Purification process method of 2-bromo-6-methoxypyridine

Abstract

The invention discloses a purification process of 2-bromo-6-methoxypyridine, and belongs to the technical field of chemical pharmacy. The process comprises a synthetic reaction and a two-stage rectification step: firstly, methanol, sodium hydroxide and 2, 6-dibromopyridine react to obtain a mixture; then separating through a first rectifying tower at normal pressure and 300-310 DEG C, and fractionating 2-bromo-6-methoxypyridine as a light component; and refining in a second rectifying tower at the temperature of 200-210 DEG C under normal pressure to obtain a high-purity product as a heavy component. By optimizing parameters such as the number of feeding tower plates and the reflux ratio, the purity of the product can reach 99% or above, the yield is about 92%, and the process is short and efficient and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical preparation technology, and specifically relates to a purification process for 2-bromo-6-methoxypyridine. Background Technology

[0002] With the development of my country's pharmaceutical research industry, the purity requirements for various pharmaceutical chemicals are gradually increasing. Due to its superior chemical structure, 2-bromo-6-methoxypyridine, as a heterocyclic aromatic hydrocarbon product, is widely used in the preparation of various pharmaceuticals, and its purity has a significant impact on the yield of these drugs.

[0003] No industrially applicable purification processes for 2-bromo-6-methoxypyridine have been reported. This purification process is the first to design an industrially applicable purification scheme with a purity of over 99%. Summary of the Invention

[0004] To address the shortcomings of existing technologies, the purpose of this invention is to provide a purification process for 2-bromo-6-methoxypyridine to improve the yield of the drug. This process features a short process flow, high product purity, and excellent quality.

[0005] The technical solution adopted in this invention is: a purification process for 2-bromo-6-methoxypyridine, the key technical points of which include the following steps: (1) First-stage distillation separation: The reaction mixture containing 2-bromo-6-methoxypyridine and 2,6-dibromopyridine is fed into the first distillation column for separation, wherein 2-bromo-6-methoxypyridine is distilled off from the top of the column as a light component and 2,6-dibromopyridine is discharged from the bottom of the column as a heavy component; the operating pressure of the first distillation column is atmospheric pressure and the bottom temperature is 300-310℃.

[0006] (2) Secondary distillation purification: The distillate obtained in step (1) is fed into a second distillation column for purification, wherein 2-bromo-6-methoxypyridine is discharged from the bottom of the column as a heavy component to obtain a high-purity 2-bromo-6-methoxypyridine product; the operating pressure of the second distillation column is atmospheric pressure and the bottom temperature is 200-220℃.

[0007] In the above scheme, before step (1), a synthesis reaction step is also included: methanol, sodium hydroxide and 2,6-dibromopyridine are added to a reaction vessel and reacted at 80-90°C and atmospheric pressure for 5-7 hours to obtain the reaction mixture containing 2-bromo-6-methoxypyridine and 2,6-dibromopyridine.

[0008] In the above scheme, the molar ratio of methanol, sodium hydroxide and 2,6-dibromopyridine in the synthesis reaction step is (1.2-1.3):(1.2-1.3):1.

[0009] In the above scheme, in step (1), the number of feed trays of the first distillation column is the 4th to 13th trays, and the reflux ratio is 1.6 to 3.4.

[0010] In the above scheme, in step (2), the number of feed trays of the second distillation column is the 4th to 11th trays, and the reflux ratio is 1.4 to 2.2.

[0011] A high-purity 2-bromo-6-methoxypyridine product, the key technical feature of which is that it is prepared by the purification process described in any one of claims 1 to 5, and its purity is ≥99%.

[0012] The beneficial effects of this invention are as follows: This purification process for 2-bromo-6-methoxypyridine is the first to design a complete and industrially scalable purification scheme for 2-bromo-6-methoxypyridine, solving the industrialization problem of high-purity preparation of this product. By performing primary separation and secondary purification on the product produced in the product reactor, the purity of the 2-bromo-6-methoxypyridine product is improved. The original purification process uses chlorine dioxide to extract the target product, followed by distillation in a distillation column, achieving a maximum purity of 97%. This patent provides a more efficient process, increasing product purity by over 99%. Attached Figure Description

[0013] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0014] Figure 1 This is a flowchart of a purification process for 2-bromo-6-methoxypyridine according to the present invention; The numbers in the diagram are explained as follows: 1 - Reactor, 11 - Reactor feed pipe, 12 - Reactor discharge pipe, 2 - First distillation column, 21 - First distillation column top discharge pipe, 22 - First distillation column bottom discharge pipe, 3 - Second distillation column, 31 - Second distillation column top discharge pipe, 32 - Second distillation column bottom discharge pipe. Detailed Implementation

[0015] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the following description is provided in conjunction with the accompanying drawings. Figure 1 The present invention will be further described in detail below with reference to specific embodiments.

[0016] The purification system in this embodiment mainly includes a reactor 1, a first distillation column 2, and a second distillation column 3. The raw material liquid enters the reactor 1 through the reactor feed pipe 11. The reactor discharge pipe 12 is connected to the first distillation column 2. The bottom outlet of the first distillation column 2 is discharged through the bottom outlet pipe 22. The top outlet of the second distillation column is discharged through the top outlet pipe 21 of the first distillation column and is connected to the feed inlet of the second distillation column 3. The top distillate of the second distillation column 3 is discharged through the top outlet pipe 31 of the second distillation column, and the bottom distillate is discharged through the bottom outlet pipe 32 of the second distillation column.

[0017] The purification process for 2-bromo-6-methoxypyridine includes: The reactants enter reactor 1 through feed pipe 11 for synthesis. After complete reaction, the product is discharged through reactor outlet pipe 12 and enters the first distillation column 2. After processing in the first distillation column 2, 2-bromo-6-methoxypyridine containing impurities is distilled off at the top of the column, while other heavy components such as 2,6-dibromopyridine are discharged through bottom outlet pipe 22. 2-bromo-6-methoxypyridine and unreacted 2,6-dibromopyridine are thus separated. The distillate from the top of the first distillation column 2 enters the second distillation column 3 through top outlet pipe 21. After purification, impurities are discharged through top outlet pipe 31 of the second distillation column, while high-purity 2-bromo-6-methoxypyridine is discharged through bottom outlet pipe 32 of the second distillation column. Example 1:

[0018] First-stage distillation separation: In this embodiment, methanol, 2,6-dibromopyridine, and sodium hydroxide are used as feed solutions and fed into reactor 1 through reactor inlet 11 for synthesis reaction. The reaction is carried out at 85°C and atmospheric pressure, with a residence time of 6 hours. The feed amounts of each material are shown in Table 1. Table 1 shows the material allocation table. name Input unit methanol 1.25 Kmol / h Sodium hydroxide 1.25 Kmol / h 2,6-Dibromopyridine 1 Kmol / h After the reaction is complete, the resulting mixture contains 2-bromo-6-methoxypyridine, sodium bromide, water, and unreacted 2,6-dibromopyridine, methanol, and sodium methoxide, as shown in Table 2. This mixture enters the first distillation column 2 via discharge pipe 2. The first distillation column 2 is an atmospheric pressure column with a pressure of 101 kPa and a designed reflux ratio of 2.2. The mixture is separated in this column. Light components such as 2-bromo-6-methoxypyridine, water, and methanol are distilled from the top of the column and enter the next process via the discharge pipe 21 at the top of the first distillation column. Heavy components such as 2,6-dibromopyridine and sodium bromide are discharged from the bottom of the first distillation column 2 via the discharge pipe 22.

[0019] Table 2 shows the feed table for the first distillation column. name Yield unit methanol 0.32 Kmol / h Sodium hydroxide 0.32 Kmol / h 2,6-Dibromopyridine 0.07 Kmol / h 2-Bromo-6-methoxypyridine 0.93 Kmol / h water 0.93 Kmol / h Sodium bromide 0.93 Kmol / h Table 3 shows that when the number of feed trays is less than 4, separation is insufficient, and heavy components are easily carried to the top of the column, resulting in a low yield of the target product (e.g., the yield is only 0.7566 Kmol / h at the second tray). When the number of feed trays reaches 4, the yield significantly increases to 0.7782 Kmol / h; continuing to increase to the fifth tray, the yield is 0.7794 Kmol / h; thereafter, further increasing the number of trays (6th to 10th trays) stabilizes the yield at around 0.7799 Kmol / h. This indicates that after the number of trays reaches 4, the separation efficiency is close to its limit, and further increasing the number of trays no longer significantly improves the yield and increases equipment costs. Therefore, selecting the 4th to 13th trays as the feed location is the preferred range that combines high efficiency and economy.

[0020] Table 3 shows the correspondence between the number of feed trays and the target product content of the first distillation column. Number of feed trays 2-Bromo-6-methoxypyridine yield (Kmol / h) 2 0.7566 3 0.7736 4 0.7782 5 0.7794 6 0.7798 7 0.7799 8 0.7799 9 0.7799 10 0.7799 As shown in Table 4, when the reflux ratio is below 1.6, the separation efficiency is insufficient, and the yield of the target product is relatively low (e.g., the yield is 0.7777 Kmol / h when the reflux ratio is 1.0). When the reflux ratio is increased to 1.6, the yield increases significantly to 0.7794 Kmol / h. Further increasing the reflux ratio to 2.2 yields 0.7796 Kmol / h; subsequently, further increasing the reflux ratio to 3.4 stabilizes the yield at around 0.7797 Kmol / h. This indicates that after the reflux ratio reaches 1.6, the separation efficiency approaches its optimum, and further increasing the reflux ratio contributes very little to the yield increase (less than 0.04%), but significantly increases the column load and energy consumption. Therefore, selecting a reflux ratio range of 1.6-3.4 can achieve the best balance between energy consumption and yield while ensuring high separation efficiency.

[0021] Table 4 shows the correspondence between the reflux ratio and the target product content in the first distillation column. reflux ratio 2-Bromo-6-methoxypyridine yield (Kmol / h) 1 0.7777 1.2 0.7789 1.4 0.7792 1.6 0.7794 1.8 0.7795 2 0.7795 2.2 0.7796 2.4 0.7796 2.6 0.7796 2.8 0.7797 3 0.7797 3.2 0.7797 3.4 0.7797 Experiments determined that the optimal separation effect was achieved when the first distillation column was fed from the fifth theoretical tray and the reflux ratio was 2.2. Under these conditions, the reboiler temperature was set to 306°C. At this temperature, the higher-boiling-point heavy components, such as 2,6-dibromopyridine, remained in a flowing liquid state in the reboiler and were discharged from the system through the reboiler outlet pipe 22. Simultaneously, the column top temperature was stabilized at approximately 96°C, allowing the lower-boiling-point components, such as 2-bromo-6-methoxypyridine, water, and unreacted methanol, to fully vaporize and distill off from the top of the column, thus achieving efficient separation of 2-bromo-6-methoxypyridine from the heavy components. This embodiment achieved the optimal separation yield under these conditions.

[0022] The principle of the two-stage distillation purification in this embodiment is as follows: light component impurities, mainly methanol and water, are deeply removed from the top distillate of the first distillation column using the second distillation column, thereby obtaining high-purity 2-bromo-6-methoxypyridine.

[0023] Feed composition: The feed originates from the top of the first column and mainly consists of 2-bromo-6-methoxypyridine (boiling point ~205℃), methanol (boiling point 64.7℃), and water (boiling point 100℃). In this ternary system, the boiling points of methanol and water are significantly lower than those of the target product. During the second-stage distillation, the low-boiling-point methanol and water tend to accumulate at the top of the column, while the higher-boiling-point 2-bromo-6-methoxypyridine accumulates in the bottom. By controlling the reflux ratio and the number of trays, sufficient removal of methanol and water can be achieved, ensuring that the target product achieves a purity of over 99% in the bottom. In this embodiment, the bottom temperature is controlled at 200-210℃, slightly lower than the atmospheric boiling point of the target product (205℃), ensuring sufficient heat in the bottom to maintain the 2-bromo-6-methoxypyridine in a liquid state while providing sufficient vapor reflux. Excessively low temperatures may lead to excessively high material viscosity or solidification, clogging the discharge pipe, while also ensuring sufficient vapor reflux. At the same time, avoid excessively high temperatures, such as >230℃, which could lead to unnecessary vaporization, affecting the yield and composition at the top of the column.

[0024] In this embodiment, the distillate from the top of the first distillation column 2 enters the second distillation column 3 for purification through the top discharge pipe 21 of the first distillation column 2. The second distillation column 3 is also an atmospheric pressure column with a design pressure of 101 kPa, a reflux ratio of 1.4, and a bottom temperature of 201°C. In this column, water, methanol, etc., as light components, are discharged from the top discharge pipe 31 of the second distillation column 3, while high-purity 2-bromo-6-methoxypyridine, as a heavy component, is discharged from the bottom discharge pipe 32 of the second distillation column 3. The feed composition is shown in Table 5. After separation in the second purification column 3, 2-bromo-6-methoxypyridine, as a heavy component, is distilled from the bottom of the column, while water and methanol, as light components, are distilled from the top of the second distillation column.

[0025] Table 5 shows the material list for the second distillation column. name Feed rate Output unit methanol 0.32 0.0000 Kmol / h Sodium hydroxide 0.0000 0.0000 Kmol / h 2,6-Dibromopyridine 0.0002 0.0002 Kmol / h 2-Bromo-6-methoxypyridine 0.7798 0.7786 Kmol / h water 0.93 0.0047 Kmol / h Sodium bromide 0.0000 0.0000 Kmol / h This embodiment observes the effect of changing the number of trays and reflux ratio of the second distillation column 3 on the yield (Kmol / h) of the target product 2-bromo-6-methoxypyridine. The comparison results are shown in Tables 6 and 7 below: Table 6. Correspondence between the number of feed trays and the target product content of the second distillation column. Number of feed trays 2-Bromo-6-methoxypyridine yield (Kmol / h) 2 0.4987 3 0.7534 4 0.7786 5 0.7797 6 0.7797 7 0.7797 8 0.7797 9 0.7798 10 0.7798 11 0.7798 12 0.7798 13 0.7798 The product yield reaches a stable plateau of 0.7786-0.7798 Kmol / h, indicating that efficient separation can be achieved within this range. If the feed position exceeds the 11th plate (such as the 12th or 13th plate), the separation of light components may be less thorough due to the relatively insufficient number of theoretical plates in the rectification section, potentially leading to a slight decrease in yield. Based on the data in Tables 6 and 7, when the feed plate number is 4 and the reflux ratio is 1.4, the system has reached the optimal plateau for separation performance with lower energy consumption. Therefore, this condition is selected as the preferred operating condition for this embodiment.

[0026] Table 7. Correspondence between reflux ratio and target product content in the second distillation column. reflux ratio 2-Bromo-6-methoxypyridine yield 1.2 0.7689 1.3 0.7738 1.4 0.7761 1.5 0.7772 1.6 0.7779 1.7 0.7783 1.8 0.7786 1.9 0.7788 2 0.7789 2.1 0.7791 2.2 0.7791 As shown in Table 7, when the reflux ratio is below 1.4, the gas-liquid mass transfer within the column is relatively insufficient, and the removal of light components is not thorough, resulting in a low product yield (e.g., a yield of 0.7689 Kmol / h at a reflux ratio of 1.2). When the reflux ratio reaches 1.4, the yield significantly increases to 0.7761 Kmol / h, reaching a relatively optimal level. Further increasing the reflux ratio will still result in a slow increase in yield (e.g., to 0.7791 Kmol / h at a reflux ratio of 2.2), but the rate of increase will decrease significantly, exhibiting a trend of diminishing marginal returns. At the same time, a higher reflux ratio will significantly increase the liquid load within the column, as well as the energy consumption of the reboiler and condenser. Therefore, selecting a reflux ratio range of 1.4-2.2 can achieve a good engineering balance between yield improvement and energy consumption control while ensuring product purity ≥99%.

[0027] Finally, based on the content calculation of the product in the bottom of the tower in Table 5, it can be seen that 2-bromo-6-methoxypyridine with a purity of over 99% can be obtained by the above process.

[0028] Results: Gas chromatography (GC) analysis showed that the purity of 2-bromo-6-methoxypyridine in the product obtained in this experiment was 99.37%. Example 2:

[0029] 1.20 kmol / h of methanol, 1.20 kmol / h of sodium hydroxide, and 1.00 kmol / h of 2,6-dibromopyridine were added to a reaction vessel. The reaction was carried out at 85°C and atmospheric pressure for 6 hours.

[0030] First-stage distillation separation: The bottom temperature of the first distillation column is controlled at 310°C, the feed tray number of the first distillation column 2 is the 4th, and the reflux ratio is 1.6. The remaining conditions are the same as in Example 1.

[0031] Secondary distillation purification: The bottom temperature of the second distillation column is controlled at 205°C, the feed tray number of the second distillation column 3 is the 5th, and the reflux ratio is 1.5. The remaining conditions are the same as in Example 1.

[0032] GC analysis showed that the purity of the product obtained in this experiment was 99.87%. Example 3:

[0033] 1.30 kmol / h of methanol, 1.30 kmol / h of sodium hydroxide, and 1.00 kmol / h of 2,6-dibromopyridine were added to a reaction vessel. The reaction was carried out at 85°C and atmospheric pressure for 6 hours.

[0034] First-stage distillation separation: The bottom temperature of the first distillation column is controlled at 305°C, the feed tray number of the first distillation column 2 is the 6th, and the reflux ratio is 3.4. The remaining conditions are the same as in Example 1.

[0035] Secondary distillation purification: The bottom temperature of the second distillation column is controlled at 210℃, the feed tray number of the second distillation column 3 is the 4th, and the reflux ratio is 1.4. The remaining conditions are the same as in Example 1.

[0036] Results: GC analysis showed that the purity of the product obtained in this experiment was 99.93%.

[0037] Comparative Example 1 (insufficient number of trays in the first distillation column): 1.25 Kmol / h methanol, 1.25 Kmol / h sodium hydroxide and 1 Kmol / h 2,6-dibromopyridine were added to reactor 1 and reacted at 85°C and atmospheric pressure for 6 hours.

[0038] First-stage distillation separation: The feed tray number of the first distillation column is the second (deviating from optimal conditions), and the reflux ratio is 2.2. The remaining conditions are the same as in Example 1.

[0039] Secondary distillation purification: Same as in Example 1.

[0040] GC analysis showed that the purity of the product obtained in this experiment was 98.50%, and the yield was 89.63%. The results indicate that insufficient primary separation led to more impurities entering the secondary distillation, resulting in a significant decrease in the purity of the final product.

[0041] Comparative Example 2 (insufficient reflux ratio in second-stage distillation): 1.25 Kmol / h methanol, 1.25 Kmol / h sodium hydroxide and 1 Kmol / h 2,6-dibromopyridine were added to reactor 1 and reacted at 85°C and atmospheric pressure for 6 hours.

[0042] First-stage distillation separation: Same as in Example 1.

[0043] Secondary distillation purification: The feed tray number of the second distillation column is the 4th tray, and the reflux ratio is 1.2 (deviation from optimal conditions). The remaining conditions are the same as in Example 1.

[0044] GC analysis showed that the purity of the product obtained in this experiment was 98.80%. The results indicate that insufficient reflux ratio during the purification stage reduced separation efficiency, leading to substandard product purity.

[0045] Under the optimal operating conditions of the examples, the present invention conducted three repeated experiments, obtaining 2-bromo-6-methoxypyridine products with purities of 99.91%, 99.87%, and 99.93%, respectively, with an average purity of 99.90% and a stable yield of approximately 92%. However, the comparative examples show that when the number of trays, reflux ratio, and other key parameters deviate from the optimal range determined by the present invention, both product purity and yield decrease significantly.

[0046] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A purification process for 2-bromo-6-methoxypyridine, characterized in that, Includes the following steps: (1) First-stage distillation separation: The reaction mixture containing 2-bromo-6-methoxypyridine and 2,6-dibromopyridine is fed into the first distillation column for separation, wherein 2-bromo-6-methoxypyridine is distilled off from the top of the column as a light component, and 2,6-dibromopyridine is discharged from the bottom of the column as a heavy component; the operating pressure of the first distillation column is atmospheric pressure, and the bottom temperature is 300-310℃; (2) Secondary distillation purification: The distillate obtained in step (1) is fed into a second distillation column for purification, wherein 2-bromo-6-methoxypyridine is discharged from the bottom of the column as a heavy component to obtain a high-purity 2-bromo-6-methoxypyridine product; the operating pressure of the second distillation column is atmospheric pressure and the bottom temperature is 200-210℃.

2. The purification process for 2-bromo-6-methoxypyridine according to claim 1, characterized in that, Before step (1), a synthesis reaction step is also included: methanol, sodium hydroxide and 2,6-dibromopyridine are added to a reaction vessel and reacted at 80-90°C and atmospheric pressure for 5-7 hours to obtain the reaction mixture containing 2-bromo-6-methoxypyridine and 2,6-dibromopyridine.

3. The purification process for 2-bromo-6-methoxypyridine according to claim 2, characterized in that, In the synthesis reaction step, the molar ratio of methanol, sodium hydroxide and 2,6-dibromopyridine is (1.2-1.3):(1.2-1.3):

1.

4. The purification process for 2-bromo-6-methoxypyridine according to claim 1, characterized in that, In step (1), the number of feed trays of the first distillation column is the 4th to 13th trays, and the reflux ratio is 1.6 to 3.

4.

5. The purification process for 2-bromo-6-methoxypyridine according to claim 1, characterized in that, In step (2), the number of feed trays of the second distillation column is the 4th to 11th trays, and the reflux ratio is 1.4 to 2.

2.

6. A high-purity 2-bromo-6-methoxypyridine product, characterized in that, It is prepared by any one of the purification processes described in claims 1 to 5, and its purity is ≥99%.

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