A method for synthesizing a candesartan cilexetil intermediate

Abstract

The present invention relates to a continuous flow production process for synthesizing candesartan cilexetil intermediates, and belongs to the technical field of fine chemicals. Specifically, a process for continuously preparing 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate using a microchannel reactor is provided, comprising: allowing 2-(chlorocarbonyl)-3-nitrobenzoate and sodium azide to stay in a first reaction module for reaction; then the reaction solution and water simultaneously enter a continuous separator for separation; the separated organic layer reacts with tert-butyl alcohol in a second reaction module to obtain a target product. The method provided by the present invention is safe, simple to operate, efficient, and easy to mass produce.

Description

Technical Field

[0001] The invention relates to a continuous flow production process for synthesizing a candesartan cilexetil intermediate, and belongs to the technical field of application of fine chemical processes in the production of raw materials. Background Art

[0002] Candesartan cilexetil is an effective and highly selective angiotensin II receptor antagonist antihypertensive drug developed by Takeda Pharmaceuticals of Japan and first launched in Sweden in November 1997. Its chemical name is (±)-2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester, and its chemical structure is shown in Formula I:

[0003]

[0004] 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate is a key intermediate in the synthesis of candesartan cilexetil, and its structural formula is shown in Formula II:

[0005]

[0006] Wherein R is methyl or ethyl.

[0007] The synthesis routes of compound (II) reported in the literature (US5196444, WO2011145100, WO2013186792) are mainly as follows:

[0008]

[0009] In the literature, compound (II) is prepared by Curtius rearrangement reaction, where acyl chloride reacts with azide to generate acyl azide, and rearrangement reaction occurs in the presence of tert-butyl alcohol to generate compound (II). Since acyl azide has poor thermal stability and is easily decomposed and exploded, the heat exchange efficiency of the reactor is usually poor. Once the local temperature in the reactor suddenly rises, it is easy to induce a large amount of acyl azide in the reactor to explode, which poses a huge safety hazard; the rearrangement reaction has a very high reaction heat, and requires an extremely slow feeding speed to control heat transfer. The process operation is cumbersome, the production takes a long time, and the production efficiency is low; furthermore, acyl azide is unstable and is easily decomposed to produce products, consume raw materials, and affect product quality. Summary of the invention

[0010] The technical problem to be solved by the present invention is to provide a process for continuously preparing 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate using a microchannel reactor, and to provide a continuous flow production process for candesartan cilexetil intermediates that is safe, simple to operate, efficient, and easy to mass produce.

[0011] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0012] A process for continuously preparing 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate as shown in Formula II using a microchannel reactor,

[0013]

[0014] Wherein R in formula II is methyl or ethyl;

[0015] The following steps are involved:

[0016] 1) injecting the pre-cooled organic solution of 2-(chlorocarbonyl)-3-nitrobenzoate of formula I and the sodium azide solution into the first reaction module of the microchannel reactor through a connecting pipe and leaving them to react; the reaction liquid flowing out of the first reaction module enters a continuous separator together with water for separation;

[0017]

[0018] wherein R in Formula I is defined the same as R in Formula II;

[0019] 2) The organic layer separated by the continuous separator in step 1) is mixed with tert-butanol or tert-butanol solution in the mixing module of the microchannel reactor, and then injected into the second reaction module of the microchannel reactor and allowed to remain there to react to obtain compound II.

[0020] The following is a preferred embodiment of the present invention:

[0021] The reaction temperature in the first reaction module is -10 to 10°C; the reaction temperature in the second reaction module is 75 to 95°C.

[0022] The solvent in the organic solution of 2-(chlorocarbonyl)-3-nitrobenzoate described in step 1 is a non-polar organic solvent, and is further preferably toluene, dichloromethane, chloroform, methyl tert-butyl ether, ethylbenzene, chlorobenzene, and the concentration of the organic solution of 2-(chlorocarbonyl)-3-nitrobenzoate is preferably 0.01 to 3 mol / L.

[0023] The solvent in the sodium azide solution in step 1 is a polar solution, more preferably water, DMF, DMAc, or DMSO. The concentration of the sodium azide solution is preferably 0.01 to 3 mol / L.

[0024] The organic solution of 2-(chlorocarbonyl)-3-nitrobenzoate and the sodium azide solution described in step 1 are pre-cooled to -10 to 5°C respectively.

[0025] The residence time in step 1 is 1 second to 10 minutes, preferably 15 to 60 seconds.

[0026] In step 1, the molar ratio of 2-(chlorocarbonyl)-3-nitrobenzoate to sodium azide in the first microchannel reaction module is 1:1.0 to 1:1.1.

[0027] The continuous separator described in step 1 is a continuous liquid-liquid separation device that utilizes the difference in wettability between a porous membrane and an aqueous phase and an organic phase to separate oil and water, such as Corning's Zaiput high-efficiency liquid-liquid separator.

[0028] In step 2, the molar ratio of 2-(chlorocarbonyl)-3-nitrobenzoate to tert-butanol in the second microchannel reaction module is 1:1.2 to 1:3.

[0029] The solvent in the tert-butanol solution in step 2 is a non-polar organic solvent, more preferably toluene, dichloromethane, chloroform, methyl tert-butyl ether, ethylbenzene, chlorobenzene, and the concentration of the tert-butanol solution is preferably 0.05 to 5 mol / L.

[0030] As in the embodiment of the present invention, the process for continuously preparing 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate using a microchannel reactor comprises the following steps:

[0031] 1) Using a metering pump, the organic solution of 2-(chlorocarbonyl)-3-nitrobenzoate and the sodium azide solution of formula I are respectively injected into two precooling modules of the microchannel reactor for precooling, and then simultaneously enter the first reaction module of the microchannel reactor to stay at -10 to 10° C. for reaction. After the reaction is completed, they enter the continuous separator for separation simultaneously with the water injected by the metering pump;

[0032]

[0033] wherein R in Formula I is defined the same as R in Formula II;

[0034] 2) The water layer from the continuous separator enters the wastewater system, and the organic layer separated from the continuous separator and tert-butanol or tert-butanol solution are simultaneously injected into the mixing module of the microchannel reactor by a metering pump for mixing, and then enter the second reaction module of the microchannel reactor to stay at 75-95° C. for reaction to obtain compound II.

[0035] The microchannel reactor device comprises a storage tank, a mixing module, a cooling module, a continuous liquid-liquid separator and a product collector, wherein the storage tank is connected in series with the hot-cold module, and two precooling or preheating modules are connected in parallel with the mixing module through a pipeline. The reaction raw materials and products are input and output through a syringe pump or an HPLC pump.

[0036] Beneficial effects of the present invention:

[0037] The present invention provides a process for continuously preparing 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate using a microchannel reactor. When the original traditional batch production process performs acyl azide reaction and Curtius rearrangement reaction, an extremely slow feeding speed is required to control heat transfer, and the intermediate acyl azide needs to be produced in advance and stored at a low temperature. Acyl azide is a heat-sensitive substance, which will decompose during the storage process and induce explosion after heat accumulation. The storage and use of acyl azide requires very high storage requirements. If the production process is shut down due to non-resistance factors, the storage of the produced acyl azide will face huge safety hazards; at the same time, if the acyl azide feed is out of control during the production process, a large amount of acyl azide will react violently and cause an explosion, which poses a huge safety hazard.

[0038] The present invention utilizes microchannel continuous flow reaction: 1. Continuous production of acyl azide reaction and Curtius rearrangement reaction is realized, and the immediately generated acyl azide immediately enters the next process with a short residence time, thereby avoiding and eliminating the huge safety hazards in the mass production and storage process of the hazardous material acyl azide; 2. The immediately generated acyl azide undergoes a rearrangement reaction with tert-butyl alcohol without being decomposed, thereby reducing raw material consumption and by-product generation, improving raw material utilization, and greatly improving product quality and yield; 3. Due to the short reaction residence time, the production efficiency and capacity are greatly improved, thereby solving the production bottleneck problem that the acyl azide reaction and the Curtius rearrangement reaction require extremely slow feeding.

[0039] The present invention realizes continuous, efficient, safe and atom-economical industrial production through microchannel technology, has simple preparation process, mild conditions, short residence time, stable product quality and high yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 :Microchannel process flow chart of the present invention DETAILED DESCRIPTION

[0041] In order to make the purpose, technical scheme, and advantages of the present application more clearly understood, the present application is further described in detail through the following embodiments. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present application.

[0042] Common test methods for this application:

[0043] Instrument: High performance liquid chromatograph equipped with UV detector;

[0044] Chromatographic column: Agilent XDB C8 250*4.6mm 5μm or equivalent;

[0045] Buffer solution: 1.36 g potassium dihydrogen phosphate dissolved in 1000 ml water, and adjusted to pH 2.5 with concentrated phosphoric acid;

[0046] Mobile phase A: buffer: acetonitrile = 60:40 (V / V);

[0047] Mobile phase B: buffer: acetonitrile = 15:85 (V / V);

[0048] Flow rate: 1.0 ml / min; Column temperature: 30°C;

[0049] Injection volume: 10 μl; Detection wavelength: 210 nm;

[0050] Gradient table:

[0051]

[0052] Example 1

[0053] Synthesis of Ethyl 2-((tert-Butoxycarbonyl)amino)-3-nitrobenzoate

[0054] Dissolve ethyl 2-(chlorocarbonyl)-3-nitrobenzoate in a non-polar organic solvent to prepare a 1 mol / L solution, and dissolve sodium azide in a polar solvent to prepare a 0.5 mol / L solution; in a continuous flow reactor, pass the ethyl 2-(chlorocarbonyl)-3-nitrobenzoate solution through a first precooling module using a metering pump (flow rate 1 mL / s), and the temperature of the precooling medium is controlled at 0°C; pass the sodium azide solution through a second precooling module using a metering pump (flow rate 2 mL / s), and the precooling medium is controlled at 0°C; after the two solutions are mixed, they pass through a first reaction module at 0°C within 30 seconds; drinking water passes through a third precooling module using a metering pump (flow rate 1 mL / s), and the precooling medium is controlled at 2°C. After the feed liquid is output from the first reaction module, it is mixed with the drinking water that has passed through the precooling module and enters a continuous flow separator, and the organic phase is collected and output.

[0055] Tert-butyl alcohol was dissolved in a non-polar organic solvent to 1 mol / L, and was input into the mixing module by a metering pump (1.5 mL / s). The organic liquid flowing out of the continuous separator in the previous step was simultaneously input into the mixing module by a metering pump (1 mL / s), and then passed through the second reaction module at 85°C within 30 seconds. The second reaction module was equipped with a gas overflow device. The liquid output from the second reaction module was concentrated and post-processed with ethanol crystallization to obtain 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate. The yield and quality of the two steps are as follows:

[0056] Serial number Non-polar organic solvents Polar solvents Two-step yield purity 1 Toluene DMF 95％ 99.4％ 2 Toluene water 90％ 98.8％ 3 Toluene DMSO 92％ 97.8％ 4 Dichloromethane DMF 86％ 89.3％ 5 Chloroform DMF 91％ 98.2％ 6 Methyl tert-butyl ether DMF 88％ 97.4％ 7 Ethylbenzene DMF 91％ 99.0％ 8 chlorobenzene DMF 90％ 98.6％

[0057] Example 2

[0058] Synthesis of Ethyl 2-((tert-Butoxycarbonyl)amino)-3-nitrobenzoate

[0059] Dissolve ethyl 2-(chlorocarbonyl)-3-nitrobenzoate in toluene to prepare a toluene solution, and dissolve sodium azide in water to prepare an aqueous solution; in a continuous flow reactor, use a metering pump to pass the ethyl 2-(chlorocarbonyl)-3-nitrobenzoate toluene solution through the first precooling module at a flow rate of 1 mL / s, and the temperature of the precooling medium is controlled at 0°C; use a metering pump to pass the sodium azide DMF solution through the second precooling module at a flow rate of 1 mL / s, and the precooling medium is controlled at 0°C; after the two solutions are mixed, they pass through the first reaction module at 0°C within 30 seconds; use a metering pump to pass the drinking water through the third precooling module at a flow rate of 0.5 mL / s, and the precooling medium is controlled at 2°C. After the feed liquid is discharged from the first reaction module, it is mixed with the drinking water that has passed through the precooling module and enters a continuous flow separator, and the organic phase is collected and discharged.

[0060] Tert-butyl alcohol was dissolved in toluene and fed into the mixing module at a flow rate of 1 mL / s using a metering pump. The organic phase obtained above was simultaneously fed into the mixing module and then passed through the second reaction module at 90°C within 30 seconds. The second reaction module was equipped with a gas overflow device. The feed liquid output from the second reaction module was concentrated and post-processed with ethanol crystallization to obtain ethyl 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate. The two-step yield and quality are as follows:

[0061]

[0062] Example 3

[0063] Synthesis of Methyl 2-((tert-Butyloxycarbonyl)amino)-3-nitrobenzoate

[0064] Dissolve methyl 2-(chlorocarbonyl)-3-nitrobenzoate in toluene to prepare a 0.5 mol / L solution, and dissolve sodium azide in water to prepare a 0.5 mol / L solution; in a continuous flow reactor, pass the ethyl 2-(chlorocarbonyl)-3-nitrobenzoate solution through the first precooling module with a metering pump (flow rate 1 mL / s), and the temperature of the precooling medium is controlled to be 0°C; pass the sodium azide solution through the second precooling module with a metering pump (flow rate 1 mL / s), and the precooling medium is controlled to be 0°C; after the two solutions are mixed, pass through the first reaction module at 0°C within 30 seconds; drink water passes through the third precooling module with a metering pump (flow rate 0.5 mL / s), and the precooling medium is controlled to be 2°C. After the feed liquid is output from the first reaction module, it is mixed with the drink water that has passed through the precooling module and enters the continuous flow separator, and the organic phase is collected and output.

[0065] Tert-butyl alcohol was dissolved in toluene to a concentration of 0.6 mol / L, and was fed into a mixing module by a metering pump (1 mL / s). The organic liquid discharged from the continuous separator in the previous step was simultaneously fed into the mixing module by a metering pump (1 mL / s), and then passed through a second reaction module at 90° C. within 30 seconds. The second reaction module was equipped with a gas overflow device. The liquid output from the second reaction module was concentrated and post-processed with ethanol crystallization to obtain methyl 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate, with a two-step yield of 92% and a purity of 96.5%.

[0066] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present application shall be included in the scope of protection of the present application.

Claims

1. A method for continuously preparing 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate of formula II using a microchannel reactor, Wherein R in formula II is methyl or ethyl; The following steps are involved: 1) injecting the pre-cooled organic solution of 2-(chlorocarbonyl)-3-nitrobenzoate of formula I and the sodium azide solution into the first reaction module of the microchannel reactor through a connecting pipe and leaving them to react; the reaction liquid flowing out of the first reaction module enters a continuous separator together with water for separation; wherein R in Formula I is defined the same as R in Formula II; 2) The organic layer separated by the continuous separator in step 1) is mixed with the tert-butyl alcohol solution in the mixing module of the microchannel reactor, and then injected into the second reaction module of the microchannel reactor and allowed to remain there for reaction to obtain compound II; The solvent in the organic solution of 2-(chlorocarbonyl)-3-nitrobenzoate in step 1 is a non-polar organic solvent, and the non-polar organic solvent is selected from toluene, dichloromethane, chloroform, methyl tert-butyl ether, ethylbenzene, and chlorobenzene; The solvent in the sodium azide solution in step 1 is a polar solvent, and the polar solvent is selected from water, DMF, DMAc, and DMSO; The solvent in the tert-butyl alcohol solution in step 2 is a non-polar organic solvent, and the non-polar organic solvent is toluene, dichloromethane, chloroform, methyl tert-butyl ether, ethylbenzene, or chlorobenzene; The reaction temperature in the first reaction module is -10 to 10°C; the reaction temperature in the second reaction module is 75 to 95°C; The molar ratio of 2-(chlorocarbonyl)-3-nitrobenzoate to tert-butanol in the second microchannel reaction module in step 2 is 1:1.2 to 1:

3.

2. The method according to claim 1, wherein the concentration of the organic solution of 2-(chlorocarbonyl)-3-nitrobenzoate in step 1 is 0.01 to 3 mol / L.

3. The method according to claim 1, wherein the concentration of the sodium azide solution in step 1 is 0.01 to 3 mol / L.

4. The method according to claim 1, wherein the organic solution of 2-(chlorocarbonyl)-3-nitrobenzoate and the sodium azide solution in step 1 are pre-cooled to -10 to 5°C, respectively.

5. The method according to claim 1, wherein the residence time in step 1 is 1 second to 10 minutes.

6. The method according to claim 5, wherein the residence time in step 1 is 15 to 60 seconds.

7. The method according to claim 1, wherein in step 1, the molar ratio of 2-(chlorocarbonyl)-3-nitrobenzoate to sodium azide in the first microchannel reaction module is 1:1.0 to 1:1.

1.

8. The method according to claim 1, wherein the concentration of the tert-butyl alcohol solution in step 2 is 0.05-5 mol / L.

9. The method according to claim 1, comprising the steps of: 1) Using a metering pump, the organic solution of 2-(chlorocarbonyl)-3-nitrobenzoate and the sodium azide solution of formula I are respectively injected into two precooling modules of the microchannel reactor for precooling, and then simultaneously enter the first reaction module of the microchannel reactor to stay at -10 to 10° C. for reaction. After the reaction is completed, they enter the continuous separator for separation simultaneously with the water injected by the metering pump; wherein R in Formula I is defined the same as R in Formula II; 2) The water layer from the continuous separator enters the wastewater system, and the organic layer and the tert-butanol solution separated from the continuous separator are simultaneously injected into the mixing module of the microchannel reactor by a metering pump for mixing, and then enter the second reaction module of the microchannel reactor to stay at 75-95° C. for reaction to obtain compound II.

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