CN114315749A - Method for synthesizing aliskiren intermediate by continuous flow microreactor - Google Patents
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Abstract
The invention relates to a continuous flow micro-reaction synthesis method of an aliskiren intermediate, belonging to the technical field of medicine preparation. The preparation method adopts a continuous flow microreactor technology to carry out technical optimization on the key intermediate of the aliskiren raw material medicine, takes S-4-benzyl-2-oxazolidinone and isovaleryl chloride as starting materials, and synthesizes the aliskiren intermediate through reactions such as substitution reaction, addition reaction and the like. Meanwhile, the influence of the factors such as the molar ratio of materials, the reaction residence time, the reaction temperature and the like on the yield and the purity in the process flow is considered, and the optimal process conditions are determined. The optimized process has the characteristics of high yield, less post-treatment wastewater, low energy consumption and labor cost, low total project cost and capacity improvement.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a method for synthesizing an aliskiren intermediate by a continuous flow microreactor.
Background
Aliskiren (aliskiren), CAS number: 173334-57-1, a non-peptide inhibitor of human renin developed by Nowa company, has a long-chain structure similar to the peptide chain structure of natural renin, has good renin inhibitory activity, and IC50 reaches nanomole. Aliskiren received U.S. FDA approval for the treatment of hypertension in 5 months of 2007. The chemical structural formula is shown as the following formula I:
the compound represented by the formula SM8 is a key intermediate of aliskiren, and has the following chemical structural formula:
the preparation processes of SM8 reported at present are many, and most of the processes are batch processes of a traditional tank reactor. The preparation process has many challenges, the synthetic route of the compounds is complicated, the total yield is low, the separation and purification of a plurality of core intermediates need to adopt column chromatography or column chromatography, the production and preparation process usually involves dangerous and highly toxic chemicals and high-risk chemical reactions, and simultaneously produces a lot of waste water and byproducts, which is very easy to cause environmental pollution.
As in the original novanual patent WO2007045420, the following synthetic route is disclosed:
the route uses hydrogenation and lactam ring closing reaction, the hydrogenation reaction uses Pd/C as a catalyst, and heavy metal in a finished product is difficult to control. Chinese patent CN101679213 reports the following route:
the reagent ammonium tetra-n-propylperruthenate (TPAP) used in this route is expensive and the yield is not high because the reaction product is a mixture of two main stereoisomers.
The research and application field of the microchannel reaction technology is gradually expanded from micro-processing to a new subject with an independent concept, and compared with the conventional kettle type reaction, the microchannel reactor has the following advantages: a) by arranging the preheating device, the material is heated before entering the reactor, and the reaction temperature is reached after entering the reactor, so that the reaction temperature is saved compared with that of a kettle type reactorTime, reaction efficiency is improved by more than 5 times; b) the reaction device adopts a continuous flow pipeline which is communicated through a baffle box, the volume is reduced to 10 percent of that of the kettle type, and the occupied area and the plant investment are greatly reduced; c) the reaction tube is spirally wound, and the reactant forms spiral tangential motion along the spiral tube, so that the reactant can obtain high Reynolds number (Reynolds number) under the condition of low flow velocity>5500) Side reactions caused by long-time stay in the reaction system are avoided; d) when chemical reaction is carried out, the material in the microchannel reactor is 1 percent of that of the kettle type reactor, and the microchannel reactor can resist the high pressure of 4Mpa which is 20 times that of the kettle type reactor. Solves the problems of inflammable, explosive, high-toxicity and strong corrosion (such as NaN)3Hydrogen peroxide, cyclopentene, tetrazole, concentrated sulfuric acid); e) the device is an integral pipeline, has good tightness, does not have the connection of various kettle-type valves and flanges, realizes the zero emission of harmful gases, namely sulfur dioxide and hydrogen chloride, and avoids the problems of environmental pollution and personal health damage; f) the chemical reaction result is monitored in real time by online monitoring equipment such as an online gas phase detector and an online liquid phase monitor, and the reaction temperature and pressure can be regulated within 1 min; g) the multi-stage feeding device, the mixing device, the preheating device and the reaction device are communicated through a continuous flow pipeline, so that the method is suitable for continuous multi-stage reaction, reduces the steps of repeated material storage and feeding, can fully utilize the waste heat of the previous stage reaction, improves the production efficiency and reduces the energy consumption; h) the water is used as a cleaning agent, and the material residue of the last reaction in the system can be efficiently removed by the water at high temperature and high pressure, so that the environment-friendly, low-carbon and environment-friendly effects are achieved. Therefore, the synthesis process completed in the microchannel reactor can always obtain a product with higher purity in a shorter time range.
The gradual popularization and application of the microreactor obviously promotes the research on the high-efficiency preparation of chemical substances, the high-throughput screening of cells and proteins, reaction kinetics and the like.
The invention develops a set of continuous-flow microreactors, develops a new process route, and simultaneously applies the continuous-flow microreaction technology to a new preparation process of a key intermediate compound SM8 of aliskiren so as to solve the problems of low raw material conversion rate, high danger, environmental pollution and the like in the process.
Disclosure of Invention
Aiming at the technical problems of low raw material conversion rate, high risk, environmental pollution and the like of the preparation method of the key intermediate compound SM8 of aliskiren, the invention provides a continuous flow micro-reaction synthesis method of the key intermediate compound SM8 of aliskiren, and compared with an intermittent process using a traditional kettle-type reactor, the method has the characteristics of high yield, less post-treatment wastewater, low energy consumption and labor cost, low project total cost and capacity improvement by using a continuous flow process.
The invention provides a continuous flow micro-reaction synthesis method of a key intermediate compound SM8 of aliskiren. An aliskiren intermediate, designated compound SM8, having the structure shown below:
the method provided by the invention can use S-4-benzyl-2-oxazolidinone and isovaleryl chloride as starting materials, and obtain a compound SM2 through substitution reaction in a microreactor; carrying out substitution reaction on the compound SM2 in a microreactor to obtain a compound SM3, and optionally carrying out post-treatment; carrying out addition reaction on the compound SM3 in a microreactor to obtain a compound SM4, and optionally carrying out post-treatment; carrying out substitution reaction on the compound SM4 in a microreactor to obtain a compound SM5, and optionally carrying out post-treatment; carrying out addition reaction on the compound SM5 in a microreactor to obtain a compound SM6, and optionally carrying out post-treatment; carrying out substitution reaction on the compound SM6 in a microreactor to obtain a compound SM7, and optionally carrying out post-treatment; carrying out substitution reaction on the compound SM7 in a microreactor to obtain a compound SM8, and optionally carrying out post-treatment; the specific reaction route is as follows:
the specific process route is shown in figure 1.
In one aspect, the present invention provides a method for preparing compound SM2, comprising the steps of: mixing S-4-benzyl-2-oxazolidinone, dimethylaminopyridine, triethylamine and a solvent to prepare a solution A-1 for later use, inputting the solution A-1 and isovaleryl chloride into a microreactor system by using a metering pump, quenching after a reaction liquid flows out, entering a post-treatment system to obtain SM2,
the solvent in the step a is at least one selected from the group consisting of toluene, xylene, THF and methylene chloride. Preferably, the solvent in step a is toluene.
The reaction temperature in the microreactor in the step a is-10-20 ℃. In some embodiments, the reaction temperature in the microreactor of step a is from 0 ℃ to-5 ℃.
The flow rate in the microchannel reactor in the step a is 1 ml/min-50 ml/min.
The molar ratio of S-4-benzyl-2-oxazolidinone to isovaleryl chloride in the microchannel reactor in the step a is 0.5: 1 to 1.5: 1.
the residence time of the reaction in the microchannel reactor in the step a is 10 seconds to 120 seconds.
And b, quenching the reaction solution in the step a by using a 1% sodium hydroxide aqueous solution after the reaction solution flows out.
The preparation method of the compound SM2 is characterized in that after the reaction in the step a is completed, the post-treatment is optionally carried out.
In some embodiments, the method for preparing compound SM2, step a post-treatment comprises: extraction, combination of organic phases, washing with water, drying and removal of the solvent gave compound SM 2.
In some embodiments, a method of preparing compound SM2, comprising step a: mixing S-4-benzyl-2-oxazolidinone, dimethylaminopyridine, triethylamine and toluene to prepare a solution A-1 for later use, inputting the solution A-1 and isovaleryl chloride into a microreactor system at a set flow rate of 1 ml/min-50 ml/min by using two plunger type metering pumps, quenching the reaction solution by using a 1% sodium hydroxide aqueous solution after flowing out, and entering a post-treatment system to obtain SM 2.
Compared with the traditional kettle type reaction, the preparation method of the continuous flow microreactor adopted in the step a has the technical effects of avoiding the overflow of the isovaleryl chloride, reducing ring-opening byproducts and reducing post-treatment wastewater.
In some embodiments, a method of preparing compound SM3, comprising step b: preparing SM2 and N, N-dimethyl propylene urea into a solution A-2, inputting the solution A-2, bis-trimethylsilyl amido lithium and trans-1, 4-dibromo-2-butylene into a micro-reactor system by a metering pump, quenching after the reaction liquid flows out, entering a post-treatment system to obtain SM3,
the reaction temperature in the microreactor in the step b is-10-90 ℃.
In some embodiments, the reaction temperature in the microreactor of step b is from 0 ℃ to 50 ℃. In some embodiments, the reaction temperature in the microreactor of said step b is 30 ℃.
The flow rate in the microchannel reactor in the step b is 1 ml/min-50 ml/min.
The molar ratio of SM2 to trans-1, 4-dibromo-2-butene in the microchannel reactor in the step b is 0.5: 1 to 1.5: 1.
the reaction residence time in the microchannel reactor in the step b is 10 seconds to 100 seconds.
And b, quenching the reaction solution in the step b by using a 10% hydrochloric acid aqueous solution after the reaction solution flows out.
The preparation method of the compound SM3 is characterized in that after the reaction in the step b is completed, the post-treatment is optionally carried out. In some embodiments, the method for preparing compound SM3, step b post-treatment comprises: after the reaction, extraction, combining the organic phases, washing with water, drying, and removing the solvent, compound SM3 was obtained.
In some embodiments, a method of preparing compound SM3, comprising step b: preparing SM2 and N, N-dimethyl propylene urea into a solution A-2, inputting the solution A-2, bis-trimethylsilyl amido lithium and trans-1, 4-dibromo-2-butylene into a microreactor system at a set flow rate of 1 ml/min-50 ml/min by using a metering pump, quenching reaction liquid by using a 10% hydrochloric acid aqueous solution after flowing out, and entering a post-processing system to obtain SM 3.
And step b, a preparation method of the continuous flow micro-reactor is adopted, and compared with the traditional kettle type reaction, the preparation method has the technical effect of avoiding ultralow temperature reaction.
In some embodiments, a method of preparing compound SM4, comprising step c: preparing solution A-3 from N-bromosuccinimide and water, inputting SM3 and solution A-3 into a microreactor system by using a metering pump, separating liquid after reaction liquid flows out, entering a post-processing system to obtain SM4,
the reaction temperature in the microreactor in the step c is 10-40 ℃. In some embodiments, the reaction temperature in the microreactor of said step c is from 20 ℃ to 35 ℃.
The flow rate in the microchannel reactor in the step c is 1ml/min to 50 ml/min.
The molar ratio of SM3 to N-bromosuccinimide in the microchannel reactor in the step c is 0.5: 1 to 1.5: 1.
the reaction residence time in the microchannel reactor in the step c is 10 seconds to 100 seconds.
The preparation method of the compound SM4 is characterized in that after the reaction in the step c is completed, the post-treatment is optionally carried out. In some embodiments, the method for preparing compound SM4, step c post-treatment comprises: after the reaction, extraction, combining the organic phases, washing with water, drying, and removing the solvent, compound SM4 was obtained.
In some embodiments, a method of preparing compound SM4, comprising step c: preparing solution A-3 from N-bromosuccinimide and water, inputting SM3 and the solution A-3 into a microreactor system at a set flow rate of 1-50 ml/min by using a metering pump, separating the reaction liquid after the reaction liquid flows out, and entering a post-treatment system to obtain SM 4.
And step c, a preparation method of the continuous flow microreactor is adopted, and compared with the traditional kettle type reaction, the preparation method has the technical effects of reducing byproducts in the elimination reaction of hydrogen bromide and reducing post-treatment wastewater.
In some embodiments, a method of preparing compound SM5, comprising step d: preparing SM4, 2-methylimidazole and toluene into a solution A-4, preparing sodium azide, sodium bicarbonate and purified water into a solution A-4-2, inputting the solution A-4 and the solution A-4-2 into a microreactor system by using a metering pump, separating the reaction liquid after the reaction liquid flows out, entering a post-treatment system to obtain SM5,
the reaction temperature in the microreactor in the step d is 60-90 ℃. In some embodiments, the reaction temperature in the microreactor of said step d is from 75 ℃ to 85 ℃.
The flow rate in the microchannel reactor in the step d is 1ml/min to 50 ml/min.
The molar ratio of SM4 to sodium azide in the microchannel reactor in the step d is 0.5: 1 to 1.5: 1.
the reaction residence time in the microchannel reactor in the step d is 10 seconds to 100 seconds.
The preparation method of the compound SM5 is characterized in that after the step d reaction is completed, the post-treatment is optionally carried out. In some embodiments, the method for preparing compound SM5, step d post-treatment comprises: after the reaction, extraction, combining the organic phases, washing with water, drying, and removing the solvent, compound SM5 was obtained.
In some embodiments, a method of preparing compound SM5, comprising step d: preparing solution A-4 from SM4, 2-methylimidazole and toluene, preparing solution A-4-2 from sodium azide, sodium bicarbonate and purified water, inputting SM3 and solution A-3 into a microreactor system at a set flow rate of 1-50 ml/min by using a metering pump, separating liquid after reaction liquid flows out, and entering a post-treatment system to obtain SM 5.
And d, a preparation method of the continuous-flow microreactor is adopted, and compared with the traditional kettle type reaction, the method has the technical effect of avoiding the explosion danger of sodium azide. In some embodiments, a method of preparing compound SM6, comprising step e: preparing SM5, palladium carbon and methanol into solution A-5, inputting the solution A-5 and hydrogen into a microreactor system by using a metering pump, allowing reaction liquid to flow out, allowing the reaction liquid to enter a post-processing system to obtain SM6,
the reaction temperature in the microreactor in the step e is 10-40 ℃. In some embodiments, the reaction temperature in the microreactor of said step e is from 15 ℃ to 35 ℃.
And e, controlling the flow in the microchannel reactor in the step e to be 1 ml/min-50 ml/min.
The reaction residence time in the microchannel reactor in the step e is 10 seconds to 100 seconds.
The preparation method of the compound SM6 is characterized in that after the reaction in the step e is completed, the post-treatment is optionally carried out. In some embodiments, the method for preparing compound SM6, step e post-treatment comprises: after the reaction, extraction, combining the organic phases, washing with water, drying, and removing the solvent, compound SM6 was obtained.
In some embodiments, a method of preparing compound SM6, comprising step e: preparing SM5, palladium carbon and methanol into a solution A-5, inputting the solution A-5 and hydrogen into a micro-reactor system at a set flow rate of 1-50 ml/min by using a metering pump, and allowing a reaction solution to flow out and enter a post-processing system to obtain SM 6.
And step e, a preparation method of the continuous flow microreactor is adopted, and compared with the traditional kettle type reaction, the preparation method has the technical effect of avoiding explosion danger in the hydrogenation process.
In some embodiments, a method of preparing compound SM7, comprising step f: preparing SM6 and p-toluenesulfonic acid into solution A-6, inputting the solution A-6 into a microreactor system by using a metering pump, allowing reaction liquid to flow out, allowing the reaction liquid to enter a post-processing system to obtain SM7,
the reaction temperature in the microreactor of the step f is 30-100 ℃. In some embodiments, the reaction temperature in the microreactor of step f is from 45 ℃ to 55 ℃.
And f, controlling the flow in the microchannel reactor to be 1 ml/min-50 ml/min.
The molar ratio of SM6 to p-toluenesulfonic acid in the microchannel reactor in the step f is 0.5: 1 to 1.5: 1.
the residence time of the reaction in the microchannel reactor in the step f is 10 seconds to 100 seconds.
The preparation method of the compound SM7 is characterized in that after the step f reaction is completed, the compound is optionally subjected to post-treatment. In some embodiments, the method for preparing compound SM7, step f post-treatment comprises: after the reaction, extraction, combining the organic phases, washing with water, drying, and removing the solvent, compound SM7 was obtained.
In some embodiments, a method of preparing compound SM7, comprising step f: preparing SM6 and p-toluenesulfonic acid into a solution A-6, inputting the solution A-6 into a microreactor system at a set flow rate of 1-50 ml/min by using a metering pump, and allowing a reaction solution to flow out and enter a post-processing system to obtain SM 7.
And f, a preparation method of the continuous-flow microreactor is adopted, and compared with the traditional kettle type reaction, the preparation method has the technical effect of reducing the generation of ring-opening byproducts.
In some embodiments, a method of preparing compound SM8, comprising the step of g: preparing SM7, dimethylaminopyridine, triethylamine and toluene into a solution A-7, preparing di-tert-butyl dicarbonate and toluene into a solution A-7-2, inputting the solution A-7 and the solution A-7-2 into a microreactor system by using a metering pump, allowing reaction liquid to flow out, allowing the reaction liquid to enter a post-processing system to obtain SM8,
the reaction temperature in the microreactor of the step g is 30-100 ℃. In some embodiments, the reaction temperature in the microreactor of step g is from 45 ℃ to 55 ℃.
And g, the flow in the microchannel reactor in the step g is 1 ml/min-50 ml/min.
The molar ratio of SM7 to di-tert-butyl dicarbonate in the microchannel reactor in step g is 0.5: 1 to 1.5: 1.
and the reaction residence time in the microchannel reactor in the step g is 10 seconds to 100 seconds.
The preparation method of the compound SM8 is characterized in that after the step g reaction is completed, the post-treatment is optionally carried out. In some embodiments, the method of preparing compound SM8, step g post-treatment, comprises: after the reaction, extraction, combining the organic phases, washing with water, drying, and removing the solvent, compound SM8 was obtained.
In some embodiments, a method of preparing compound SM8, comprising the step of g: preparing SM7, dimethylaminopyridine, triethylamine and toluene into a solution A-7, preparing di-tert-butyl dicarbonate and toluene into a solution A-7-2, inputting the solution A-7 and the solution A-7-2 into a microreactor system at a set flow rate of 1-50 ml/min by using a metering pump, and allowing a reaction solution to flow out and enter a post-treatment system to obtain SM 8.
And step g, a preparation method of the continuous flow micro-reactor is adopted, and compared with the traditional kettle type reaction, the preparation method has the technical effect of reducing the generation of ring-opening byproducts.
The preparation method of the compound SM8 comprises at least one of the steps of a, b, c, d, e, f and g.
In some embodiments, the method of preparing compound SM8 of the present invention comprises at least 2 steps out of steps a through g; or at least 3 steps; or at least 4 steps; or at least 5 steps; or at least 6 steps; or 7 steps.
In the technical scheme of the invention, a continuous flow microreactor is creatively adopted, an improved method is adopted to synthesize the aliskiren key intermediate compound SM8, the optimal process conditions are determined by observing the influence of the factors such as the molar ratio of materials, the reaction residence time, the reaction temperature and the like on the yield and the purity, and the compound SM8 prepared by the optimized process has high purity, high yield and less three wastes and meets the requirements of registration and market sale. The preparation process method of the key intermediate has the characteristics of high yield, less post-treatment wastewater, low energy consumption and labor cost, low total project cost and capacity improvement.
In summary, the present invention includes the following beneficial effects:
1. according to the method for synthesizing the aliskiren intermediate compound SM8 by using the continuous-flow microreactor, compared with the traditional kettle-type reaction, in the step a, the isovaleryl chloride is prevented from overflowing, ring-opening byproducts are reduced, and post-treatment wastewater is reduced; in step b, ultralow temperature reaction is avoided; in step c, the elimination of hydrogen bromide reaction byproducts is reduced, and the post-treatment wastewater is reduced; in the step d, the explosion danger of sodium azide is avoided; in step e, the explosion hazard of the hydrogenation process is avoided; in step f or g, the production of ring-opening by-products is reduced. Meanwhile, the continuous flow microreactor can meet the higher requirements of environmental protection safety and stable process parameters in the step due to a relatively closed reaction system and high-efficiency mass transfer heat exchange performance.
2. According to the continuous flow micro-reaction synthesis method of the aliskiren intermediate compound SM8, provided by the invention, the optimal process conditions are determined by observing the influence of the factors such as the material molar ratio, the reaction residence time and the reaction temperature on the yield and the purity, and the method has the characteristics of high yield, less post-treatment wastewater, low energy consumption and labor cost, low project total cost and capacity improvement.
In the description of the present invention, it is to be understood that the terms "first", "second" and the like are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
In the present invention, the expression "compound A" and "compound represented by formula A" and "formula A" means the same compound.
In the present invention, "optional" or "optionally" means that it may or may not be present; or may not be performed; the phrase "optionally adding a reaction solvent to the crude product obtained in step (C)" means that the reaction solvent may or may not be added to the crude product obtained in step (C).
Drawings
Figure 1 is a scheme of a continuous flow process scheme of the key intermediate compound SM8 of aliskiren.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, min represents minutes; h represents an hour; g represents g; ml means ml; kg means Kg.
In the present invention, HPLC means high performance liquid chromatography.
EXAMPLE 1 preparation of Compound SM2
Mixing 1mol of S-4-benzyl-2-oxazolidinone, 0.2mol of dimethylaminopyridine, 0.5mol of triethylamine and 15mL of toluene to prepare a solution A-1, placing the solution A in a liquid storage bottle A, mixing 1.5mol of isovaleryl chloride and 5mL of toluene to place the solution B in a liquid storage bottle B, setting the reaction temperature to be 0 ℃, respectively pumping the materials in A, B bottles into a microchannel reactor by using two plunger type metering pumps at the flow rate of 1:2, keeping the flow time for 20 seconds, collecting liquid products, monitoring the reaction by HPLC (high performance liquid chromatography), quenching the reaction liquid after flowing out by using 1% sodium hydroxide aqueous solution, entering a post-treatment system, extracting, drying and removing an organic solvent to obtain SM2, wherein the purity is 99.5%, and the yield is 95%.
EXAMPLE 2 preparation of Compound SM3
Mixing 1mol of SM2 and 0.3mol of N, N-dimethylpropyleneurea to prepare a solution A-2, placing the solution A-2 in a liquid storage bottle C, mixing 0.2mol of bis-trimethylsilyl amido lithium and 1.2mol of trans-1, 4-dibromo-2-butene, placing the mixture in a liquid storage bottle D, setting the reaction temperature to be 30 ℃, respectively pumping the materials in a C, D bottle into a microchannel reactor by using two plunger type metering pumps at the flow rate of 1:1, keeping the flow time for 40 seconds, collecting liquid products, monitoring the reaction by HPLC (high performance liquid chromatography), quenching the reaction liquid by using 10% hydrochloric acid aqueous solution after flowing out, entering a post-treatment system, extracting, drying and removing an organic solvent to obtain SM3, wherein the purity is 96.5%, and the yield is 91%.
EXAMPLE 3 preparation of Compound SM4
Mixing 2mol of N-bromosuccinimide with 20mL of water to prepare a solution A-3, placing the solution A-3 in a liquid storage bottle E, placing 1mol of SM3 in a liquid storage bottle F, setting the reaction temperature to be 20 ℃, respectively pumping materials in a E, F bottle into a microchannel reactor by using two plunger type metering pumps according to the flow rate of 1:1, keeping the residence time to be 10 seconds, collecting liquid products, monitoring the reaction completion by HPLC, allowing the reaction liquid to flow out, then entering a post-treatment system, extracting, drying, and removing organic solvents to obtain SM4, wherein the purity is 99.6%, and the yield is 83%.
EXAMPLE 4 preparation of Compound SM5
Mixing 1mol of SM4, 0.2mol of 2-methylimidazole and 15mL of methylbenzene to prepare a solution A-4, placing the solution A-4 in a liquid storage bottle G, mixing 1.5mol of sodium azide, 0.2mol of sodium bicarbonate and 15mL of purified water, placing the mixture in a liquid storage bottle H, setting the reaction temperature to 80 ℃, respectively pumping the materials in G, H bottles into a microchannel reactor by using two plunger type metering pumps at the flow rate of 1:1, keeping the reaction time to be 30 seconds, collecting liquid products, monitoring the completion of the reaction by HPLC, separating the liquid after the reaction liquid flows out, entering a post-treatment system, extracting, drying, removing an organic solvent to obtain SM5, wherein the purity is 95.6%, and the yield is 96%.
EXAMPLE 5 preparation of Compound SM6
Mixing 1mol of SM5, 0.1mol of palladium carbon and 10mL of methanol to prepare a solution A-5, placing the solution A-5 in a liquid storage bottle I, setting the reaction temperature to be 25 ℃, respectively pumping the material and hydrogen in the bottle I and a microchannel reactor by using two plunger type metering pumps at the flow rate of 1:1.2, keeping the reaction time for 40 seconds, collecting a liquid product, monitoring the reaction completion by HPLC, allowing the reaction liquid to flow out, entering a post-treatment system, extracting, drying, and removing an organic solvent to obtain SM6, wherein the purity is 98.6%, and the yield is 92%.
EXAMPLE 6 preparation of Compound SM7
Mixing 1mol of SM6 and 0.1mol of p-toluenesulfonic acid to prepare a solution A-6, placing the solution A-6 in a liquid storage bottle J, setting the reaction temperature to 50 ℃, pumping the material in the bottle J into a micro-channel reactor by using a plunger type metering pump at the flow rate of 1ml/min, keeping the time for 10 seconds, collecting a liquid product, monitoring the reaction completion by HPLC (high performance liquid chromatography), allowing the reaction liquid to flow out, then entering a post-treatment system, extracting, drying, and removing an organic solvent to obtain SM7, wherein the purity is 99%, and the yield is 82%.
EXAMPLE 7 preparation of Compound SM8
Mixing 1mol of SM7SM6, 0.1mol of dimethylaminopyridine, 0.1mol of triethylamine p-toluenesulfonic acid and 20mL of toluene to prepare a solution A-67, placing the solution A-67 in a liquid storage bottle JK, mixing 2mol of di-tert-butyl dicarbonate and 10mL of toluene to prepare a solution A-7-2, placing the solution A-7-2 in a liquid storage bottle L, setting the reaction temperature to 50 ℃, pumping the material in a K, L bottle into a microchannel reactor by using a plunger type metering pump at a flow rate of 1:1.2, keeping the flow for 10 seconds, collecting liquid products, monitoring the reaction by HPLC (high performance liquid chromatography), allowing the reaction liquid to flow out, then entering a post-treatment system, extracting, drying, and removing an organic solvent to obtain SM8, wherein the purity is 99% and the yield is 99.5%.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
1. A method for preparing compound SM2, comprising the steps of a: mixing S-4-benzyl-2-oxazolidinone, dimethylaminopyridine, triethylamine and a solvent to prepare a solution A-1 for later use, inputting the solution A-1 and isovaleryl chloride into a microreactor system by using a metering pump, setting the reaction temperature of the microreactor for reaction, quenching after the reaction liquid flows out, entering a post-treatment system to obtain SM2,
wherein the reaction temperature of the microreactor is from-10 ℃ to 20 ℃.
2. A method for preparing compound SM3, comprising step b: preparing SM2 and N, N-dimethyl propylene urea into a solution A-2, inputting the solution A-2, bis-trimethylsilyl amido lithium and trans-1, 4-dibromo-2-butylene into a micro-reactor system by a metering pump, setting the reaction temperature of the micro-reactor for reaction, quenching after the reaction liquid flows out, entering a post-processing system to obtain SM3,
wherein the reaction temperature of the microreactor is from-10 ℃ to 90 ℃.
3. A method for preparing compound SM4, comprising step c: preparing solution A-3 from N-bromosuccinimide and water, inputting SM3 and the solution A-3 into a microreactor system by using a metering pump, setting the reaction temperature of the microreactor for reaction, separating liquid after the reaction liquid flows out, entering a post-processing system to obtain SM4,
wherein the reaction temperature of the microreactor is 10-40 ℃.
4. A process for the preparation of compound SM5, comprising the steps of d: preparing SM4, 2-methylimidazole and toluene into a solution A-4, preparing sodium azide, sodium bicarbonate and purified water into a solution A-4-2, inputting the solution A-4 and the solution A-4-2 into a microreactor system by using a metering pump, setting the reaction temperature of the microreactor for reaction, separating liquid after reaction liquid flows out, entering a post-treatment system to obtain SM5,
wherein the reaction temperature of the microreactor is 60-90 ℃.
5. A process for the preparation of compound SM6, comprising the steps of e: preparing SM5, palladium carbon and methanol into solution A-5, inputting the solution A-5 and hydrogen into a microreactor system by using a metering pump, setting the reaction temperature of the microreactor for reaction, allowing the reaction liquid to flow out, allowing the reaction liquid to enter a post-processing system to obtain SM6,
wherein the reaction temperature of the microreactor is 10-40 ℃.
6. A method for preparing compound SM7, comprising step f: preparing SM6 and p-toluenesulfonic acid into solution A-6, inputting the solution A-6 into a microreactor system by using a metering pump, setting the reaction temperature of the microreactor for reaction, allowing the reaction solution to flow out, allowing the reaction solution to enter a post-processing system to obtain SM7,
wherein the reaction temperature of the microreactor is 30-100 ℃.
7. A process for the preparation of compound SM8, comprising the steps of g: preparing SM7, dimethylaminopyridine, triethylamine and toluene into a solution A-7, preparing di-tert-butyl dicarbonate and toluene into a solution A-7-2, inputting the solution A-7 and the solution A-7-2 into a microreactor system by using a metering pump, setting the reaction temperature of the microreactor for reaction, allowing the reaction liquid to flow out, allowing the reaction liquid to enter a post-processing system to obtain SM8,
wherein the reaction temperature of the microreactor is 30-100 ℃.
8. A method of preparing compound SM8, comprising at least one of step a, step b, step c, step d, step e, step f and step g as described in any one of the above.
9. A process for the preparation of compound SM8, comprising steps a, b, c, d, e, f and g as described above,
10. the production process according to any one of claims 1 to 9, wherein the residence time of the reaction in the microchannel reactor is from 10 seconds to 100 seconds; and/or the flow rate in the microchannel reactor is 1ml/min to 50 ml/min.
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