-substituted acylation reaction system according to claim 1, characterized in that, The pH adjustment and quenching unit includes an online pH meter for monitoring the pH value of the system and ensuring that it remains stable between 7 and 8.

5. The olmesartan medoxomil phosgene-substituted acylation reaction system according to claim 1, characterized in that, The mixed solvent in the solvent recovery and crystallization unit is a mixture of isopropanol and cyclohexane.

6. A method for preparing 4,5-dimethyl-1,3-dioxacyclopenten-2-one using the system according to any one of claims 1-5, characterized in that, The process includes the following steps: S1: Solid phosgene is added to the reaction vessel through a solid phosgene dosing device, and solvent is added through a solvent delivery unit to dissolve and form a reaction solution; S2: A mixed solution of 3-hydroxybutanone and solvent is slowly added to the reaction vessel through a mixed solution feeding unit, and the reaction temperature is controlled by a temperature control module; S3: After the reaction is completed, an alkaline solution is added to the reaction vessel through a pH adjustment and quenching unit for quenching and pH adjustment; S4: The material is transferred to a layering and separation module for static layering and separation to obtain an organic phase; S5: The organic phase is transported to a solvent recovery and crystallization unit, and after distillation to recover part of the solvent, a mixed solvent is added, followed by programmed cooling to crystallize, and then filtration to obtain crude 4,5-dimethyl-1,3-dioxane-2-one.

7. The method according to claim 6, characterized in that, The process after step S5 includes a purification step: the crude product is dissolved in a mixed solvent of isopropanol and cyclohexane, heated to reflux to dissolve, then cooled to crystallize, filtered, and dried to obtain high-purity 4,5-dimethyl-1,3-dioxacyclopenten-2-one.

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