CN112225722A - Method for preparing crizotinib intermediate by using microchannel reactor - Google Patents
Method for preparing crizotinib intermediate by using microchannel reactor Download PDFInfo
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Abstract
The invention discloses a method for preparing a crizotinib intermediate by using a microchannel reactor, which relates to the technical field of synthesis of medical intermediates and comprises the following steps: (1) respectively feeding the 1-Boc-4-methane sulfonyloxy piperidine solution and the 4-X pyrazole solution into a premixer for premixing to form a mixed solution; (2) sending the mixed solution obtained in the step (1) to a micro-channel module for complete reaction, and outputting the generated reaction solution to a low-temperature water tank; (3) after the reaction is finished, the material in the low-temperature water tank is post-treated to obtain the target product crizotinib intermediate [4- (4-X pyrazol-1-yl) piperidine-1-tert-butyl formate ]. The method has the advantages of high selectivity, high yield, less solid waste, environmental protection and convenient industrial production.
Description
Technical Field
The invention relates to the technical field of synthesis of medical intermediates, in particular to a method for preparing a crizotinib intermediate by using a microchannel reactor.
Background
Crizotinib is an effective drug for the treatment of Anaplastic Lymphoma Kinase (ALK) positive locally advanced and metastatic non-small cell lung cancer (NSCLC). Crizotinib showed significant therapeutic activity in ALK-positive NSCLC patients and could prolong patient survival. The crizotinib has huge market demand and development prospect, and continuous, efficient and low-cost mass production is urgently needed.
At present, Chinese application 201610695554.7 discloses a preparation method of a crizotinib intermediate, which has the defects that: firstly, intermittent operation is carried out, the productivity per unit time is low, and the energy consumption is high; secondly, the amplification effect is large, the temperature control effect of single-kettle reaction is poor, the reaction temperature is high, the mixing and removing time is long, the separation is slow, byproducts are easy to generate, and the molar yield is not high; thirdly, the usage amount of strong base and weak acid salt is large, which causes a large amount of solid waste and waste liquid.
The micro-channel reactor greatly improves the heat transfer and mass transfer performance of the chemical fluid in the micro-channel compared with the conventional system due to the miniaturization of the size, can meet the requirements of sustainable and high-tech development, and can meet the continuous large-scale production, thereby being widely concerned by people. The micro-reactor has extremely large specific surface area, thereby bringing the fundamental advantages of extremely large heat exchange efficiency and mixing efficiency, and being capable of accurately controlling the reaction temperature and instantly mixing reaction materials according to accurate proportion, thereby improving the yield, selectivity, safety and product quality. For example, chinese patent application 201310171684.7 discloses a method for continuously synthesizing arylboronic acid ester using a microreactor, belonging to the technical field of green organic synthesis application. The method takes substituted arylamine, acetonitrile, nitrite tert-butyl ester and duplex pinacolyl diborane as initial raw materials, and completes the processes of preheating the three raw materials of the substituted arylamine, the nitrite tert-butyl ester and the duplex pinacolyl diborane, reacting the mixture of the substituted arylamine and the duplex pinacolyl diborane with the nitrite tert-butyl ester and the like in a continuous flow microchannel reactor system. In the reaction, the molar ratio of the substituted aromatic amine to the bis-pinacolyl diborane is 1:0.5-1:1.25, the molar ratio of the substituted aromatic amine to the isoamyl nitrite is 1:1.1-1:1.5, the reaction temperature is 60-120 ℃, the reaction time is 50s-3600s, and the effective conversion rate of the substituted aromatic amine can reach 50-90%. The continuous flow micro-reactor with the effects of enhancing mixing, mass transfer and heat transfer is particularly suitable for carrying out the homogeneous reaction of the method, and has the characteristics of stable temperature control, safe process and less waste.
Chinese patent application 201810078593.1 discloses a method for synthesizing crizotinib intermediate by a microchannel reactor, which comprises the steps of adding 3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -2-nitropyridine into an organic solvent, adding a noble metal-loaded active carbon catalyst to serve as a material I, and conveying the material I to a preheating module of the microchannel reactor for preheating; respectively conveying the preheated material I and hydrogen to a reaction module group of a microchannel reactor for reaction, collecting reaction liquid flowing out of an outlet of the microchannel reactor, and carrying out aftertreatment to obtain the 3- (1- (2, 6-dichloro-3-fluorophenyl) ethoxy) pyridine-2-amine.
And as Chinese patent application 201310171684.7 discloses a method for continuously synthesizing arylboronic acid ester by utilizing a microreactor, the method takes substituted arylamine, acetonitrile, nitroso-butyl nitrite and duplex pinacol-based diborane as initial raw materials, and completes the processes of preheating the three raw materials of the substituted arylamine, the nitroso-butyl nitrite and the duplex pinacol-based diborane, mixing the substituted arylamine and the duplex pinacol-based diborane, reacting the mixture with the nitroso-butyl nitrite and the like in a continuous flow microchannel reactor system. In the reaction, the molar ratio of the substituted aromatic amine to the bis-pinacolyl diborane is 1:0.5-1:1.25, the molar ratio of the substituted aromatic amine to the isoamyl nitrite is 1:1.1-1:1.5, the reaction temperature is 60-120 ℃, the reaction time is 50s-3600s, and the effective conversion rate of the substituted aromatic amine can reach 50-90%. The continuous flow micro-reactor with the effects of enhancing mixing, mass transfer and heat transfer is particularly suitable for carrying out the homogeneous reaction of the method, and has the characteristics of stable temperature control, safe process and less waste.
The application provides a method for preparing a crizotinib intermediate by using 1-Boc-4-methanesulfonyloxy piperidine and 4-X pyrazole as raw materials and using a microchannel reactor, which solves the problems in the prior art, reduces energy consumption, removes amplification effect, shortens reaction time, and reduces generation of solid liquid and waste liquid.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide the method for preparing the crizotinib intermediate by using the microchannel reactor, which has the advantages of high selectivity, high yield, less solid waste, environmental protection and convenience for industrial production.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a process for preparing a crizotinib intermediate using a microchannel reactor, comprising the steps of:
(1) respectively feeding the 1-Boc-4-methane sulfonyloxy piperidine solution and the 4-X pyrazole solution into a premixer for premixing to form a mixed solution;
(2) sending the mixed solution obtained in the step (1) to a micro-channel module for complete reaction, and outputting the generated reaction solution to a low-temperature water tank;
(3) after the reaction is finished, the material in the low-temperature water tank is post-treated to obtain the target product crizotinib intermediate [4- (4-X pyrazol-1-yl) piperidine-1-tert-butyl formate ].
Wherein, X is halogen, preferably Br or I, and more preferably I.
The chemical structural formula of the obtained crizotinib intermediate [4- (4-X pyrazol-1-yl) piperidine-1-tert-butyl formate ] is as follows:
preferably, the premixer and the microchannel module form the microchannel reactor, and the equipment connected with the microchannel reactor further comprises a low-temperature water tank, a filter 1, a stirring crystallization kettle, a filter 2 and a drying kettle; wherein, a discharge pipe at the discharge end of the microchannel reactor is communicated with a low-temperature water tank through a discharge pipe with a discharge valve, a discharge pipe of the low-temperature water tank is arranged at the upper part of the low-temperature water tank and communicated with a filter 1, a discharge pipe of the filter 1 is arranged at the upper part of the filter 1, a discharge pipe of the filter 1 is arranged at the bottom of the discharge pipe of the filter 1, a first circulating pump is arranged at the bottom of the discharge pipe of the filter 1, the discharge pipe of the filter 1 is communicated with a stirred crystallization kettle, a discharge pipe of the stirred crystallization kettle with a valve is arranged at the bottom of the stirred crystallization kettle, the discharge pipe of the stirred crystallization kettle is communicated with a filter 2, a discharge pipe of the filter 2 is arranged at the upper part of the filter 2, a discharge pipe of the filter 2 is arranged at the, is communicated to the storage tank.
Further preferably, a sampling valve is arranged on a discharge pipe at the discharge end of the micro-channel module.
Preferably, in the step (1), the mass concentration of the 1-Boc-4-methanesulfonyloxypiperidine solution is 10 to 45%, more preferably 20 to 30%, and most preferably 30%.
Preferably, the 1-Boc-4-methanesulfonyloxypiperidine solution is prepared according to the following steps: the preparation method comprises the following steps of stirring 1-Boc-4-methane sulfonyl piperidine and DMF at room temperature.
Preferably, in the step (1), the mass concentration of the 4-X pyrazole solution is 10 to 45%, more preferably 25 to 30%, and most preferably 30%.
Preferably, in step (1), the 4-X pyrazole solution is prepared according to the following steps: mixing 4-X pyrazole with DMF at normal temperature, cooling to below 5 ℃, reacting with sodium hydrogen for 2h, and preparing the product.
Preferably, the molar ratio of 1-Boc-4-methanesulfonyloxypiperidine to 4-X pyrazole is 0.85 to 1.15:1, more preferably 0.95 to 1.05:1, and most preferably 1:1.
Preferably, in step (1), the 1-Boc-4-methanesulfonyloxypiperidine solution and the 4-X pyrazole solution are respectively pumped into a premixer by two micropumps.
Preferably, in the step (1), the flow rate of the 1-Boc-4-methanesulfonyloxy piperidine DMF solution is 5-25mL/min, and the flow rate of the 4-X pyrazole DMF solution is 6-20 mL/min.
Preferably, in the step (2), the hydraulic diameter of the micro-channel in the micro-channel module is 0.1-1.0mm, the length is 50-100m, and the temperature of the micro-channel module is controlled at 30-70 ℃; further preferably, the hydraulic diameter of the micro-channel module is 0.5mm, the length of the micro-channel module is 100m, and the temperature of the micro-channel module is controlled to be 30-40 ℃.
The temperature of the microchannel module is controlled by a temperature control tank.
Preferably, in the step (2), the residence time of the mixed liquid in the microchannel of the microchannel module is 15 to 90s, and more preferably 30 to 60 s.
Preferably, in the step (2), the temperature of the low-temperature water tank is 0 to 20 ℃, and more preferably 0 to 10 ℃.
Preferably, in step (3), the post-treatment comprises: filtering, crystallizing and drying; further preferably, the post-treatment specifically comprises:
filtering the upper material in the low-temperature water tank in a filter, feeding the filter cake in the filter into a stirring crystallization kettle for stirring crystallization, and then feeding the filter cake into a drying kettle for drying.
More preferably, the temperature in the crystallization kettle is-5-10 ℃, and the temperature in the drying kettle is 10-40 ℃.
Compared with the prior art, the invention has the following beneficial effects:
(1) the microchannel reactor has small pipe diameter and large specific surface area, the material is in a laminar flow state, and the molecular diffusion phenomenon is very obvious due to the small pipe diameter, so that uniform dispersion can be formed at a very high speed (only 20ms is needed for 500 mu m), and the material can be instantly and uniformly mixed in an accurate proportion;
(2) the temperature is accurately controlled, and the local overheating phenomenon is effectively eliminated, so that not only can the reaction efficiency and the product quality be improved, but also the selectivity of the product can be greatly improved, and the generation of byproducts can be effectively reduced, thereby greatly improving the molar yield;
(3) the reaction does not generate a large amount of solid waste, thereby being beneficial to environmental protection;
(4) the mixing uniformity of the reaction raw materials is greatly improved, the reaction raw materials are contacted more fully, and the reaction time and the production period are shortened;
(5) the whole reaction system has no amplification effect and is convenient for industrial application.
Drawings
FIG. 1 is a schematic diagram of the arrangement of a production apparatus used in the present invention;
FIG. 2 shows the preparation of intermediate iodide according to the invention1H-NMR spectrum.
Detailed Description
The present invention will be further explained with reference to specific embodiments in order to make the technical means, the original characteristics, the achieved objects and the effects of the present invention easy to understand, but the following embodiments are only preferred embodiments of the present invention, and not all embodiments are possible. In the interest of clarity, not all features of an actual implementation are described. In the following description, well-known functions or constructions are not described in detail since they would obscure the invention in unnecessary detail. It will of course be appreciated that in the development of any such actual embodiment, numerous implementation-specific details must be set forth in order to achieve the developer's specific goals. Based on the embodiments in the implementation, other embodiments obtained by those skilled in the art without any creative efforts belong to the protection scope of the present invention.
In order to make the objects and features of the present invention more comprehensible, embodiments of the present invention are described in detail below with reference to the accompanying drawings. It is to be noted that the drawings are in a very simplified form and are intended to use non-precision ratios for the purpose of facilitating and clearly facilitating the description of the embodiments of the invention.
The experimental methods in the following examples are conventional methods unless otherwise specified, and materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The DMF solution for preparing the 1-Boc-4-methane sulfonyl oxy piperidine is prepared by stirring the 1-Boc-4-methane sulfonyl oxy piperidine and DMF at room temperature; the following DMF solutions of 4-X pyrazole were prepared as follows: mixing 4-X pyrazole and DMF at normal temperature, then cooling to 0-5 ℃, continuously stirring and slowly adding sodium hydrogen, and completing solution preparation after 2h, wherein the molar ratio of sodium hydrogen to 4-X pyrazole is 1.2: 1.
The invention utilizes a microchannel reactor to prepare a crizotinib intermediate, the structure of the used production equipment is shown in figure 1, and the production equipment comprises a microchannel reactor 5 arranged in a temperature control mechanism, and a low-temperature water tank 6, a filter 7, a stirring crystallization kettle 9, a filter 10 and a drying kettle 21 which are sequentially communicated;
the temperature control mechanism comprises a temperature control tank 4, cooling liquid is arranged in the temperature control tank 4, and the cooling liquid is continuously circulated through a circulating pump;
the microchannel reactor 5 comprises a premixer 3 and a microchannel module 11 which are communicated with each other, wherein the premixer 3 is communicated with a micropump 1 and a micropump 2. The discharge end of the micro-channel module 11 is provided with a discharge pipe 12, and the discharge pipe 12 is further provided with a sampling valve 13. The discharge pipe 12 is communicated with a low-temperature water tank 6 which is provided with an external circulation refrigeration device. An output pipe 14 with a valve is arranged at the upper part of the low-temperature water tank 6, and the output pipe 14 is communicated with the filter 7. The upper portion of filter 7 is provided with filter discharging pipe 15, the bottom of filter 7 is provided with outlet pipe 16, the bottom of outlet pipe 16 communicates with first circulating pump 8, first circulating pump 8 is used for pumping the filtrate in filter 7 into low temperature basin 6, discharging pipe 15 communicates with stirring crystallization kettle 9, stirring crystallization kettle 9 bottom is provided with row material pipe 17 with valve, row material pipe 17 connects filter 10, the upper portion of filter 10 is provided with filter discharging pipe 18, the bottom of filter 10 is provided with drain pipe 19, the bottom of drain pipe 19 communicates with second circulating pump 20, second circulating pump 20 is used for pumping the filtrate in filter 10 into stirring crystallization kettle 9. The discharge pipe 18 of the stirring crystallization kettle is communicated with the drying kettle 21, the bottom of the drying kettle is provided with an output pipe 22, and the output end of the output pipe 22 is communicated with a storage tank 23.
Example 1
(1) Setting the temperature of the temperature control tank 4 at 30-40 ℃, and synchronously pumping a DMF solution of 4-iodopyrazole with the mass concentration of 30% and a DMF solution of 1-Boc-4-methanesulfonyloxy piperidine with the mass concentration of 30% into a premixer 3 by two micropumps 1 and 2 respectively for premixing and cooling to form a mixed solution. Wherein the flow rate of the DMF solution of 4-iodopyrazole is 16.56mL/min, and the flow rate of the DMF solution of 1-Boc-4-methanesulfonyloxypiperidine is 22.69 mL/min; the molar ratio of 1-Boc-4-methanesulfonyloxypiperidine to 4-iodopyrazole was 1:1.
(2) The mixed liquid in the premixer 3 is injected into the micro-channel of the micro-channel module 11 for reaction, the hydraulic diameter of the micro-channel in the micro-channel module 11 is 0.5mm, the length of the micro-channel is 100m, and the reaction materials stay in the micro-channel for 30 s. The conversion of 4-iodopyrazole as determined by gas chromatography after sampling from the sampling valve 13 was 99.92%.
Reaction liquid generated by complete reaction in the micro-channel is output to the low-temperature water tank 6 from the discharge pipe 12, the temperature of the low-temperature water tank 6 is controlled at 0-5 ℃, and after a large amount of white solids appear, upper-layer materials in the low-temperature water tank enter the filter 7 through the discharge pipe 14 for filtering.
(3) And (3) feeding a filter cake in the filter 7 into a stirring crystallization kettle 9 through a discharge pipe 15 for stirring crystallization, controlling the temperature in the stirring crystallization kettle at-5-10 ℃, feeding the material in the crystallization kettle into a drying kettle 21 for drying, setting the temperature of the drying kettle at 30-40 ℃, finishing drying after the water content in the drying kettle to be detected is less than 0.5%, and obtaining a target product crizotinib intermediate with the purity of 98.59% and the molar yield of 77.27%.
Example 2
(1) Setting the temperature of the temperature control tank 4 at 30-40 ℃, synchronously pumping a DMF solution of 25% by mass of 4-iodopyrazole and a DMF solution of 25% by mass of 1-Boc-4-methanesulfonyloxy piperidine into a premixer 3 by two micropumps 1 and 2 respectively, and premixing and cooling to form a mixed solution. Wherein the flow rate of the DMF solution of 4-iodopyrazole is 12.27mL/min, and the flow rate of the DMF solution of 1-Boc-4-methanesulfonyloxypiperidine is 17.02 mL/min; the molar ratio of 1-Boc-4-methanesulfonyloxypiperidine to 4-iodopyrazole was 1:1.
(2) The mixed liquid in the premixer 3 is injected into the micro-channel of the micro-channel module 11 for reaction, the hydraulic diameter of the micro-channel in the micro-channel module 11 is 0.5mm, the length of the micro-channel is 100m, and the reaction materials stay in the micro-channel for 90 s. The conversion of 4-iodopyrazole as determined by gas chromatography after sampling from the sampling valve 13 was 99.79%.
Reaction liquid generated by complete reaction in the micro-channel is output to the low-temperature water tank 6 from the discharge pipe 12, the temperature of the low-temperature water tank 6 is controlled to be 0-10 ℃, and after a large amount of white solids appear, upper-layer materials in the low-temperature water tank enter the filter 7 through the discharge pipe 14 for filtering.
(3) And (3) feeding a filter cake in the filter 7 into a stirring crystallization kettle 9 through a discharge pipe 15 for stirring crystallization, controlling the temperature in the stirring crystallization kettle at-5-10 ℃, feeding the material in the crystallization kettle into a drying kettle 21 for drying, setting the temperature of the drying kettle at 40-50 ℃, and finishing drying after the water content in the drying kettle to be detected is less than 0.5%, thus obtaining the target product crizotinib intermediate with the purity of 98.43% and the molar yield of 75.55%.
Example 3
(1) Setting the temperature of the temperature control tank 4 at 60-70 ℃, synchronously pumping a DMF solution of 4-iodopyrazole with the mass concentration of 30% and a DMF solution of 1-Boc-4-methanesulfonyloxy piperidine with the mass concentration of 20% into a premixer 3 by two micropumps 1 and 2 respectively, premixing and cooling to form a mixed solution. Wherein the flow rate of the DMF solution of 4-iodopyrazole is 7.71mL/min, and the flow rate of the DMF solution of 1-Boc-4-methanesulfonyloxypiperidine is 15.84 mL/min; the molar ratio of 1-Boc-4-methanesulfonyloxypiperidine to 4-iodopyrazole was 1:1.
(2) The mixed liquid in the premixer 3 is injected into the micro-channel of the micro-channel module 11 for reaction, the hydraulic diameter of the micro-channel in the micro-channel module 11 is 0.5mm, the length of the micro-channel is 100m, and the reaction materials stay in the micro-channel for 15 s. The conversion of 4-iodopyrazole as determined by gas chromatography after sampling from the sampling valve 13 was 99.85%.
Reaction liquid generated by complete reaction in the micro-channel is output to the low-temperature water tank 6 from the discharge pipe 12, the temperature of the low-temperature water tank 6 is controlled to be 0-10 ℃, and after a large amount of white solids appear, upper-layer materials in the low-temperature water tank enter the filter 7 through the discharge pipe 14 for filtering.
(3) And (3) feeding a filter cake in the filter 7 into a stirring crystallization kettle 9 through a discharge pipe 15 for stirring crystallization, controlling the temperature in the stirring crystallization kettle at-5-10 ℃, feeding the material in the crystallization kettle into a drying kettle 21 for drying, setting the temperature of the drying kettle at 40-50 ℃, and finishing drying after the water content in the drying kettle to be detected is less than 0.5%, thus obtaining the target product crizotinib intermediate with the purity of 98.43% and the molar yield of 75.55%.
Example 4
(1) Setting the temperature of the temperature control tank 4 at 50-60 ℃, synchronously pumping a DMF solution of 25% by mass of 4-bromopyrazole and a DMF solution of 30% by mass of 1-Boc-4-methanesulfonyloxy piperidine into a premixer 3 by two micropumps 1 and 2 respectively, and premixing and cooling to form a mixed solution. Wherein the flow rate of the DMF solution of 4-bromopyrazole is 12.64mL/min, and the flow rate of the DMF solution of 1-Boc-4-methanesulfonyloxypiperidine is 6.98 mL/min; the molar ratio of 1-Boc-4-methanesulfonyloxypiperidine to 4-iodopyrazole was 1:1.
(2) The mixed liquid in the premixer 3 is injected into the micro-channel of the micro-channel module 11 for reaction, the hydraulic diameter of the micro-channel in the micro-channel module 11 is 0.5mm, the length of the micro-channel is 100m, and the reaction materials stay in the micro-channel for 60 s. The conversion of 4-iodopyrazole as determined by gas chromatography after sampling from the sampling valve 13 was 99.73%.
Reaction liquid generated by complete reaction in the micro-channel is output to the low-temperature water tank 6 from the discharge pipe 12, the temperature of the low-temperature water tank 6 is controlled at 0-5 ℃, and after a large amount of white solids appear, upper-layer materials in the low-temperature water tank enter the filter 7 through the discharge pipe 14 for filtering.
(3) And (3) feeding a filter cake in the filter 7 into a stirring crystallization kettle 9 through a discharge pipe 15 for stirring crystallization, controlling the temperature in the stirring crystallization kettle at 0-10 ℃, feeding the material in the crystallization kettle into a drying kettle 21 for drying, setting the temperature of the drying kettle at 20-40 ℃, finishing drying after the water content in the drying kettle to be detected is less than 0.5%, and obtaining a target product crizotinib intermediate with the purity of 98.32% and the molar yield of 76.90%.
Example 5
In contrast to example 1, this example 1-Boc-4-methanesulfonyloxypiperidine and 4-iodopyrazole had a molar ratio of 0.85:1, and the rest were the same.
The purity of the obtained target product crizotinib intermediate is 98.15%, and the molar yield is 66.71%.
Example 6
In contrast to example 1, this example 1-Boc-4-methanesulfonyloxypiperidine and 4-iodopyrazole had a molar ratio of 0.95:1, and the rest were the same.
The obtained target product crizotinib intermediate has the purity of 98.24% and the molar yield of 73.12%.
Example 7
In contrast to example 1, this example 1-Boc-4-methanesulfonyloxypiperidine and 4-iodopyrazole had a molar ratio of 1.05:1, and the rest were the same.
The purity of the obtained target product crizotinib intermediate is 98.22%, and the molar yield is 73.34%.
Example 8
In contrast to example 1, this example 1-Boc-4-methanesulfonyloxypiperidine and 4-iodopyrazole had a molar ratio of 1.15:1, and the rest were the same.
The purity of the obtained target product crizotinib intermediate is 98.17%, and the molar yield is 67.21%.
Example 9
In contrast to example 1, this example uses 4-bromopyrazole, the remainder being identical.
The obtained target product crizotinib intermediate has the purity of 97.26% and the molar yield of 67.88%.
Example 10
In contrast to example 1, this example uses 4-chloropyrazole, the remainder being identical.
The purity of the obtained target product crizotinib intermediate is 96.27%, and the molar yield is 64.33%.
Comparative example 1
Unlike example 1, this comparative example 1-Boc-4-methanesulfonyloxypiperidine and 4-iodopyrazole had a molar ratio of 1.5:1, and the rest were the same.
The purity of the obtained target product crizotinib intermediate is 98.32%, and the molar yield is 51.35%.
Comparative example 2
Unlike example 1, the temperature of the microchannel module of this comparative example was 80 ℃, and the rest was the same.
The purity of the obtained target product crizotinib intermediate is 98.25%, and the molar yield is 68.23%.
Comparative example 3
Unlike example 1, the flow rate of the 1-Boc-4-methanesulfonyloxypiperidine DMF solution in this comparative example was 23.22mL/min, the flow rate of the 4-X pyrazole DMF solution was 4.63mL/min, and the rest was the same.
The obtained target product crizotinib intermediate has the purity of 95.15% and the molar yield of 30.12%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. The method for preparing the crizotinib intermediate by using the microchannel reactor is characterized by comprising the following steps of:
(1) respectively feeding the 1-Boc-4-methane sulfonyloxy piperidine solution and the 4-X pyrazole solution into a premixer for premixing to form a mixed solution;
(2) sending the mixed solution obtained in the step (1) to a micro-channel module for complete reaction, and outputting the generated reaction solution to a low-temperature water tank;
(3) after the reaction is finished, the material in the low-temperature water tank is post-treated to obtain a target product crizotinib intermediate [4- (4-X pyrazol-1-yl) piperidine-1-tert-butyl formate ],
wherein X is halogen, and the molar ratio of the 1-Boc-4-methanesulfonyloxy piperidine to the 4-X pyrazole is 0.85-1.15: 1;
the chemical structural formula of the obtained crizotinib intermediate [4- (4-X pyrazol-1-yl) piperidine-1-tert-butyl formate ] is as follows:
the premixer and the microchannel module form the microchannel reactor.
2. The method of claim 1, wherein X is Br or I.
3. The method of claim 1, wherein the microchannel reactor connected apparatus further comprises a low temperature water tank, a filter 1, a stirred crystallizer, a filter 2, and a drying kettle; wherein, a discharge pipe at the discharge end of the microchannel reactor is communicated with a low-temperature water tank through a discharge pipe with a discharge valve, a discharge pipe of the low-temperature water tank is arranged at the upper part of the low-temperature water tank and communicated with a filter 1, a discharge pipe of the filter 1 is arranged at the upper part of the filter 1, a discharge pipe of the filter 1 is arranged at the bottom of the discharge pipe of the filter 1, a first circulating pump is arranged at the bottom of the discharge pipe of the filter 1, the discharge pipe of the filter 1 is communicated with a stirred crystallization kettle, a discharge pipe of the stirred crystallization kettle with a valve is arranged at the bottom of the stirred crystallization kettle, the discharge pipe of the stirred crystallization kettle is communicated with a filter 2, a discharge pipe of the filter 2 is arranged at the upper part of the filter 2, a discharge pipe of the filter 2 is arranged at the, is communicated to the storage tank.
4. The method of claim 3, wherein a sampling valve is disposed on a discharge pipe at the discharge end of the microchannel module.
5. The method as claimed in claim 1, wherein in the step (1), the concentration by mass of the 1-Boc-4-methanesulfonyloxypiperidine solution is 10 to 45%, and the concentration by mass of the 4-X pyrazole solution is 10 to 45%.
6. The method of claim 1, wherein in step (1), the 1-Boc-4-methanesulfonyloxypiperidine solution is prepared by the following steps: stirring 1-Boc-4-methane sulfonyl piperidine and DMF at room temperature to prepare the compound; the 4-X pyrazole solution is prepared according to the following steps: mixing 4-X pyrazole with DMF at normal temperature, cooling to below 5 ℃, reacting with sodium hydrogen for 2h, and preparing the product.
7. The process of claim 1, wherein in step (1), the molar ratio of 1-Boc-4-methanesulfonyloxypiperidine to 4-X pyrazole is 0.95 to 1.05: 1.
8. The method of claim 1, wherein in step (1), the flow rate of the 1-Boc-4-methanesulfonyloxypiperidine DMF solution is 5-25mL/min and the flow rate of the 4-X pyrazole DMF solution is 6-20 mL/min.
9. The method according to claim 1, wherein in the step (2), the hydraulic diameter of the microchannel in the microchannel module is 0.1-1.0mm, the length is 50-100m, the temperature of the microchannel module is controlled at 30-70 ℃, and the temperature of the microchannel module is controlled by a temperature control groove; the residence time of the mixed liquid in the micro-channel module is 15-90 s.
10. The method of claim 1, wherein in step (3), the post-processing comprises: filtering, crystallizing and drying.
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