CN113461759A - Method for synthesizing zidovudine azide intermediate based on continuous flow micro-reaction technology - Google Patents
Method for synthesizing zidovudine azide intermediate based on continuous flow micro-reaction technology Download PDFInfo
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Abstract
The invention provides a method for synthesizing zidovudine azide intermediate, which comprises the following steps: (1) mixing a zidovudine oxygen bridge compound, an azidation reagent and a solvent to dissolve the zidovudine oxygen bridge compound and the azidation reagent in the solvent to prepare a reaction raw material solution; (2) and inputting the reaction raw material solution into a microchannel reactor for reaction to obtain a product solution containing the zidovudine azide intermediate. The invention applies continuous flow micro-reaction technology, adopts a micro-channel reactor as core reaction equipment, and has the advantages of continuous azidation reaction, reduction of the dosage of azidation reagents, acceleration of reaction rate, reduction of reaction risk and the like.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a method for synthesizing zidovudine azide intermediates based on a continuous flow micro-reaction technology.
Background
Zidovudine (the structural formula of which is shown in formula 1) is the first anti-AIDS drug approved and produced by the United states FDA and is generally used for treating AIDS patients or AIDS-related syndromes. Zidovudine is by far the first choice for the treatment of aids in many developing countries.
In the production process of zidovudine, the synthesis of zidovudine azide intermediate (the structural formula of which is shown in formula 3) from zidovudine oxygen bridge (the structural formula of which is shown in formula 2) and azide reagent is a crucial step.
The traditional kettle reactor has low mixing efficiency, low heat and mass transfer rate and large liquid holdup, and easily causes the nonuniformity of a concentration field and a temperature field. The traditional batch process utilizes a kettle type reactor to carry out the azide reaction, needs to use a large amount of azide reagents with explosive risks, has serious safety problems, has the reaction time as long as 60 hours, and is difficult to further expand the production.
Therefore, there is a need in the art for a method for synthesizing zidovudine azido intermediates from zidovudine oxygen-bridged ring compounds that allows for continuous azidation reactions, reduced amounts of azidation reagents, faster reaction rates, and reduced reaction risks.
Disclosure of Invention
Aiming at the problems, the invention provides a method for realizing continuous synthesis of zidovudine azidation intermediates by azidation of zidovudine oxygen bridge ring compounds based on a continuous flow micro-reaction technology. The invention applies continuous flow micro-reaction technology, adopts a micro-channel reactor as core reaction equipment, and has the advantages of continuous azidation reaction, reduction of the dosage of azidation reagents, acceleration of reaction rate, reduction of reaction risk and the like.
Specifically, the invention provides a method for synthesizing zidovudine azide intermediates, which comprises the following steps:
(1) mixing a zidovudine oxygen bridge compound, an azidation reagent and a solvent, and dissolving the zidovudine oxygen bridge compound and the azidation reagent in the solvent to prepare a reaction raw material solution, wherein the structural formula of the zidovudine oxygen bridge compound is as follows:
(2) inputting the reaction raw material solution into a microchannel reactor for reaction to obtain a product solution containing the zidovudine azide intermediate, wherein the structural formula of the zidovudine azide intermediate is as follows:
in one or more embodiments, the reaction feed solution is prepared at 80 to 100 ℃.
In one or more embodiments, the molar ratio of the azidation reagent to the zidovudine oxibridge in the reaction feed solution is from 1:1 to 5: 1.
In one or more embodiments, the concentration of the zidovudine oxygen bridge in the reaction feed solution is 0.1 to 1 mol/L.
In one or more embodiments, the concentration of the azidation reagent in the reaction feed solution is from 0.1 to 2 mol/L.
In one or more embodiments, the azidation reagent is sodium azide.
In one or more embodiments, the solvent is selected from one or more of water, ethanol, dimethyl sulfoxide, and N, N-dimethylformamide.
In one or more embodiments, in step (2), the reaction time is from 2 to 60 minutes.
In one or more embodiments, in step (2), the reaction temperature is 60-200 deg.C, preferably 120-200 deg.C.
In one or more embodiments, in step (2), the reaction pressure is from 0.1 to 1 MPa.
In one or more embodiments, the method further comprises the steps of:
(3) and dropping the product solution into water, violently stirring, filtering, washing and drying to obtain the zidovudine azide intermediate.
In one or more embodiments, the reaction feed solution is free of ammonium salts.
In one or more embodiments, the microchannel reactor is an in-line microreactor or a chip-type microreactor.
Drawings
FIG. 1 is a line graph of the yield of the zidovudine azide intermediate synthesized in the microchannel reactor as a function of the concentration of the zidovudine oxygen bridge as the starting material, the concentration values corresponding to the points in the graph are 0.11mol/L, 0.19mol/L, 0.26mol/L, 0.33mol/L and 0.46mol/L from left to right, which correspond to examples 4-8, respectively.
FIG. 2 is a line graph showing the yield of zidovudine azide intermediate synthesized in a microchannel reactor as a function of residence time, the points in the graph corresponding to residence times from left to right of 2.5min, 5min, 7.5min, 10min and 12.5min, respectively corresponding to examples 9-13.
Figure 3 is a line graph of the yield of zidovudine azide intermediate synthesized in the microchannel reactor as a function of reaction temperature and residence time in example 14.
Detailed Description
To make the features and effects of the present invention comprehensible to those skilled in the art, general description and definitions are made below with reference to terms and expressions mentioned in the specification and claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The theory or mechanism described and disclosed herein, whether correct or incorrect, should not limit the scope of the present invention in any way, i.e., the present disclosure may be practiced without limitation to any particular theory or mechanism.
The terms "comprising," including, "" containing, "and the like, herein, encompass the meanings of" consisting essentially of … … "and" consisting of … …, "e.g., when" A comprises B and C, "A consists of B and C" is disclosed herein is to be considered disclosed herein.
All features defined herein as numerical ranges or percentage ranges, such as numbers, amounts, levels and concentrations, are for brevity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be considered to cover and specifically disclose all possible subranges and individual numerical values (including integers and fractions) within the range. Herein, numerical ranges and percentage ranges are inclusive, unless otherwise specified.
Herein, unless otherwise specified, percentages refer to mass percentages, ratios refer to mass ratios, and parts refer to parts by mass.
Herein, when embodiments or examples are described, it is to be understood that they are not intended to limit the invention to these embodiments or examples. On the contrary, all alternatives, modifications, and equivalents of the methods and materials described herein are intended to be included within the scope of the invention as defined by the appended claims.
In this context, for the sake of brevity, not all possible combinations of features in the various embodiments or examples are described. Therefore, the respective features in the respective embodiments or examples may be arbitrarily combined as long as there is no contradiction between the combinations of the features, and all the possible combinations should be considered as the scope of the present specification.
The method for realizing continuous synthesis of zidovudine azidation intermediates by zidovudine oxygen bridge ring compounds (also called zidovudine oxygen bridge compounds) azidation based on continuous flow microreaction technology comprises the following steps:
(1) mixing a zidovudine oxygen bridge compound, an azidation reagent and a solvent to dissolve the zidovudine oxygen bridge compound and the azidation reagent in the solvent to prepare a reaction raw material solution;
(2) and inputting the reaction raw material solution into a microchannel reactor for reaction to obtain a product solution containing the zidovudine azide intermediate.
In the step (1), a reaction raw material solution is prepared. The mixing is generally carried out at a temperature of from 80 to 100 ℃. For example, in some embodiments, the reaction raw material solution is prepared by adding the zidovudine oxygen bridge compound and the azidation reagent to a solvent at 80 to 100 ℃ and dissolving with stirring.
In the reaction raw material solution of the present invention, the molar ratio of the azidation reagent to the zidovudine oxygen bridge may be 1:1 to 5:1, for example, 1:1 to 2.5:1, 1:1 to 2:1, 1.5: 1. In some embodiments, the molar ratio of the azidation reagent to the zidovudine oxibridge is 1:1 to 1.8:1, e.g., 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7: 1. The present invention achieves comparable or even higher reaction yields using less amount of azidation reagent relative to the tank reaction.
The concentration of the zidovudine oxygen bridge compound in the reaction raw material solution of the present invention may be 0.1 to 1mol/L, for example, 0.1 to 0.5mol/L, 0.25 to 0.5mol/L, 0.3 to 0.5mol/L, 0.4 to 0.5 mol/L. In the reaction raw material solution of the present invention, the concentration of the azidation reagent may be 0.1 to 2mol/L, for example, 0.25mol/L, 0.3mol/L, 0.4mol/L, 0.5mol/L, 0.6mol/L, 0.7mol/L, 0.75mol/L, 0.8mol/L, 0.9mol/L, 1 mol/L. In some embodiments, the azidation reagent is sodium azide.
The solvent of the reaction raw material solution of the present invention may be selected from one or more of water, ethanol, dimethyl sulfoxide (DMSO), and N, N-Dimethylformamide (DMF). In some embodiments, the solvent of the reaction feedstock solution is DMSO.
In some embodiments, the reaction feed solution is free of ammonium salts. In some embodiments, the reaction feed solution is free of inorganic reagents. The method optimizes the azidation reaction condition, avoids using inorganic reagents such as ammonium salt and the like, reduces waste salt generated by the reaction, optimizes the solid-liquid two-phase reaction in the kettle type reaction process into the homogeneous reaction in the continuous flow reaction, does not generate explosive azido acid gas in the kettle type reaction in the reaction process, and obviously improves the safety.
In the step (2), the zidovudine oxygen bridge compound and the azidation reagent react in a microchannel reactor to generate the zidovudine azidation intermediate. The reaction raw material solution may be fed into the microchannel reactor by a fluid pump, such as a syringe pump, a advection pump, as a fluid feeding means. In some embodiments, the fluid delivery device is a syringe pump. The flow rate of the material into the microchannel reactor may be in the range of 0.05 to 0.2mL/min, for example 0.11. + -. 0.2 mL/min. The residence time (reaction time) of the material in the microchannel reactor may be 2 to 60 minutes, preferably 2 to 15 minutes, for example 2.5 minutes, 5 minutes, 7.5 minutes, 10 minutes, 12.5 minutes. The reaction temperature may be 60-200 deg.C, preferably 120-200 deg.C, such as 140 deg.C, 150 deg.C, 160 deg.C, 170 deg.C, 180 deg.C, 190 deg.C. The method provided by the invention realizes the azide reaction at high temperature while ensuring the safety, and the reaction yield is obviously improved due to the increase of the reaction temperature. The reaction pressure may be from 0.1 to 1MPa, for example from 0.2 to 0.8MPa, from 0.4 to 0.6MPa, 75 psi. A back pressure valve can be added at the rear end of the microchannel reactor to control the reaction pressure. And after the reaction is finished, the reaction liquid can flow out from the outlet of the microchannel reactor through a back pressure valve to obtain a product solution. In step (2), one or more microchannel reactors may be used. The microchannel reactor can be an in-line micro-reactor or a chip micro-reactor. In some embodiments, the microchannel reactor is an in-line microchannel reactor.
In some embodiments, the methods of the present invention further comprise the steps of:
(3) and dropping the product solution into water, stirring vigorously, filtering, washing and drying to obtain the zidovudine azide intermediate.
In step (3), the product solution is usually cooled to room temperature and then dropped into water. In some embodiments, the product solution is cooled to room temperature through a back pressure valve via a water bath and then dropped into water.
In some embodiments, the methods of the invention comprise the steps of:
(1) preparing a reaction raw material solution: mixing the zidovudine oxygen bridge compound, the azidation reagent and the solvent at the temperature of 80-100 ℃, and stirring to dissolve the zidovudine oxygen bridge compound and the azidation reagent in the solution, thereby preparing and obtaining a reaction raw material solution;
(2) conveying the reaction raw material solution into a microchannel reactor through a fluid pump for reaction, and after the reaction is finished, allowing the reaction raw material solution to flow out of an outlet of the microchannel reactor through a back pressure valve to obtain an effluent liquid;
(3) and (3) cooling the effluent liquid obtained in the step (2) to room temperature, slowly dropping the product solution into water, violently stirring, filtering to obtain a filter cake, washing and drying to obtain the zidovudine azide intermediate.
According to the method, the nitridization reaction conditions are optimized, inorganic reagents such as amine salt and the like are avoided, waste salt generated by reaction is greatly reduced, meanwhile, the solid-liquid two-phase reaction in the kettle type reaction process is optimized to be a homogeneous reaction in a continuous flow reaction, a microchannel reactor is used for reaction, the nitridization reaction time is optimized from 60 hours to not more than 1 hour, and the reaction efficiency is remarkably improved. The azide reaction can generate a large amount of explosive azido acid in the kettle type production process, and can be accumulated in the top space of the reaction kettle in a large amount in a gas form along with the progress of the reaction, so that the azide reaction has potential explosive danger.
The invention applies the continuous flow micro-reaction technology, adopts the micro-channel reactor as the core reaction equipment, and has the advantages of continuous azidation reaction, reduction of the dosage of azidation reagent, acceleration of reaction rate, improvement of reaction yield and selectivity, reduction of reaction risk, easy parallel amplification and the like. Compared with the existing kettle type azidation process, the method disclosed by the invention has the advantages that the process for synthesizing the zidovudine azidation intermediate is strengthened based on the continuous flow micro-reaction technology, the liquid holdup of the reaction is obviously reduced, the safety risk in the azidation production process is reduced, the reaction time is reduced from 60 hours to no more than 1 hour, the yield is increased from 80% to more than 90%, the selectivity is also improved, the reaction has no obvious amplification effect, and the industrial amplification is easy.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims. The methods, devices and materials used in the examples are, unless otherwise indicated, conventional in the art. The starting compounds in the examples are all commercially available.
Example 1
4.66g of zidovudine oxygen bridge and 0.975g of sodium azide are added into 20mL of DMSO in sequence at 100 ℃, namely, the mol ratio of the zidovudine oxygen bridge compound to the azidation reagent is 1:1.5, the solution is slowly and evenly stirred until the solution is clear and transparent, the reaction raw material solution is prepared and absorbed by an injector, inputting into a microchannel reactor through an injection pump, setting the flow rate to be 0.11mL/min, carrying out azide reaction on sodium azide and a zidovudine oxygen bridge substance in a pipeline micro-reactor at the reaction temperature of 180 ℃ for 10min, adding a back pressure valve at the rear end of the microchannel reactor, controlling the reaction pressure to be 75psi, cooling the product solution to room temperature through the back pressure valve in a water bath, adding the product solution into water dropwise, violently stirring, filtering to obtain filter residue, washing and drying to obtain the zidovudine azide intermediate product with the yield of 92%. No gas was found during the reaction.
Example 2
Adding 4.66g of zidovudine oxygen bridge and 1.3g of sodium azide into 20mL of DMSO (dimethyl sulfoxide) sequentially at 90 ℃, wherein the molar ratio of the zidovudine oxygen bridge to the azide reagent is 1:2, slowly and uniformly stirring the solution until the solution is clear and transparent to prepare a reaction raw material solution, sucking the reaction raw material solution by using an injector, conveying the reaction raw material solution into a microchannel reactor through an injection pump, setting the flow rate to be 0.11mL/min, reacting the sodium azide and the zidovudine oxygen bridge in a pipeline microreactor at the reaction temperature of 180 ℃ for 10min, adding a back pressure valve at the rear end of the microchannel reactor, controlling the reaction pressure to be 75psi, cooling the product solution to room temperature through the back pressure valve in a water bath, dropwise adding the product solution into water, violently stirring, filtering to obtain filter residues, washing and drying to obtain a zidovudine azide intermediate product, wherein the yield is 92%. No gas was found during the reaction.
Example 3
Adding 4.66g of zidovudine oxygen bridge and 0.975g of sodium azide into 20mL of DMSO (dimethyl sulfoxide) sequentially at 90 ℃, wherein the molar ratio of the zidovudine oxygen bridge to an azide reagent is 1:1.5, slowly and uniformly stirring the solution until the solution is clear and transparent to prepare a reaction raw material solution, sucking the reaction raw material solution by using an injector, conveying the reaction raw material solution into a microchannel reactor through an injection pump, setting the flow rate to be 0.11mL/min, reacting the sodium azide and the zidovudine oxygen bridge in an in-line microreactor at the reaction temperature of 180 ℃ for 7.5min, adding a back pressure valve at the rear end of the microchannel reactor, controlling the reaction pressure to be 75psi, cooling the product solution to room temperature through the back pressure valve through a water bath, dropwise adding the product solution into water, violently stirring, filtering to obtain filter residues, washing and drying to obtain a zidovudine azide intermediate product, wherein the yield is 90%. No gas was found during the reaction.
Example 4
Under the condition of 100 ℃, the zidovudine oxygen bridge and sodium azide are sequentially added into 20mL of DMSO, and the solution is slowly and uniformly stirred until the solution is clear and transparent, so as to prepare a reaction raw material solution (the concentration of the zidovudine oxygen bridge is 0.11mol/L, and the molar ratio of the zidovudine oxygen bridge to the azide reagent is 1: 1.5). Sucking a reaction raw material solution by using an injector, inputting the reaction raw material solution into a microchannel reactor through an injection pump, setting the flow rate to be 0.11mL/min, carrying out an azidation reaction on sodium azide and a zidovudine oxygen bridge substance in an in-line microreactor at the reaction temperature of 170 ℃ for 10min, adding a back pressure valve at the rear end of the microchannel reactor, controlling the reaction pressure to be 75psi, cooling the product solution to room temperature through the back pressure valve in a water bath, dropwise adding the product solution into water, violently stirring, filtering to obtain filter residues, washing and drying to obtain a zidovudine azidation intermediate product, wherein the yield is shown in figure 1. No gas was found during the reaction.
Example 5
Under the condition of 100 ℃, the zidovudine oxygen bridge and sodium azide are sequentially added into 20mL of DMSO, and the solution is slowly and uniformly stirred until the solution is clear and transparent, so as to prepare a reaction raw material solution (the concentration of the zidovudine oxygen bridge is 0.19mol/L, and the molar ratio of the zidovudine oxygen bridge to the azide reagent is 1: 1.5). Sucking a reaction raw material solution by using an injector, inputting the reaction raw material solution into a microchannel reactor through an injection pump, setting the flow rate to be 0.11mL/min, carrying out an azidation reaction on sodium azide and a zidovudine oxygen bridge substance in an in-line microreactor at the reaction temperature of 170 ℃ for 10min, adding a back pressure valve at the rear end of the microchannel reactor, controlling the reaction pressure to be 75psi, cooling the product solution to room temperature through the back pressure valve in a water bath, dropwise adding the product solution into water, violently stirring, filtering to obtain filter residues, washing and drying to obtain a zidovudine azidation intermediate product, wherein the yield is shown in figure 1. No gas was found during the reaction.
Example 6
Under the condition of 100 ℃, the zidovudine oxygen bridge and sodium azide are sequentially added into 20mL of DMSO, and the solution is slowly and uniformly stirred until the solution is clear and transparent, so as to prepare a reaction raw material solution (the concentration of the zidovudine oxygen bridge is 0.26mol/L, and the molar ratio of the zidovudine oxygen bridge to the azide reagent is 1: 1.5). Sucking a reaction raw material solution by using an injector, inputting the reaction raw material solution into a microchannel reactor through an injection pump, setting the flow rate to be 0.11mL/min, carrying out an azidation reaction on sodium azide and a zidovudine oxygen bridge substance in an in-line microreactor at the reaction temperature of 170 ℃ for 10min, adding a back pressure valve at the rear end of the microchannel reactor, controlling the reaction pressure to be 75psi, cooling the product solution to room temperature through the back pressure valve in a water bath, dropwise adding the product solution into water, violently stirring, filtering to obtain filter residues, washing and drying to obtain a zidovudine azidation intermediate product, wherein the yield is shown in figure 1. No gas was found during the reaction.
Example 7
Under the condition of 100 ℃, the zidovudine oxygen bridge and sodium azide are sequentially added into 20mL of DMSO, and the solution is slowly and uniformly stirred until the solution is clear and transparent, so as to prepare a reaction raw material solution (the concentration of the zidovudine oxygen bridge is 0.33mol/L, and the molar ratio of the zidovudine oxygen bridge to the azide reagent is 1: 1.5). Sucking a reaction raw material solution by using an injector, inputting the reaction raw material solution into a microchannel reactor through an injection pump, setting the flow rate to be 0.11mL/min, carrying out an azidation reaction on sodium azide and a zidovudine oxygen bridge substance in an in-line microreactor at the reaction temperature of 170 ℃ for 10min, adding a back pressure valve at the rear end of the microchannel reactor, controlling the reaction pressure to be 75psi, cooling the product solution to room temperature through the back pressure valve in a water bath, dropwise adding the product solution into water, violently stirring, filtering to obtain filter residues, washing and drying to obtain a zidovudine azidation intermediate product, wherein the yield is shown in figure 1. No gas was found during the reaction.
Example 8
Under the condition of 100 ℃, the zidovudine oxygen bridge and sodium azide are sequentially added into 20mL of DMSO, and the solution is slowly and uniformly stirred until the solution is clear and transparent, so as to prepare a reaction raw material solution (the concentration of the zidovudine oxygen bridge is 0.46mol/L, and the molar ratio of the zidovudine oxygen bridge to the azide reagent is 1: 1.5). Sucking a reaction raw material solution by using an injector, inputting the reaction raw material solution into a microchannel reactor through an injection pump, setting the flow rate to be 0.11mL/min, carrying out an azidation reaction on sodium azide and a zidovudine oxygen bridge substance in an in-line microreactor at the reaction temperature of 170 ℃ for 10min, adding a back pressure valve at the rear end of the microchannel reactor, controlling the reaction pressure to be 75psi, cooling the product solution to room temperature through the back pressure valve in a water bath, dropwise adding the product solution into water, violently stirring, filtering to obtain filter residues, washing and drying to obtain a zidovudine azidation intermediate product, wherein the yield is shown in figure 1. No gas was found during the reaction.
As can be seen from FIG. 1, under the reaction conditions of examples 4-8, the yield of zidovudine azido intermediate increased with increasing concentration of zidovudine oxygen bridge.
Example 9
4.66g of zidovudine oxygen bridge and 0.975g of sodium azide are added into 20mL of DMSO in sequence at 100 ℃, namely, the mol ratio of the zidovudine oxygen bridge compound to the azidation reagent is 1:1.5, the solution is slowly and evenly stirred until the solution is clear and transparent, the reaction raw material solution is prepared and absorbed by an injector, inputting into a microchannel reactor through an injection pump, setting the flow rate to be 0.11mL/min, carrying out azide reaction on sodium azide and a zidovudine oxygen bridge substance in a tubular microreactor at the reaction temperature of 180 ℃ for 2.5min, adding a back pressure valve at the rear end of the microchannel reactor, controlling the reaction pressure to be 75psi, cooling the product solution to room temperature through the back pressure valve in a water bath, adding the product solution into water dropwise, violently stirring, filtering to obtain filter residue, washing and drying to obtain the product zidovudine azide intermediate, wherein the yield is shown in figure 2. No gas was found during the reaction.
Example 10
4.66g of zidovudine oxygen bridge and 0.975g of sodium azide are added into 20mL of DMSO in sequence at 100 ℃, namely, the mol ratio of the zidovudine oxygen bridge compound to the azidation reagent is 1:1.5, the solution is slowly and evenly stirred until the solution is clear and transparent, the reaction raw material solution is prepared and absorbed by an injector, inputting into a microchannel reactor through an injection pump, setting the flow rate to be 0.11mL/min, carrying out azide reaction on sodium azide and a zidovudine oxygen bridge substance in a tubular microreactor at the reaction temperature of 180 ℃ for 5min, adding a back pressure valve at the rear end of the microchannel reactor, controlling the reaction pressure to be 75psi, cooling the product solution to room temperature through the back pressure valve in a water bath, adding the product solution into water dropwise, violently stirring, filtering to obtain filter residue, washing and drying to obtain the product zidovudine azide intermediate, wherein the yield is shown in figure 2. No gas was found during the reaction.
Example 11
4.66g of zidovudine oxygen bridge and 0.975g of sodium azide are added into 20mL of DMSO in sequence at 100 ℃, namely, the mol ratio of the zidovudine oxygen bridge compound to the azidation reagent is 1:1.5, the solution is slowly and evenly stirred until the solution is clear and transparent, the reaction raw material solution is prepared and absorbed by an injector, inputting into a microchannel reactor through an injection pump, setting the flow rate to be 0.11mL/min, carrying out azide reaction on sodium azide and a zidovudine oxygen bridge substance in a tubular microreactor at the reaction temperature of 180 ℃ for 7.5min, adding a back pressure valve at the rear end of the microchannel reactor, controlling the reaction pressure to be 75psi, cooling the product solution to room temperature through the back pressure valve in a water bath, adding the product solution into water dropwise, violently stirring, filtering to obtain filter residue, washing and drying to obtain the product zidovudine azide intermediate, wherein the yield is shown in figure 2. No gas was found during the reaction.
Example 12
4.66g of zidovudine oxygen bridge and 0.975g of sodium azide are added into 20mL of DMSO in sequence at 100 ℃, namely, the mol ratio of the zidovudine oxygen bridge compound to the azidation reagent is 1:1.5, the solution is slowly and evenly stirred until the solution is clear and transparent, the reaction raw material solution is prepared and absorbed by an injector, inputting into a microchannel reactor through an injection pump, setting the flow rate to be 0.11mL/min, carrying out azide reaction on sodium azide and a zidovudine oxygen bridge substance in a pipeline micro-reactor at the reaction temperature of 180 ℃ for 10min, adding a back pressure valve at the rear end of the microchannel reactor, controlling the reaction pressure to be 75psi, cooling the product solution to room temperature through the back pressure valve in a water bath, adding the product solution into water dropwise, violently stirring, filtering to obtain filter residue, washing and drying to obtain the product zidovudine azide intermediate, wherein the yield is shown in figure 2. No gas was found during the reaction.
Example 13
4.66g of zidovudine oxygen bridge and 0.975g of sodium azide are added into 20mL of DMSO in sequence at 100 ℃, namely, the mol ratio of the zidovudine oxygen bridge compound to the azidation reagent is 1:1.5, the solution is slowly and evenly stirred until the solution is clear and transparent, the reaction raw material solution is prepared and absorbed by an injector, inputting into a microchannel reactor through an injection pump, setting the flow rate to be 0.11mL/min, carrying out azide reaction on sodium azide and a zidovudine oxygen bridge substance in a tubular micro-reactor at the reaction temperature of 180 ℃ for 12.5min, adding a back pressure valve at the rear end of the microchannel reactor, controlling the reaction pressure to be 75psi, cooling the product solution to room temperature through the back pressure valve in a water bath, adding the product solution into water dropwise, violently stirring, filtering to obtain filter residue, washing and drying to obtain the product zidovudine azide intermediate, wherein the yield is shown in figure 2. No gas was found during the reaction.
As can be seen from FIG. 2, under the reaction conditions of examples 9-13, the yield of zidovudine azido intermediate increased first and then decreased slightly with increasing residence time.
Example 14
4.66g of zidovudine oxygen bridge and 0.975g of sodium azide are added into 20mL of DMSO in sequence at 100 ℃, namely, the mol ratio of the zidovudine oxygen bridge compound to the azidation reagent is 1:1.5, the solution is slowly and evenly stirred until the solution is clear and transparent, the reaction raw material solution is prepared and absorbed by an injector, inputting into a microchannel reactor through an injection pump, setting the flow rate to be 0.11mL/min, carrying out the azide reaction of sodium azide and zidovudine oxygen bridge in an in-line microreactor at the reaction temperature of 413K, 423K, 433K, 443K or 453K for 2.5min, 5min, 7.5min, 10min or 12.5min, adding a back pressure valve at the rear end of the microchannel reactor, controlling the reaction pressure to be 75psi, cooling the product solution to room temperature through the back pressure valve in a water bath, adding the product solution into water dropwise, and (3) violently stirring, filtering to obtain filter residues, washing and drying to obtain the zidovudine azide intermediate. No gas was found during the reaction. The yields of zidovudine azide intermediate at different reaction temperatures and residence times are shown in figure 3.
As can be seen from fig. 3, under the reaction conditions of example 14, the yield of zidovudine azido intermediate at different residence times as a whole increased with increasing reaction temperature, except that the yields at 453K and 443K were substantially the same when the reaction time was 12.5 minutes; the yield of zidovudine azidation intermediate generally increased with increasing residence time at different reaction temperatures, except that the yield increased first and then decreased slightly with increasing residence time when the reaction temperature was 453K.
Comparative example 1
Adding 8g of zidovudine oxygen bridge, 2.2g of sodium azide and 1g of ammonium chloride into a 100mL round-bottom flask, adding 40mL of DMF, reacting at 100 ℃ for 60 hours, accumulating a large amount of gas at the top of a reaction kettle when the reaction is finished, cooling to room temperature, adding a product solution into water under vigorous stirring, separating out a solid, performing suction filtration to obtain a filter residue, washing, and drying to obtain a zidovudine azide intermediate product, wherein the yield is 89%.
The results of the examples and comparative examples show that the process of the invention has significantly improved safety compared to the prior tank-type azide process and allows comparable or even higher reaction yields to be obtained while significantly reducing the reaction time.
The foregoing detailed description may be modified in various ways by those skilled in the art without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and not by the specific embodiments described above.
Claims (10)
1. A method of synthesizing zidovudine azide intermediates, comprising the steps of:
(1) mixing a zidovudine oxygen bridge compound, an azidation reagent and a solvent, and dissolving the zidovudine oxygen bridge compound and the azidation reagent in the solvent to prepare a reaction raw material solution, wherein the structural formula of the zidovudine oxygen bridge compound is as follows:
(2) inputting the reaction raw material solution into a microchannel reactor for reaction to obtain a product solution containing the zidovudine azide intermediate, wherein the structural formula of the zidovudine azide intermediate is as follows:
2. the method of claim 1, wherein the reaction feed solution is prepared at 80-100 ℃.
3. The method of claim 1, wherein the molar ratio of the azidation reagent to the zidovudine oxido bridge in the reaction feed solution is from 1:1 to 5: 1.
4. The method according to claim 1, wherein the concentration of the zidovudine oxygen bridge in the reaction raw material solution is 0.1 to 1 mol/L.
5. The method according to claim 1, wherein the concentration of the azidation reagent in the reaction raw material solution is 0.1 to 2 mol/L.
6. The method of claim 1, wherein the azidation reagent is sodium azide.
7. The method of claim 1, wherein the solvent is selected from one or more of water, ethanol, dimethylsulfoxide, and N, N-dimethylformamide.
8. The method of claim 1, wherein, in step (2),
the reaction time is 2-60 minutes; and/or
The reaction temperature is 60-200 ℃, preferably 120-200 ℃; and/or
The reaction pressure is 0.1-1 MPa; and/or
The microchannel reactor is a pipeline micro-reactor or a chip micro-reactor.
9. The method of claim 1, further comprising the steps of:
(3) and dropping the product solution into water, violently stirring, filtering, washing and drying to obtain the zidovudine azide intermediate.
10. The method of claim 1, wherein the reaction feed solution is free of ammonium salts.
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