Purification method of octyldodecanol

Abstract

The invention provides a purification method of octyldodecanol, and belongs to the technical field of chromatographic purification. The purification method comprises the following steps: preparing a sample solution from an octyldodecanol crude product; carrying out balance operation on the normal phase chromatographic column filled with the stationary phase by adopting a first mobile phase; loading the sample liquid into a normal phase chromatographic column; eluting the normal-phase chromatographic column by using a first mobile phase, and collecting a first eluent; eluting the normal-phase chromatographic column by using a second mobile phase, and collecting a second eluent; the second eluent is concentrated, and high-purity octyldodecanol is obtained; the first mobile phase is a low-polarity organic solvent; the second mobile phase is a mixed solvent of a low-polarity organic solvent and a high-polarity organic solvent. According to the method disclosed by the invention, high-purity octyldodecanol can be directly obtained by purifying an industrial-grade octyldodecanol crude product subjected to primary separation only through normal-pressure column chromatography, and further refining and purification are not needed. And the whole separation process is a pure physical process, and chemical reaction is not involved.

Description

Technical Field

[0001] This invention belongs to the field of chromatographic purification technology, and specifically relates to a method for purifying octyldodecyl alcohol. Background Technology

[0002] Octyldodecyl alcohol is an important member of the Guerbert alcohol family. As a high-performance fatty alcohol, it is widely used in surfactants, pharmaceuticals, and cosmetics. Given its applications in the pharmaceutical field, drug regulatory agencies have extremely strict control requirements on the impurity content of octyldodecyl alcohol as a pharmaceutical excipient. The USP Pharmacopeia specifies that the sum of the contents of the six known impurities that may be present in octyldodecyl alcohol (including n-nonadecane, 9-methylnonadecane, 2-octyl-1-decanol, 2-hexyl-1-dodecyl alcohol, 2-octyl-1-tetradecyl alcohol, and 2-decyl-1-dodecyl alcohol) should be ≤1.5%; for unknown impurities, the sum should be ≤1.0%.

[0003] Existing purification technologies primarily rely on distillation. For example, patent CN1105095C describes a method for preparing metal-free Guerbert alcohol, involving flash evaporation, thin-layer evaporation, and molecular distillation. While this method avoids metal ion contamination, it requires specific distillation equipment and operates at high temperatures, posing a risk of pyrolysis of the target product or the generation of additional byproducts (such as trimers). Furthermore, the patent text does not specify the purity of the final product or the control of specific impurities. Similarly, patents CN102020533A and US6911567B2 also employ vacuum distillation for product purification; the former reports a product purity exceeding 96%, but focuses only on the trimer as a single impurity, failing to comprehensively reflect the control of other impurities; the latter provides no data on purity, raising questions about its purification effectiveness.

[0004] Distillation, due to its inherent limitations, often requires maintaining high temperatures to achieve sufficient separation efficiency when dealing with high-boiling-point organic compounds (such as octyldodecyl alcohol). This inherently contradicts the requirements of high-quality pharmaceutical excipients, which demand low impurities, low color values, and high stability. Furthermore, patent CN114853569B provides a non-distillation crystallization purification method using ethyl acetate as a solvent to purify octyldodecyl alcohol through low-temperature crystallization. While the product quality meets pharmacopoeia standards, the entire crystallization, precipitation, and solvent removal process must be carried out at temperatures ranging from -7°C to -20°C, accumulating to over 8 hours. These stringent requirements for sustained low-temperature environments and long working hours undoubtedly increase energy consumption and control costs in the production process, hindering its large-scale industrial application.

[0005] In summary, existing octyldodecyl alcohol purification technologies have significant shortcomings: the mainstream distillation method faces the risk of product decomposition and impurity formation due to high temperatures; while the crystallization method is constrained by harsh low-temperature conditions and lengthy production cycles. Therefore, there is an urgent need in this field to develop a new octyldodecyl alcohol purification process that can operate efficiently under mild conditions (especially at room temperature) and effectively avoid the aforementioned drawbacks. Summary of the Invention

[0006] In view of this, the present invention provides a method for purifying octyldodecyl alcohol, which aims to solve at least one technical problem in the background art.

[0007] This invention is implemented as follows: This invention provides a method for purifying octyldodecyl alcohol, the purification method comprising the following steps: S1. Prepare a sample solution from crude octyldodecyl alcohol; S2. The first mobile phase is used to equilibrate the normal-phase chromatographic column packed with the stationary phase; S3. Load the sample solution into an equilibrated normal-phase chromatographic column; S4. Elute the normal phase column with the first mobile phase at a predetermined first volume, and collect the first eluent rich in impurities; S5. Elute the normal phase column with a second mobile phase at a predetermined second volume, and collect the second eluent rich in octyldodecyl alcohol; S6. Concentrate the second eluent to obtain high-purity octyldodecyl alcohol; The purity of the crude octyldodecyl alcohol is ≥90.0%. The high-purity octyldodecyl alcohol has a purity ≥97.0%, the sum of known impurities ≤1.5%, and the sum of unknown impurities ≤1.0%.

[0008] The first mobile phase is a low-polarity organic solvent; The second mobile phase is a mixture of low-polarity organic solvents and high-polarity organic solvents.

[0009] Furthermore, the low-polarity organic solvents in the first and second mobile phases are selected from at least one of n-hexane, cyclohexane, n-heptane, and petroleum ether.

[0010] Furthermore, the highly polar organic solvent is selected from at least one of ethyl acetate, propyl acetate, isobutyl acetate, and methyl tert-butyl ether.

[0011] Furthermore, when preparing the second mobile phase, the volume percentage of the highly polar organic solvent is ≥20%.

[0012] Furthermore, the stationary phase is unbonded silicone, and its shape is spherical or amorphous; The unbonded silica gel has a particle size of 74μm~149μm and a pore size of 100 mesh~200 mesh.

[0013] Furthermore, the sample solution is prepared by mixing crude octyldodecyl alcohol with the first mobile phase and stirring until homogeneous.

[0014] Furthermore, the first amount of the first mobile phase is 0.8 to 1.0 times the capacity of the normal phase column.

[0015] Furthermore, the second amount of the second mobile phase is 1.2 to 2.0 times the capacity of the normal phase column.

[0016] Furthermore, during sample loading, the mass of crude octyldodecyl alcohol in the sample solution is 0.05 to 0.3 times the mass of the stationary phase.

[0017] Compared with the prior art, the present invention has the following beneficial effects: 1. This invention allows for the direct purification of industrial-grade crude octyldodecyl alcohol, after preliminary separation, using only atmospheric pressure column chromatography to obtain a high-purity product that meets the USP Pharmacopoeia requirements for pharmaceutical excipient grade octyldodecyl alcohol, without further purification. Furthermore, the entire separation process is purely physical and does not involve any chemical reactions.

[0018] 2. The method of the present invention uses low organic solvent consumption, large sample loading capacity, and high yield, thereby effectively improving efficiency and reducing product cost.

[0019] 3. The atmospheric pressure column chromatography purification method of the present invention can be applied and promoted to industrial production. Attached Figure Description

[0020] Figure 1 The chromatograms are of the raw materials used in the embodiments and comparative examples of this invention; Figure 2 This is a chromatogram of the purified product in Example 1 of the present invention. Detailed Implementation

[0021] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0022] A method for purifying octyldodecyl alcohol involves using commonly used non-bonded silica gel as the chromatographic column packing material. Normal-phase preparative chromatography is employed with two mobile phases for elution. Octyldodecyl alcohol is separated and purified at room temperature, yielding a first eluent and a second eluent. Removing the solvent from the second eluent yields high-purity octyldodecyl alcohol that meets the requirements for pharmaceutical excipient use. The sample loading flow rate and the mobile phase flow rate are determined based on the column size, the pressure the column withstands, and the resolution of the mobile phase against impurities. Due to the relatively large sample loading volume, a flat-topped peak may form in the chromatogram. The start and end times of collection can be determined based on the separation effect, dividing the eluent into eluents. If the impurity separation effect is particularly good, collection can begin as soon as the product emerges; if the impurity separation effect is relatively poor, a segment in the middle of the flat-topped peak can be collected. After collecting the eluent containing the product, the solvent is recovered under reduced pressure to obtain the product. The purity of the product is detected using a gas chromatograph equipped with a flame ionization detector.

[0023] The two mobile phases include: a first mobile phase consisting only of a certain low-polarity organic solvent, and a second mobile phase consisting of a mixed solvent of a low-polarity organic solvent and a high-polarity organic solvent.

[0024] The low-polarity organic solvents in the first and second mobile phases are selected from at least one of n-hexane, cyclohexane, n-heptane, and petroleum ether.

[0025] The highly polar organic solvent in the second mobile phase is selected from at least one of ethyl acetate, propyl acetate, isobutyl acetate, and methyl tert-butyl ether, and the volume percentage of the highly polar organic solvent is ≥20%.

[0026] The purification method for octyldodecyl alcohol includes steps S1 to S6.

[0027] S1. Prepare a sample solution from crude octyldodecyl alcohol; The crude octyldodecyl alcohol contains ≥90.0% octyldodecyl alcohol. The crude octyldodecyl alcohol can be used directly as a sample solution; or it can be mixed with the first mobile phase and stirred evenly before being used as a sample solution. There is no limitation on the mixing ratio of the two and it can be adjusted according to actual needs. In the following examples, the mass-volume ratio of 1g:1ml is used for mixing.

[0028] S2. The first mobile phase is used to equilibrate the normal-phase chromatographic column packed with the stationary phase; The stationary phase is the packing material for a normal-phase chromatographic column, using spherical or amorphous non-bonded silica gel with a particle size of 74μm~149μm and a pore size of 100 mesh~200 mesh.

[0029] S3. Load the sample solution into an equilibrated normal-phase chromatographic column; During sample loading, the mass of crude octyldodecyl alcohol in the sample solution is 0.05 to 0.3 times the mass of the stationary phase.

[0030] S4. Elute the normal phase column with the first mobile phase at a predetermined first amount and collect the first eluent rich in impurities; The first dosage is 0.8 to 1.0 times the capacity of the normal phase chromatography column.

[0031] S5. Elute the normal phase column with a second mobile phase at a predetermined second volume, and collect the second eluent rich in octyldodecyl alcohol; The second dosage is 1.2 to 2.0 times the capacity of the normal phase chromatographic column.

[0032] S6. Concentrate the second eluent to obtain high-purity octyldodecyl alcohol.

[0033] The normal phase chromatographic column used in the following examples is an open-ended column (φ40*500mm) with a column volume of 250ml (1BV); it is packed with 150g of Qingdao Bangkai coarse-pore spherical non-bonded silica gel with a particle size of 74μm~149μm and a pore size of 100mesh~200mesh.

[0034] Example 1 The purification method for octyldodecyl alcohol is as follows: S1. Add 24.0g of industrial-grade octyldodecyl alcohol (purity 90.04%, its gas chromatogram is as follows). Figure 1 (As shown), 24 ml of n-hexane was added to a 100 ml beaker and stirred until homogeneous to obtain the sample solution; S2. Equilibrate the normal-phase chromatography column with n-hexane; S3. Load the sample solution into the equilibrated normal-phase column at a flow rate of approximately 5 ml / min; S4. Elute with 1.0 BV n-hexane as the first mobile phase at a flow rate of approximately 5 ml / min, and collect the first eluent. S5. Elute with a 1.4 BV mixture (20% propyl acetate + 80% n-hexane by volume) as the second mobile phase at a flow rate of approximately 5 ml / min, and collect the second eluent. S6. After recovering the solvent under reduced pressure with the first eluent, the pre-impurity fraction was obtained; after recovering the solvent under reduced pressure with the second eluent, the high-purity octyldodecyl alcohol fraction was obtained, and its chromatogram is shown below. Figure 2 As shown, the content of octyldodecyl alcohol is 97.56%, the total content of known impurities is 1.45%, the total content of unknown impurities is 0.99%, and the yield is 71.64%.

[0035] Example 2 The purification method for octyldodecyl alcohol is as follows: S1. Add 7.5g of industrial grade octyldodecyl alcohol (purity 90.04%) and 7.5ml of cyclohexane to a 100ml beaker, stir well, and prepare the sample solution; S2. Equilibrate the normal-phase chromatographic column with cyclohexane; S3. Load the sample solution into the equilibrated normal-phase column at a flow rate of approximately 5 ml / min; S4. Use 0.8 BV cyclohexane as the first mobile phase for elution at a flow rate of approximately 5 ml / min, and collect the first eluent. S5. Elute with a 1.5 BV mixture (50% methyl tert-butyl ether + 50% cyclohexane by volume) as the second mobile phase at a flow rate of approximately 5 ml / min, and collect the second eluent. S6. The first eluent was used to recover the solvent under reduced pressure to obtain the pre-impurity fraction; the second eluent was used to recover the solvent under reduced pressure to obtain a high-purity octyldodecyl alcohol fraction, wherein the octyldodecyl alcohol content was 98.93%, the sum of the contents of known impurities was 0.73%, the sum of the contents of unknown impurities was 0.34%, and the yield was 88.18%.

[0036] Example 3 The purification method for octyldodecyl alcohol is as follows: S1. Add 15.0g of industrial grade octyldodecyl alcohol (purity 90.04%) and 15ml of petroleum ether to a 100ml beaker, stir well to prepare the sample solution; S2. Equilibrate the normal-phase chromatographic column with petroleum ether; S3. Load the sample solution into the equilibrated normal-phase column at a flow rate of approximately 5 ml / min; S4. Elute with 1.0 BV petroleum ether as the first mobile phase at a flow rate of approximately 5 ml / min, and collect the first eluent. S5. Elute with a 2.0 BV mixture (40% ethyl acetate + 60% petroleum ether by volume) as the second mobile phase at a flow rate of approximately 5 ml / min, and collect the second eluent. S6. The first eluent was used to recover the solvent under reduced pressure to obtain the pre-impurity fraction; the second eluent was used to recover the solvent under reduced pressure to obtain a high-purity octyldodecyl alcohol fraction, wherein the octyldodecyl alcohol content was 97.76%, the sum of the contents of known impurities was 1.42%, the sum of the contents of unknown impurities was 0.82%, and the yield was 77.21%.

[0037] Example 4 The purification method for octyldodecyl alcohol is as follows: S1. Add 45.0g of industrial grade octyldodecyl alcohol (purity 90.04%) and 45ml of n-heptane to a 500ml beaker, stir well to obtain the sample solution; S2. Equilibrate the normal-phase chromatography column with n-heptane; S3. Load the sample solution into the equilibrated normal-phase column at a flow rate of approximately 5 ml / min; S4. Elute with 1.0 BV n-heptane as the first mobile phase at a flow rate of approximately 5 ml / min, and collect the first eluent. S5. Elute with a 2.0 BV mixture (30% ethyl acetate + 70% n-heptane by volume) as the second mobile phase at a flow rate of approximately 5 ml / min, and collect the second eluent. S6. The first eluent was used to recover the solvent under reduced pressure to obtain the pre-impurity fraction; the second eluent was used to recover the solvent under reduced pressure to obtain a high-purity octyldodecyl alcohol fraction, wherein the octyldodecyl alcohol content was 97.82%, the sum of the contents of known impurities was 1.31%, the sum of the contents of unknown impurities was 0.87%, and the yield was 64.87%.

[0038] The normal phase chromatographic column used in the following examples is an open-ended column (φ14*100cm) with a column volume of 8000ml (1BV); it is packed with 5kg of Qingdao Bangkai coarse-pore spherical unbonded silica gel with a particle size of 74μm~149μm and a pore size of 100 mesh~200 mesh.

[0039] Example 5 The purification method for octyldodecyl alcohol is as follows: S1. Add 500.0g of industrial grade octyldodecyl alcohol (purity 90.04%) and 500ml of n-heptane to a 2000ml beaker, stir well to obtain the sample solution; S2. Equilibrate the normal-phase chromatography column with n-heptane; S3. Load the sample solution into the equilibrated normal-phase column at a flow rate of approximately 80 ml / min; S4. Elute with 0.9 BV n-heptane as the first mobile phase at a flow rate of approximately 80 ml / min, and collect the first eluent. S5. Elute with a 1.8 BV mixture (60% n-heptane + 40% isobutyl acetate by volume) as the second mobile phase at a flow rate of approximately 80 ml / min, and collect the second eluent. S6. The first eluent was used to recover the solvent under reduced pressure to obtain the pre-impurity fraction; the second eluent was used to recover the solvent under reduced pressure to obtain a high-purity octyldodecyl alcohol fraction, wherein the octyldodecyl alcohol content was 97.64%, the sum of the contents of known impurities was 1.39%, the sum of the contents of unknown impurities was 0.97%, and the yield was 81.28%.

[0040] Comparative Example 1 This comparative example uses the method and conditions described in Example 1 of patent CN114853569B to process the industrial-grade crude octyldodecyl alcohol (purity 90.04%) in this application.

[0041] The specific steps are as follows: Add 100.0 g of industrial-grade crude octyldodecyl alcohol (purity 90.04%) and 100 g of ethyl acetate to a 500 mL three-necked flask and stir until homogeneous. Turn on the cooling circulation pump to lower the temperature of the three-necked flask to -7 °C. After the solid precipitates, stir to crystallize for 6 h. After crystallization, filter to remove the ethyl acetate solvent at -15 °C, wash once with 10 mL of ethyl acetate solvent, remove the ethyl acetate by rotary evaporation, and then distill under reduced pressure to obtain the octyldodecyl alcohol product.

[0042] Testing revealed that the final product contained 94.53% octyldodecyl alcohol, with a total content of 3.81% for known impurities and 1.66% for unknown impurities, resulting in a yield of 85.23%. The test results of the raw materials and purified components in Examples 1 to 5 and Comparative Example 1 are shown in Table 1 below.

[0043] Table 1

[0044] As shown in Table 1, after purification by the embodiments of the present invention, the purity of octyldodecyl alcohol increased from 90.04% to over 97.50%, and the acid value, iodine value, peroxide value, etc. of the product were further reduced, thus improving the quality of octyldodecyl alcohol and making it meet the corresponding standards of USP Pharmacopoeia for pharmaceutical excipient grade octyldodecyl alcohol.

[0045] Based on the product quality of Comparative Example 1, the method described in patent CN114853569B has limited purification effect on industrial-grade octyldodecanol with low purity, and cannot obtain pharmaceutical-grade octyldodecanol through a single purification.

[0046] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A purification method of octyldodecanol, characterized by, The purification method includes the following steps: S1. Prepare a sample solution from crude octyldodecyl alcohol; S2. The first mobile phase is used to equilibrate the normal-phase chromatographic column packed with the stationary phase; S3. Load the sample solution into an equilibrated normal-phase chromatographic column; S4. Elute the normal phase column with the first mobile phase at a predetermined first volume, and collect the first eluent rich in impurities; S5. Elute the normal phase column with a second mobile phase at a predetermined second volume, and collect the second eluent rich in octyldodecyl alcohol; S6. Concentrate the second eluent to obtain high-purity octyldodecyl alcohol; The first mobile phase is a low-polarity organic solvent; The second mobile phase is a mixture of low-polarity organic solvents and high-polarity organic solvents.

2. The purification method of octyldodecanol according to claim 1, characterized by, The purity of the crude octyldodecyl alcohol is ≥90.0%.

3. The purification method of octyldodecanol according to claim 1, characterized by, The high-purity octyldodecyl alcohol obtained has a purity ≥97.0%, the sum of known impurities ≤1.5%, and the sum of unknown impurities ≤1.0%.

4. The purification method of octyldodecanol according to claim 1, characterized by, The low-polarity organic solvents in the first and second mobile phases are selected from at least one of n-hexane, cyclohexane, n-heptane, and petroleum ether. The highly polar organic solvent is selected from at least one of ethyl acetate, propyl acetate, isobutyl acetate, and methyl tert-butyl ether.

5. The method of purifying octyldodecanol according to claim 4, wherein When preparing the second mobile phase, the volume percentage of the highly polar organic solvent is ≥20%.

6. The method of purifying octyldodecanol according to claim 1, wherein The stationary phase is unbonded silicone, and its shape is spherical or amorphous; The unbonded silica gel has a particle size of 74μm~149μm and a pore size of 100 mesh~200 mesh.

7. The method of purifying octyldodecanol according to claim 1, wherein The sample solution was prepared by mixing crude octyldodecyl alcohol with the first mobile phase and stirring until homogeneous.

8. The method of purifying octyldodecanol according to claim 1, wherein The first amount of the first mobile phase is 0.8 to 1.0 times the capacity of the normal phase column.

9. The method for purifying octyldodecyl alcohol according to claim 1, characterized in that, The second amount of the second mobile phase is 1.2 to 2.0 times the capacity of the normal phase column.

10. The method for purifying octyldodecyl alcohol according to claim 1, characterized in that, When loading the sample, the mass of crude octyldodecyl alcohol in the sample solution is 0.05 to 0.3 times the mass of the stationary phase.

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