A method for separating methoxylamine hydrochloride from ammonium chloride

Abstract

This invention belongs to the field of methoxyamine hydrochloride preparation technology and discloses a method for separating methoxyamine hydrochloride and ammonium chloride. The method involves cooling a mixed solution containing ammonium chloride and methoxyamine hydrochloride to selectively crystallize out ammonium chloride, which is then separated to obtain ammonium chloride crystals and a mother liquor enriched with methoxyamine hydrochloride. The mother liquor is then concentrated or dissolved by heating, followed by ultra-low temperature crystallization, separation, and drying to obtain methoxyamine hydrochloride crystals. This invention uses ultra-low temperature segmented crystallization to selectively precipitate ammonium chloride, resulting in methoxyamine hydrochloride crystals with a purity ≥99.9% and ammonium chloride crystals with a purity ≥98%.

Description

Technical Field

[0001] This invention relates to the field of methoxyamine hydrochloride preparation technology, and more particularly to a method for separating methoxyamine hydrochloride from ammonium chloride. Background Technology

[0002] Methoxyamine hydrochloride is an important pharmaceutical and chemical intermediate, primarily used in the production of pharmaceuticals and pesticides. The hydrolysis of oxime ethers to synthesize methoxyamine hydrochloride readily produces ammonium chloride, which becomes interfering with methoxyamine hydrochloride and is difficult to separate, significantly impacting the purity of the methoxyamine hydrochloride. Since the pharmaceutical industry generally requires high purity of methoxyamine hydrochloride, separating the ammonium chloride doping from methoxyamine hydrochloride is of great importance for its application in the pharmaceutical industry.

[0003] CN114920665B discloses a method for separating methoxyamine hydrochloride and N-methylmethoxyamine hydrochloride. It mentions that current industrial production processes use distillation for purification, primarily by adding an alkaline aqueous solution such as sodium hydroxide to a mixture containing methoxyamine hydrochloride and N-methylmethoxyamine hydrochloride to neutralize the hydrochloric acid, releasing methoxyamine and N-methylmethoxyamine. This is then further separated and purified by high-efficiency distillation. However, methoxyamine and N-methylmethoxyamine readily form explosive reactions with air, requiring nitrogen protection throughout the distillation process, posing a serious safety hazard. Several explosions have occurred in actual production, leading to factory shutdowns.

[0004] CN113185426A discloses a purification method for methoxyamine hydrochloride, which mentions that by utilizing the principle of the different solubilities of methoxyamine hydrochloride and inorganic salts in organic solvents, the inorganic salt is precipitated by adding organic solvent, and then the inorganic salt is removed by filtration using a hydrophilic polysulfone microporous filter membrane. After evaporating the organic solvent, the purified methoxyamine hydrochloride is obtained by crystallization.

[0005] CN103990382B discloses a method for separating methoxyamine from a distillate using electrodialysis. The specific process involves: filtering the methoxyamine distillate through a micropore filtration system; pumping the solution into either the salt chamber or the salt / dilute chamber of a bipolar membrane electrodialysis device; injecting an electrolyte solution of a certain concentration into the other chambers; connecting the cathode and anode of the device to the negative and positive terminals of a DC power supply, respectively; starting the bipolar membrane electrodialysis device; and controlling the current density of its DC electric field to be 10~150 A / m. 2 At temperatures ranging from 5 to 30°C, a methoxyamine solution is obtained in the acid chamber, with a recovery rate exceeding 95% and a current efficiency of approximately 70%. However, the presence of current in the electrodialysis method can lead to partial decomposition of the methoxyamine, affecting the yield and posing safety hazards.

[0006] Therefore, how to provide a method for separating methoxyamine hydrochloride from ammonium chloride is an urgent problem to be solved. Summary of the Invention

[0007] The purpose of this invention is to provide a method for separating methoxyamine hydrochloride and ammonium chloride, thereby solving the aforementioned problems in the prior art.

[0008] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for separating methoxyamine hydrochloride and ammonium chloride, comprising the following steps: (1) Cool the mixed solution containing ammonium chloride and methoxyamine hydrochloride to a first temperature to allow ammonium chloride to selectively crystallize out, and then separate it to obtain ammonium chloride crystals and a mother liquor enriched with methoxyamine hydrochloride; (2) The mother liquor enriched with methoxyamine hydrochloride is heated to a second temperature for concentration or precipitation to obtain methoxyamine hydrochloride crystals and concentrated solution; (3) Cool the concentrate to the third temperature, perform ultra-low temperature crystallization, and then separate and dry to obtain methoxyamine hydrochloride crystals.

[0009] Preferably, the first temperature in step (1) is -60~-40℃.

[0010] Preferably, the cooling rate in step (1) is 0.5~5℃ / min.

[0011] Preferably, the separation in step (1) is vacuum filtration or centrifugal filtration.

[0012] Preferably, the second temperature in step (2) is 0~25℃.

[0013] Preferably, the heating rate in step (2) is 1~10℃ / min.

[0014] Preferably, the method of dissolution in step (2) is to add a polar alcohol solvent as a dissolution agent for crystallization; the polar alcohol solvent is methanol, ethanol, n-propanol or isopropanol.

[0015] Preferably, the vacuum degree of the concentration in step (2) is -0.09 MPa.

[0016] Preferably, the third temperature in step (3) is -120~-60℃.

[0017] As can be seen from the above technical solution, compared with the prior art, the present invention has the following beneficial effects: (1) Methoxyamine hydrochloride is easily decomposed by heating, which poses a risk of explosion. The temperature of the entire process of this invention does not exceed 40°C, making it safer. (2) The solubility of ammonium chloride drops sharply at ultra-low temperatures, while methoxyamine hydrochloride still has high solubility. A single cooling can effectively separate methoxyamine hydrochloride and ammonium chloride, improving the purity of methoxyamine hydrochloride. The ultra-low temperature range of -120~-60℃ can further precipitate methoxyamine hydrochloride, improving the yield. (3) The methoxyamine hydrochloride obtained by ultra-low temperature crystallization has high purity and does not require recrystallization; (4) Synergistic dissolution / concentration, the mother liquor can be directly recycled and reused, and the solvent utilization rate is high; (5) Low-temperature slow crystallization can produce crystals with uniform particle size and good crystal form, which is beneficial for centrifugation. After centrifugation, the moisture content is low, reducing drying energy consumption. Detailed Implementation

[0018] This invention provides a method for separating methoxyamine hydrochloride and ammonium chloride, comprising the following steps: (1) Cool the mixed solution containing ammonium chloride and methoxyamine hydrochloride to a first temperature to allow ammonium chloride to selectively crystallize out, and then separate it to obtain ammonium chloride crystals and a mother liquor enriched with methoxyamine hydrochloride; (2) The mother liquor enriched with methoxyamine hydrochloride is heated to a second temperature for concentration or precipitation to obtain methoxyamine hydrochloride crystals and concentrated solution; (3) Cool the concentrate to the third temperature, perform ultra-low temperature crystallization, and then separate and dry to obtain methoxyamine hydrochloride crystals.

[0019] In this invention, the mixed solution containing ammonium chloride and methoxyamine hydrochloride in step (1) is preferably one of the following: a mixed solution, a reaction solution, or a distillation solution obtained by dissolving crude methoxyamine hydrochloride solid in water or an organic solvent.

[0020] In this invention, the first temperature in step (1) is preferably -60~-40℃, and more preferably -60℃, -50℃ or -40℃.

[0021] In this invention, the cooling rate in step (1) is preferably 0.5~5℃ / min, more preferably 1~4℃ / min, and even more preferably 3℃ / min.

[0022] In this invention, the separation in step (1) is preferably vacuum filtration or centrifugal filtration, and more preferably vacuum filtration.

[0023] In this invention, the second temperature in step (2) is preferably 0~25℃, more preferably 10~25℃, and even more preferably 20℃.

[0024] In this invention, the heating rate in step (2) is preferably 1~10℃ / min, more preferably 2~8℃ / min, and even more preferably 5℃ / min.

[0025] In this invention, the method of dissolution in step (2) is preferably to add a polar alcohol solvent as a dissolution agent for dissolution and crystallization; the polar alcohol solvent is preferably methanol, ethanol, n-propanol or isopropanol, more preferably methanol or ethanol, and more preferably ethanol.

[0026] In this invention, the vacuum degree of the concentration in step (2) is preferably -0.09 MPa.

[0027] In this invention, the third temperature in step (3) is preferably -120~-60℃, more preferably -110~-80℃, and even more preferably -90℃.

[0028] In this invention, the purity of the methoxyamine hydrochloride crystals in step (3) is preferably ≥99.9%; the purity of the ammonium chloride crystals in step (1) is preferably ≥98%.

[0029] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0030] Example 1

[0031] A mixed solution containing ammonium chloride and methoxyamine hydrochloride was cooled to -40°C at a rate of 2°C / min to allow ammonium chloride to selectively crystallize out. The crystals were then separated at this temperature to obtain ammonium chloride crystals and a mother liquor enriched with methoxyamine hydrochloride. The mother liquor enriched with methoxyamine hydrochloride was heated to 20°C at a rate of 5°C / min and concentrated under a vacuum of -0.09 MPa to allow methoxyamine hydrochloride to precipitate out. The solution was then cooled to -60°C for ultra-low temperature crystallization, separation, and drying to obtain methoxyamine hydrochloride crystals.

[0032] Example 2

[0033] A mixed solution containing ammonium chloride and methoxyamine hydrochloride was cooled to -50°C at a rate of 2°C / min to allow ammonium chloride to selectively crystallize out. The crystals were then separated at this temperature to obtain ammonium chloride crystals and a mother liquor enriched with methoxyamine hydrochloride. The mother liquor enriched with methoxyamine hydrochloride was heated to 20°C at a rate of 5°C / min and concentrated under a vacuum of -0.09 MPa to allow methoxyamine hydrochloride to precipitate out. The solution was then cooled to -90°C for ultra-low temperature crystallization, separation, and drying to obtain methoxyamine hydrochloride crystals.

[0034] Example 3

[0035] A mixed solution containing ammonium chloride and methoxyamine hydrochloride was cooled to -60°C at a rate of 2°C / min to allow ammonium chloride to selectively crystallize out. The crystals were then separated at this temperature to obtain ammonium chloride crystals and a mother liquor enriched with methoxyamine hydrochloride. The mother liquor enriched with methoxyamine hydrochloride was heated to 20°C at a rate of 5°C / min and concentrated under a vacuum of -0.09 MPa to allow methoxyamine hydrochloride to precipitate out. The solution was then cooled to -120°C for ultra-low temperature crystallization, separation, and drying to obtain methoxyamine hydrochloride crystals.

[0036] Example 4

[0037] A mixed solution containing ammonium chloride and methoxyamine hydrochloride was cooled to -60°C at a rate of 2°C / min to allow ammonium chloride to selectively crystallize out. The crystals were then separated at this temperature to obtain ammonium chloride crystals and a mother liquor enriched with methoxyamine hydrochloride. The mother liquor enriched with methoxyamine hydrochloride was heated to 20°C at a rate of 5°C / min, and ethanol was added to allow methoxyamine hydrochloride to precipitate out. The solution was then cooled to -90°C for ultra-low temperature crystallization, separation, and drying to obtain methoxyamine hydrochloride crystals.

[0038] Example 5

[0039] The difference from Example 4 is that the solvent added is methanol.

[0040] Example 6

[0041] The difference from Example 4 is that the added solvent is n-propanol.

[0042] Example 7

[0043] The difference from Example 4 is that the added solvent is isopropanol.

[0044] Comparative Example 1

[0045] A mixed solution containing ammonium chloride and methoxyamine hydrochloride was concentrated under a vacuum of -0.09 MPa to precipitate methoxyamine hydrochloride. The solution was then cooled to -20°C to crystallize, separated, and dried to obtain methoxyamine hydrochloride crystals.

[0046] Comparative Example 2

[0047] A mixed solution containing ammonium chloride and methoxyamine hydrochloride was cooled to -60°C at a rate of 2°C / min to allow ammonium chloride to selectively crystallize out. The crystals were then separated at this temperature to obtain ammonium chloride crystals and a mother liquor enriched with methoxyamine hydrochloride. The mother liquor enriched with methoxyamine hydrochloride was heated to 20°C at a rate of 5°C / min, and acetone was added to allow methoxyamine hydrochloride to precipitate out. The solution was then cooled to -90°C for ultra-low temperature crystallization, separation, and drying to obtain methoxyamine hydrochloride crystals.

[0048] The content and yield of methoxyamine hydrochloride crystals finally obtained in Examples 1-7 and Comparative Examples 1-2 are shown in Table 1.

[0049] Table 1. Content and yield of methoxyamine hydrochloride crystals

[0050] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for separating methoxyamine hydrochloride and ammonium chloride, characterized in that, Includes the following steps: (1) Cool the mixed solution containing ammonium chloride and methoxyamine hydrochloride to a first temperature to allow ammonium chloride to selectively crystallize out, and then separate it to obtain ammonium chloride crystals and a mother liquor enriched with methoxyamine hydrochloride; (2) The mother liquor enriched with methoxyamine hydrochloride is heated to a second temperature for concentration or precipitation to obtain methoxyamine hydrochloride crystals and concentrated solution; (3) Cool the concentrate to the third temperature, perform ultra-low temperature crystallization, and then separate and dry to obtain methoxyamine hydrochloride crystals.

2. The method for separating methoxyamine hydrochloride and ammonium chloride according to claim 1, characterized in that, Step (1) The first temperature is -60~-40℃.

3. The method for separating methoxyamine hydrochloride and ammonium chloride according to claim 1, characterized in that, The cooling rate in step (1) is 0.5~5℃ / min.

4. The method for separating methoxyamine hydrochloride and ammonium chloride according to claim 1, characterized in that, The separation in step (1) is either vacuum filtration or centrifugal filtration.

5. The method for separating methoxyamine hydrochloride and ammonium chloride according to claim 2, characterized in that, Step (2) The second temperature is 0~25℃.

6. The method for separating methoxyamine hydrochloride and ammonium chloride according to claim 1, characterized in that, The heating rate in step (2) is 1~10℃ / min.

7. The method for separating methoxyamine hydrochloride and ammonium chloride according to claim 1, characterized in that, The method of dissolution in step (2) is to add a polar alcohol solvent as a dissolution agent for crystallization; the polar alcohol solvent is methanol, ethanol, n-propanol or isopropanol.

8. The method for separating methoxyamine hydrochloride and ammonium chloride according to claim 1, characterized in that, The vacuum degree of the concentration in step (2) is -0.09 MPa.

9. A method for separating methoxyamine hydrochloride and ammonium chloride according to any one of claims 1, 2, or 5, characterized in that, The third temperature mentioned in step (3) is -120~-60℃.

Images