Method for purifying aminomethyl propanol compound
Through the crystallization, filtration and desolation drying process, the problem of high impurity content in 2-amino-2 methyl-propanol is solved, and the production of high-purity 2-amino-2 methyl-propanol is achieved. The process is simple, environmentally friendly and efficient.
Patent Information
- Application Number
- CN202510413934.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-03
- Publication Date
- 2025-08-08
Smart Images
Figure CN120441446A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of compound purification, and in particular relates to a method for purifying an aminomethyl propanol compound. Background Art
[0002] 2-Amino-2-methyl-propanol, also known as aminoisobutanol, occurs as white crystalline blocks or a colorless liquid. It is miscible with water and soluble in alcohol, but is irritating to the eyes and skin. It can be used as a surfactant, pH adjuster, vulcanization accelerator, and acid gas absorbent.
[0003] 2-Amino-2-methyl-propanol is an industrial-grade product in both domestic and international markets, with no pharmaceutical excipient-grade product. Consequently, the quality standards for 2-amino-2-methyl-propanol are not included in the pharmacopoeias of various countries. The main impurity in 2-amino-2-methyl-propanol is 2-methyl-2-methylamino-1-propanol, which has an LD50 (rabbit) value of 500 mg / kg. Based on the LD50 and the maximum daily dose of eye drops, the limit for this impurity is 0.5%. In industrial-grade 2-amino-2-methyl-propanol products, the impurity 2-methylamino-2-methyl-propanol content is between 1-3%, which does not meet the requirements of pharmaceutical-grade excipients.
[0004] Therefore, it is very necessary to provide a method for purifying an aminomethyl propanol compound, which is of great significance for achieving the production of pharmaceutical-grade products. Summary of the Invention
[0005] The object of the present invention is to provide a method for purifying an aminomethyl propanol compound so as to achieve the production of a pharmaceutical-grade high-purity product.
[0006] To this end, the present invention provides the following technical solutions.
[0007] One aspect of the present invention provides a method for purifying an aminomethyl propanol compound, the method comprising the following steps:
[0008] S1: adding a solvent to the aminomethyl propanol compound raw material, mixing uniformly, and then stirring and crystallizing to obtain a crystalline product;
[0009] S2: The obtained crystalline product is filtered, washed, and filtered in sequence to obtain a crude aminomethyl propanol compound;
[0010] S3: vacuum rotary evaporating the obtained crude aminomethyl propanol compound to obtain a desolvated aminomethyl propanol compound;
[0011] S4: The obtained desolvated aminomethyl propanol compound is filtered to obtain a pure aminomethyl propanol compound.
[0012] In a preferred embodiment of the present invention, in step S1, the solvent is selected from one or more of acetonitrile, toluene, chloroform, and n-butanol.
[0013] In a preferred embodiment of the present invention, in step S1, the amount of the solvent added is 1 to 5 times the mass of the aminomethyl propanol compound.
[0014] In a preferred embodiment of the present invention, in step S1, the crystallization conditions are: temperature -5 to -20°C, time 1 to 5 hours.
[0015] In a preferred embodiment of the present invention, in step S1, the crystallization conditions are: temperature -8 to -12°C, time 3 to 4 hours.
[0016] In a preferred embodiment of the present invention, in step S2, the washing is performed by adding acetonitrile, toluene, chloroform or n-butanol.
[0017] In a preferred embodiment of the present invention, the amount of acetonitrile used is 10% of the mass of the raw material, and the number of washing times is 1 to 3 times.
[0018] In a preferred embodiment of the present invention, in step S3, the vacuum rotary evaporation conditions are: vacuum degree ≤ -0.095 MPa, temperature 50-70°C.
[0019] In a preferred embodiment of the present invention, in step S4, the filtration is performed using a filter membrane.
[0020] In a preferred embodiment of the present invention, the pore size of the filter membrane is 0.22-0.45 μm.
[0021] In a preferred embodiment of the present invention, in step S4, the impurity content in the pure aminomethyl propanol compound is ≤0.5%.
[0022] By means of the above technical solution, the present invention has at least the following advantages:
[0023] The present invention provides a method for purifying an aminomethyl propanol compound. The method uses industrial-grade 2-amino-2-methyl-propanol as a raw material and produces pure 2-amino-2-methyl-propanol through processes such as crystallization, filtration, and desolventizing and drying. The present invention utilizes a crystallization method to purify 2-amino-2-methyl-propanol. The resulting 2-amino-2-methyl-propanol is of high quality and meets the requirements of pharmaceutical excipients. The solvent used is recyclable, reducing waste liquid discharge. The purification method of the present invention is simple in process and has excellent purification effects. The resulting product has a high yield of 65-75% and is of highly competitive quality.
[0024] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the contents of the specification, the following is a detailed description of the preferred embodiments of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS
[0025] Figure 1 The pure 2-amino-2-methyl-propanol obtained according to Example 1 1 H NMR spectrum;
[0026] Figure 2 The pure 2-amino-2-methyl-propanol obtained according to Example 1 13 C NMR spectrum. DETAILED DESCRIPTION
[0027] In order to make the technical means, creative features, objectives and effects achieved by the present invention easier to understand, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts shall fall within the scope of protection of the present invention.
[0028] The present invention provides a method for purifying an aminomethyl propanol compound, 2-amino-2-methyl-propanol, based on the demand for its medicinal use. The main purpose of the purification method is to reduce the impurity content in the 2-amino-2-methyl-propanol and improve the purity of the 2-amino-2-methyl-propanol, thereby realizing the large-scale production of pharmaceutical-grade 2-amino-2-methyl-propanol.
[0029] For this reason, the method for purification of 2-amino-2 methyl-propanol of the present invention comprises the following steps:
[0030] The first step is stirred crystallization of the raw materials, specifically comprising: adding a solvent to the aminomethyl propanol compound raw material, mixing uniformly, and then stirring and crystallizing to obtain a crystalline product. In this step, the solvent used to dissolve the raw material includes, but is not limited to, acetonitrile, toluene, chloroform, and n-butanol, preferably acetonitrile. The amount of solvent added is 1 to 5 times the mass of the aminomethyl propanol compound, for example, 1, 2, 3, 4, or 5 times, preferably 3 times. After the raw materials and solvent are uniformly mixed, the material is crystallized using a stirred crystallization apparatus. The specific operation is as follows: turning on the cooling circulation pump of the glass reactor, lowering the temperature of the material in the glass reactor to -5 to -20°C, allowing solids to precipitate, and then stirring and crystallizing for 1 to 5 hours. After completion of crystallization, a crystalline product is obtained. The crystallization temperature can be, for example, -20°C, -15°C, -10°C, or -5°C, preferably -10°C; the crystallization time can be 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours, preferably 3 hours.
[0031] The second step is a washing process for the crystalline product, which specifically includes: filtering the obtained crystalline product at low temperature to remove the acetonitrile solvent, and then adding acetonitrile solvent to wash the crystalline product. After washing, filtering to obtain a crude 2-amino-2-methyl-propanol product. In this process, the amount of acetonitrile added is 10% of the mass of the crystalline product, and the number of washings is 1 to 3 times, for example, 1 time, 2 times or 3 times, preferably 3 times.
[0032] The third step is to vacuum rotary evaporation of the crude 2-amino-2-methyl-propanol, which specifically includes: transferring the obtained crude 2-amino-2-methyl-propanol into a single-necked flask, and rotary evaporating at 50-70°C and ≤-0.095 MPa for 2-8 hours until the residual solution is qualified, thereby obtaining desolvated 2-amino-2-methyl-propanol. The rotary evaporation temperature can be 40°C, 50°C, 60°C, 70°C, or 80°C, preferably 50-70°C; the vacuum degree can be -0.08 MPa, -0.095 MPa, or -0.098 MPa, preferably ≤-0.095 MPa.
[0033] The fourth step is to filter press the desolvated 2-amino-2-methyl-propanol, which specifically comprises filtering the desolvated 2-amino-2-methyl-propanol under a filter membrane to obtain pure 2-amino-2-methyl-propanol. The pore size of the filter membrane can be 0.22 μm or 0.45 μm, preferably 0.22 μm.
[0034] The present invention will be further described below with reference to specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. Conventional reagents used in the following examples are commercially available, and the biological experiments performed are conventional biological experiments in the art and can be performed according to the instructions in the corresponding experimental manual or kit instructions.
[0035] Unless otherwise specified, the glass reactor used in the following examples was model F-50, purchased from Nanjing Jinzheng Teaching Instrument Equipment Co., Ltd.; the distillation column was purchased from Nanjing Jinzheng Teaching Instrument Equipment Co., Ltd. The raw material 2-amino-2-methyl-propanol was purchased from Hubei Tianmen Hengchang Chemical Co., Ltd.
[0036] Example 1:
[0037] 10 kg of 2-amino-2-methyl-propanol raw material and 10 kg of acetonitrile were mixed in a glass reactor and stirred evenly to obtain a material. The material was then subjected to stirred crystallization. The specific operation was as follows: the cooling circulation pump of the glass reactor was turned on, the temperature of the material in the glass reactor was lowered to -10°C, and solids were slowly precipitated. The solids were then stirred and crystallized for 4 hours. After crystallization, a crystalline product was obtained. The resulting crystalline product was filtered under low temperature to remove the acetonitrile solvent, and then washed with 100 g of acetonitrile solvent. After washing, the crystals were filtered to obtain crude 2-amino-2-methyl-propanol. The crude 2-amino-2-methyl-propanol was transferred to a 20 L single-necked flask and rotary evaporated at 55°C under a vacuum of ≤-0.095 MPa until the acetonitrile residue was ≤0.041% to obtain the desolvated 2-amino-2-methyl-propanol. The desolvated 2-amino-2-methyl-propanol was filter-pressed through a 0.22 μm filter membrane to obtain pure 2-amino-2-methyl-propanol. By calculation, the yield of the obtained pure 2-amino-2-methyl-propanol was 73.6%.
[0038] The composition of the resulting pure 2-amino-2-methyl-propanol was determined by gas chromatography using an Agilent CP Volamine (30 m x 0.32 mm) column, an initial temperature of 40°C, maintained for 3 minutes, then ramped to 220°C at a rate of 8°C / min and maintained for 5 minutes. The inlet temperature was 250°C, the detector temperature was 300°C, the split ratio was 50:1, and the column flow rate was 1.0 ml / min. The results are shown in Table 1.
[0039] Figure 1 The pure 2-amino-2-methyl-propanol obtained according to Example 1 1 H NMR spectrum; Figure 1 As shown, two groups of hydrogens are present, with an integral ratio of 1:3 from low field to high field. The number of hydrogen protons at 1.1066 ppm is 6, attributed to two methyl hydrogens. The number of hydrogen protons at 3.3479 ppm is 2, attributed to methylene hydrogens attached to a hydroxyl group. The deuterated reagent used was deuterated water, and the solvent peak at 4.7636 ppm is consistent with the structure of 2-amino-2-methyl-propanol. Figure 2 The pure 2-amino-2-methyl-propanol obtained according to Example 1 13 C NMR spectrum. As shown in the figure, there are three groups of carbon peaks: the peak at 25.7499 ppm shows that it contains two primary carbon peaks, which are attributed to methyl carbons at positions 3 and 4; the peak at 50.1687 ppm shows that it contains one tertiary carbon peak, which is attributed to tertiary carbon at position 1; the peak at 71.3505 ppm shows that it contains one secondary carbon peak, which is attributed to methylene carbon at position 2, which is consistent with the structure of 2-amino-2-methyl-propanol.
[0040] Example 2:
[0041] 10 kg of 2-amino-2-methyl-propanol raw material and 13 kg of acetonitrile were mixed in a glass reactor and stirred evenly to obtain a material. The material was then subjected to stirred crystallization. The specific operation was as follows: the cooling circulation pump of the glass reactor was turned on, the temperature of the material in the glass reactor was lowered to -10°C, and solids were slowly precipitated. The solids were then stirred and crystallized for 4 hours. After crystallization, a crystalline product was obtained. The resulting crystalline product was filtered at low temperature to remove the acetonitrile solvent, and then washed with 100 g of acetonitrile solvent. After washing, the crystals were filtered to obtain crude 2-amino-2-methyl-propanol. The crude 2-amino-2-methyl-propanol was transferred to a 20 L single-necked flask and rotary evaporated at 45°C under a vacuum of ≤-0.095 MPa until the acetonitrile residue was ≤0.041% to obtain the desolvated 2-amino-2-methyl-propanol. The desolvated 2-amino-2-methyl-propanol was filter-pressed through a 0.22 μm filter membrane to obtain pure 2-amino-2-methyl-propanol. By calculation, the yield of the obtained pure 2-amino-2-methyl-propanol was 69.3%.
[0042] The composition of the resulting pure 2-amino-2-methyl-propanol was determined by gas chromatography using an Agilent CP Volamine (30 m x 0.32 mm) column, an initial temperature of 40°C, maintained for 3 minutes, then ramped to 220°C at a rate of 8°C / min and maintained for 5 minutes. The inlet temperature was 250°C, the detector temperature was 300°C, the split ratio was 50:1, and the column flow rate was 1.0 ml / min. The results are shown in Table 1.
[0043] Example 3:
[0044] 10 kg of 2-amino-2-methyl-propanol raw material and 10 kg of acetonitrile were mixed in a glass reactor and stirred evenly to obtain a material. The material was then subjected to stirred crystallization. The specific operation was as follows: the cooling circulation pump of the glass reactor was turned on, the temperature of the material in the glass reactor was lowered to -15°C, solids were slowly precipitated, and then stirred and crystallized for 4 hours. After crystallization, a crystalline product was obtained. The resulting crystalline product was filtered at low temperature to remove the acetonitrile solvent, and then 100 g of acetonitrile solvent was added to the crystallized product for washing. After washing, the crystalline product was filtered to obtain crude 2-amino-2-methyl-propanol. The crude 2-amino-2-methyl-propanol was transferred to a 20 L single-necked flask and rotary evaporated at 45°C under a vacuum of ≤-0.095 MPa until the acetonitrile residue was ≤0.041% to obtain the desolvated 2-amino-2-methyl-propanol. The desolvated 2-amino-2-methyl-propanol was filter-pressed through a 0.22 μm filter membrane to obtain pure 2-amino-2-methyl-propanol. By calculation, the yield of the obtained pure 2-amino-2-methyl-propanol was 74.6%.
[0045] The composition of the resulting pure 2-amino-2-methyl-propanol was determined by gas chromatography using an Agilent CP Volamine (30 m x 0.32 mm) column, an initial temperature of 40°C, maintained for 3 minutes, then ramped to 220°C at a rate of 8°C / min and maintained for 5 minutes. The inlet temperature was 250°C, the detector temperature was 300°C, the split ratio was 50:1, and the column flow rate was 1.0 ml / min. The results are shown in Table 1.
[0046] Table 1 Composition test results of pure 2-amino-2-methyl-propanol
[0047]
[0048] Note: The amount of impurity 2-methylamino-2-methyl-propanol in the raw material 2-amino-2-methyl-propanol is 0.98%.
[0049] Comparative Example 1:
[0050] 2kg of 2-amino-2-methyl-propanol raw material, batch number 20220410, with a purity of 99.08% and a 2-methylamino-2-methyl-1-propanol content of 0.57%, was distilled using a distillation column. The distillation conditions were: column height 1.5 meters, vacuum distillation, column top temperature 62-66°C, vacuum degree -99.8 to -100.1 kPa, reflux ratio 0.5, and different amounts of fractions were removed. The different fractions were then detected and examined by gas chromatography. The chromatographic conditions were: chromatographic column Agilent CP Volamine (30m*0.32mm), initial temperature 40°C, hold for 3 minutes, then increase the temperature at a rate of 8°C / min to 220°C and hold for 5 minutes. Inlet temperature: 250°C, detector temperature: 300°C, split ratio 50:1, column flow rate 1.0 ml / min. The results are shown in Table 2 below:
[0051] Table 2 Detection of aminoisobutanol purity and 2-methylamino-2-methyl-propanol content in different fractions
[0052]
[0053]
[0054] As shown in Table 2, after distillation and removal of 77.7% of the fore fraction, the purity of 2-amino-2-methyl-propanol can be increased from 99.08% to 99.58%, while the purity of 2-amino-2-methyl-propanol in Example 2 can reach 99.85%. The content of the specific impurity 2-methylamino-2-methyl-1-propanol is reduced from 0.57% to approximately 0.36%, which is significantly higher than that in Examples 1-4. These results show that the purification method of the present invention can obtain 2-amino-2-methyl-propanol of higher purity and lower 2-methylamino-2-methyl-1-propanol content.
[0055] The above description is merely a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Although the present invention has been disclosed as a preferred embodiment as above, it is not intended to limit the present invention. Any technician familiar with this profession can make slight changes or modifications to equivalent embodiments of the methods and technical contents disclosed above without departing from the scope of the technical solution of the present invention. However, any simple modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the technical solution of the present invention.
Claims
1. A method for purifying an aminomethyl propanol compound, characterized in that: The method comprises the following steps: S1: adding a solvent to the aminomethyl propanol compound raw material, mixing uniformly, and then stirring and crystallizing to obtain a crystalline product; S2: The obtained crystalline product is filtered, washed, and filtered in sequence to obtain a crude aminomethyl propanol compound; S3: vacuum rotary evaporating the obtained crude aminomethyl propanol compound to obtain a desolvated aminomethyl propanol compound; S4: The obtained desolvated aminomethyl propanol compound is filtered to obtain a pure aminomethyl propanol compound.
2. The method for purifying an aminomethyl propanol compound according to claim 1, wherein In step S1, the solvent is selected from one or more of acetonitrile, toluene, chloroform, and n-butanol.
3. The method for purifying an aminomethyl propanol compound according to claim 1, wherein In step S1, the amount of the solvent added is 1 to 5 times the mass of the aminomethyl propanol compound.
4. The method for purifying an aminomethyl propanol compound according to claim 1, wherein In step S1, the crystallization conditions are: temperature -5 to -20°C, time 1 to 5 hours.
5. The method for purifying an aminomethyl propanol compound according to claim 1, wherein In step S2, the washing is performed by adding acetonitrile, toluene, chloroform or n-butanol for washing.
6. The method for purifying an aminomethyl propanol compound according to claim 5, wherein: The amount of acetonitrile used is 10% of the mass of the raw material, and the washing times are 1 to 3 times.
7. The method for purifying an aminomethyl propanol compound according to claim 1, wherein In step S3, the vacuum rotary evaporation conditions are: vacuum degree ≤-0.095Mpa, temperature 50-70°C.
8. The method for purifying an aminomethyl propanol compound according to claim 1, wherein In step S4, the filter press is performed using a filter membrane.
9. The method for purifying an aminomethyl propanol compound according to claim 8, wherein: The pore size of the filter membrane is 0.22-0.45 μm.
10. The method for purifying an aminomethyl propanol compound according to claim 1, wherein In step S4, the impurity content in the pure aminomethyl propanol compound is ≤0.5%.