A method for synthesizing riociguat intermediates using a continuous flow microreactor

Abstract

The present invention belongs to the field of pharmaceutical preparation technology, and specifically relates to a method for synthesizing a riociguat intermediate using a continuous flow microreactor. By using a continuous flow process, compared with the batch process using a traditional kettle microreactor, this method has the characteristics of less risk, easier operation, less environmental pollution, and higher stability.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparation, and in particular to a method for synthesizing a riociguat intermediate using a continuous flow microreactor. Background Art

[0002] Riociguat (Adempas), CAS No. 625115-55-1, is a guanylate cyclase (sGC) agonist developed by Bayer. It can directly stimulate sGC and enhance its sensitivity to low levels of nitric oxide (NO). In October 2013, it was approved by the FDA for the treatment of pulmonary arterial hypertension (PAH) in adults and persistent or recurrent chronic obstructive pulmonary hypertension (CTEPH) in adults who are inoperable or who have undergone surgery. Its chemical structure is shown below:

[0003]

[0004] The compound shown in SM-3 is the core intermediate of riociguat, CAS: 256504-39-9, chemical name: 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester, and its chemical structure is shown below:

[0005]

[0006] The conventional synthetic route of this intermediate is shown in the figure below:

[0007]

[0008] Conventional synthesis methods utilize traditional kettle-type processes, which involve substitution, salt formation, and ring closure to produce the product SM-3. This reaction has the following drawbacks: First, the highly toxic hydrazine hydrate used in the first step requires a traditional kettle-type reaction at 80°C, placing high demands on equipment and posing significant risks to the environment and personnel. Second, the use of hydrogen chloride gas poses significant risks to the environment, human health, and production equipment.

[0009] The research and application of microchannel reaction technology has gradually expanded from micromachining to become a new discipline with independent concepts. Compared with conventional batch reactions, synthetic processes completed in microchannel reactors can always produce higher-purity products in a shorter time frame. The gradual promotion and application of microreactors has significantly improved the efficient preparation of chemical substances, high-throughput screening of cells and proteins, and reaction kinetics research.

[0010] The present invention develops a set of continuous flow microreactors and a new process route. At the same time, the continuous flow microreactor technology is applied to a new preparation process for riociguat core intermediate SM-3 to solve the problems of difficult control of highly toxic raw materials in the process, harsh reaction conditions, high equipment requirements, and high risks to environmental protection and personal safety. Summary of the Invention

[0011] In response to the technical problems of the above-mentioned autoclave synthesis method of riociguat intermediates, which involve the use of highly toxic raw materials that are difficult to control, pose a great challenge and pollution to the environment and production equipment, and present numerous safety risks, the present invention provides a method for synthesizing riociguat intermediate SM-3 using a continuous flow microreactor. This method has the characteristics of high mixing efficiency, highly automated process control, high process stability, robust equipment, high reaction safety, a more environmentally friendly process, and suitability for industrial production.

[0012] In order to achieve the above objectives, the following technical solutions are mainly provided:

[0013] The present invention provides a method for synthesizing a riociguat intermediate SM-3 in a continuous flow microreactor. The core intermediate of riociguat, compound SM-3, has CAS number 256504-39-9 and a chemical name of 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylic acid ethyl ester. The chemical structure thereof is shown below:

[0014]

[0015] The synthesis method provided by the present invention can use o-fluorobenzyl chloride as a starting material, undergo a substitution reaction with hydrazine hydrate in a microreactor to obtain compound SM-2, which is optionally post-treated; compound SM-2 is optionally post-treated; and cyclization with potassium 1-cyano-3-ethoxy-3-oxo-1-propen-2-olate in a microreactor to obtain compound SM-3, which is optionally post-treated; the specific reaction route is as follows:

[0016]

[0017] On the one hand, the present invention provides a method for preparing compound SM-2, comprising step a: dissolving compound SM-1 in a reaction solvent to obtain a reaction mixed solution, setting a microreactor at a reaction temperature, and pumping the above reaction mixed solution and hydrazine hydrate into the microchannel reactor at a set flow rate. After the reaction is complete, optional post-treatment is performed to obtain compound SM-2.

[0018] Wherein, the reaction solvent in step a is any one of ethanol, methanol, isopropanol, and a mixed solvent of ethanol and water.

[0019] The reaction temperature of the microreactor in step a is 0°C-50°C.

[0020] In some embodiments, the reaction temperature in step a is 0°C-30°C; or the reaction temperature in step a is 10°C, which is conducive to the reaction.

[0021] In the step a, the molar ratio of compound SM-1 to hydrazine hydrate can be 1:2-1:20.

[0022] In some embodiments, the molar ratio of compound SM-1 to hydrazine hydrate in step a is 1:5-1:15. In some embodiments, the molar ratio of compound SM-1 to hydrazine hydrate in step a is 1:13, which is conducive to the formation and acquisition of the product.

[0023] The flow rate in the microchannel reactor in step a is 2 ml / min-100 ml / min.

[0024] The reaction time in step a can be 1 h to 12 h.

[0025] In the method for preparing compound SM-2, after the reaction in step a is complete, post-treatment is optionally performed. In some embodiments, the post-treatment in step a comprises: concentrating the reaction solution under reduced pressure, adding dichloromethane to the organic layer, and then washing twice with water, extracting the aqueous layer with dichloromethane, combining the organic layers, and drying and concentrating the organic layers to produce compound SM-2.

[0026] In some embodiments, the completion of the reaction in step a comprises: monitoring compound SM-1 by TLC; when compound SM-1 shows completion of the reaction and a new compound is generated, the reaction is complete.

[0027] In some embodiments, the reaction in step a is complete, further comprising: monitoring compound SM-1 by GC or HPLC, and the reaction is complete when 0.5% to 2% of compound SM-1 remains.

[0028] In some embodiments, a method for preparing compound SM-2 includes step a: mixing compound SM-1 with ethanol to obtain a reaction mixed solution, setting the temperature of the microreactor to 0°C-30°C, and pumping the above reaction mixed solution and hydrazine hydrate into the microchannel reactor at set flow rates of 2ml / min-100ml / min and 5ml / min-100ml / min, respectively. After the reaction is complete, optional post-treatment is performed to obtain compound SM-2.

[0029] On the other hand, a method for preparing compound SM-3 includes step b: setting a microreactor at a reaction temperature, pumping compound SM-2 into the microchannel reactor at a set flow rate, then pumping a solvent and potassium 1-cyano-3-ethoxy-3-oxo-1-propene-2-olate into the microchannel reactor at a set flow rate, and after the reaction is complete, optionally post-processing to obtain compound SM-3.

[0030] Wherein, the solvent in step b is at least one of ethanol, methanol, water or a mixed solvent of ethanol and water.

[0031] In some embodiments, the solvent in step b is a mixed solvent of ethanol and water, which is conducive to the reaction.

[0032] The reaction temperature in the microreactor of step b is 50° C.-100° C. In some embodiments, the reaction temperature in the microreactor of step b is 75° C. to 80° C.

[0033] The solvent in step b, the mixing ratio of ethanol and water is 1:2-2:1. In some embodiments, the solvent in step b, the mixing ratio of ethanol and water is 1:1.

[0034] The flow rate in the microchannel reactor in step b is 5 ml / min-100 ml / min.

[0035] In the method for preparing compound SM-3, after the reaction in step b is complete, post-treatment is optionally performed. In some embodiments, the method for preparing compound SM-3, the post-treatment in step b comprises: after the reaction is complete, cooling to room temperature, concentrating the reaction solution, extracting three times with DCM, combining the organic phases, washing with water, drying, and removing the solvent to obtain compound SM-3.

[0036] In some embodiments, a method for preparing compound SM-3 includes step b: setting the microreactor at 75°C to 80°C, pumping compound SM-2 into the microchannel reactor at a set flow rate of 20ml / min-100ml / min, then fully mixing water, ethanol and potassium 1-cyano-3-ethoxy-3-oxo-1-propene-2-ol, and pumping them into the microchannel reactor at a set flow rate of 30ml / min-100ml / min, setting and cooling the microreactor to 75°C-80°C, and after the reaction is complete, optionally post-processing to obtain compound SM-3.

[0037] The inventors found that in the reaction of step b, 1-cyano-3-ethoxy-3-oxo-1-propylene-2-alcohol potassium etc. are selected as the reagent of hydrazine ring closure in SM-2, and this step ring closure reaction is the step that plays a decisive role in product yield and purity in the whole process. Because there is endothermic reaction in this reaction process, the reaction temperature reaches 80 DEG C, so the controllability of reaction condition operation etc. can have a greater impact on yield and purity. Therefore, after carrying out optimization experiment, the technical scheme of the present invention, with ethanol and water as reaction solvent, reaction adopts continuous flow micro-reaction system to complete, compared with traditional kettle reaction, reaction condition is milder, operation is easier, response speed is also faster, and yield is also higher than traditional kettle reaction.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] 1. The present invention adopts a continuous flow microreactor. Compared with the traditional kettle reaction, in step b, a mixed solvent of ethanol and water is used, and free o-fluorobenzylhydrazine is used as a raw material. The entire reaction liquid is a clear homogeneous reaction, which avoids the two-phase reaction of the traditional kettle using o-fluorobenzylhydrazine hydrochloride as a raw material and ethanol as a solvent; at the same time, the continuous flow microreactor can meet the higher requirements of environmental protection, safety and stable process parameters in this step due to its relatively closed reaction system and efficient mass transfer and heat exchange performance.

[0040] 2. The present invention provides a continuous flow micro-reaction synthesis method for the riociguat intermediate compound SM-3. Compared with the traditional hydrochloride autoclave reaction, we directly use free SM-2, which saves process operations, is more environmentally friendly, has mild reaction conditions, a faster reaction rate, more precise process control, and a higher yield than the traditional autoclave reaction. This solves the problem that hydrochloric acid is volatile and is prone to pollution and safety risks caused by conventional autoclave reactors. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 Synthesis of compound SM-2 by continuous flow microreaction;

[0042] Figure 2 Synthesis of compound SM-3 by continuous flow microreactor. DETAILED DESCRIPTION

[0043] For ease of understanding, the present application will be described more fully below, and preferred embodiments of the present application are provided. However, the present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to provide a more thorough and comprehensive understanding of the disclosure of the present invention.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. The terms used herein in the specification of the present invention are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0045] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0046] In the present invention, expressions such as "compound A", "compound represented by formula A" and "formula A" refer to the same compound.

[0047] In the present invention, "optionally" or "optionally" means that it may or may not be present; or it may or may not be performed; for example, "optionally adding a reaction solvent to the crude product obtained in step (C)" means that a reaction solvent may or may not be added to the crude product obtained in step (C).

[0048] In the present invention, HPLC stands for high performance liquid chromatography, TLC stands for thin layer chromatography, GC stands for gas chromatography, and DCM stands for dichloromethane.

[0049] Example 1 Preparation of Compound SM-2

[0050] Accurately weigh hydrazine hydrate (80%, 720 g), weigh o-fluorobenzyl chloride (200 g) and dilute with 200 mL of ethanol. Set the microreactor temperature to 10°C. First, slowly pump the hydrazine hydrate into the microchannel reactor (100 ml / min), then slowly pump the o-fluorobenzyl chloride ethanol solution into the reactor (2 ml / min). After the reaction solution flows out, it is vacuum concentrated at 80°C. The concentrated liquid forms layers. After separating the two layers, the aqueous phase is extracted 4-5 times with dichloromethane. The organic phase is added with water and extracted 4-5 times with dichloromethane. All organic phases are combined, dried, and concentrated to obtain approximately 172 g of crude product, with a yield of 85% and a purity of 96%. Compound SM-2 was tested: 1H NMR (400 MHz CDCl3) ppm: 7.31-7.23 (m, 2H), 7.09-7.02 (m, 2H), 3.93 (s, 2H), 3.37 (s, 3H).

[0051] Example 2 Preparation of Compound SM-3

[0052] Accurately weigh compound SM-2 (165 g) and pump it into the microchannel reactor at a set flow rate of 20 ml / min. Then weigh ethanol (330 mL) and water (330 mL) and 1-cyano-3-ethoxy-3-oxo-1-propene-2-ol potassium (232 g) and mix them thoroughly to prepare a uniform liquid for use. The microreactor was set at 75°C-80°C, and the prepared mixed solution was slowly pumped into the microchannel reactor at a set flow rate (100 ml / min). The reaction solution was directly concentrated under reduced pressure after outflow and extracted four times with DCM (500 mL*4). The organic phases were combined, washed once with water (1 L), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 320 g of crude compound SM-3. Recrystallization from ethyl acetate gave 285 g of pure SM-3 with a yield of 91.0% and a purity of 99%. Compound SM-3 was tested: 1H NMR (400 MHz, CDCl3) ppm: 7.34-7.30 (m, 1H), 7.15-7.09 (m, 3H), 6.13 (s, 1H), 5.37 (s, 2H), 4.44-4.38 (dd, 2H), 3.68 (s, 2H), 1.43-1.40 (t, 3H). LC-MS: Calculated Mw=263.27g / mol, found m / z[M+1]+=264.25.

[0053] Example 3 Comparative experiment between traditional kettle process and microchannel process

[0054] Accurately weigh the hydrochloride of compound SM-2 (198.5 g), ethanol (993 mL) and potassium 1-cyano-3-ethoxy-3-oxo-1-propene-2-olate (232 g). The three materials were fully stirred and the temperature was raised to 80°C for reaction. The reaction was controlled by TLC. After the raw materials were consumed, the reaction was stopped and the reaction solution was cooled to room temperature and filtered. The solid was rinsed with anhydrous ethanol (100 mL*3). The ethanol was concentrated and the obtained oily compound was dissolved in dichloromethane (1000 mL) and washed with water (300 mL*2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain 200 g of a crude product, which was recrystallized from ethyl acetate to obtain 183 g, with a yield of 73% and a purity of 98%.

[0055] Table 1 Comparison of SM-3 yields between autoclave reaction and microchannel reaction

[0056]

Claims

1. A method for synthesizing a riociguat intermediate using a continuous flow microreactor, comprising the following steps: Step a: dissolving o-fluorobenzyl chloride in a reaction solvent to obtain a reaction mixed solution, setting the microreactor at the reaction temperature, and pumping the above reaction mixed solution and hydrazine hydrate into the microchannel reactor at a set flow rate. When the reaction reaches the end point, the feed liquid enters the post-treatment system to obtain compound SM-2. Step b: The microreactor is set at the reaction temperature, and the compound SM-2 obtained in step a is pumped into the microchannel reactor at a set flow rate. Then, the solvent and potassium 1-cyano-3-ethoxy-3-oxo-1-propene-2-olate are pumped into the microchannel reactor at a set flow rate. After the reaction is complete, the mixture enters the post-processing system to obtain the riociguat intermediate. Characterized in that the reaction solvent of step a is any one of ethanol, methanol, isopropanol, and a mixed solvent of ethanol and water; the solvent of step b is a mixed solvent of ethanol and water; The reaction temperature of step a is 0°C-50°C; In step a, the molar ratio of o-fluorobenzyl chloride to hydrazine hydrate is 1:2-1:20; The reaction time of step a is 1h-12h; The flow rate in the microchannel reactor in step a is 2 ml / min-100 ml / min; The reaction temperature of step b is 50°C-100°C; The volume ratio of ethanol to water in the solvent of step b is 1:2-2:1; The flow rate in the microchannel reactor in step b is 5 ml / min to 100 ml / min.

2. A method for synthesizing a riociguat intermediate using a continuous flow microreactor, comprising the following steps: Step a: o-fluorobenzyl chloride is dissolved in a reaction solvent to obtain a mixed solution for the reaction, the microreactor is set at 0-30° C., and the mixed solution of the above reaction and hydrazine hydrate are respectively pumped into the microchannel reactor at a set flow rate of 2 ml / min-100 ml / min, the molar ratio of o-fluorobenzyl chloride to hydrazine hydrate is 1:5-1:15, the residence time is 1h-12h, and when the reaction reaches the end point, the feed liquid enters the post-treatment system to obtain compound SM-2; Step b: The microreactor is set at 75° C.-80° C., the compound SM-2 obtained in step a is pumped into the microchannel reactor at 5 ml / min-100 ml / min, and then a mixture of water, ethanol and potassium 1-cyano-3-ethoxy-3-oxo-1-propene-2-olate is pumped into the microchannel reactor at 5 ml / min-100 ml / min. After the reaction is complete, it enters the post-treatment system to obtain a riociguat intermediate.

Images