Chiral purity detection method of (S)-3-chloro-1, 2-propylene glycol

Abstract

The invention belongs to the technical field of organic matter detection, and particularly provides a chiral purity detection method of (S)-3-chloro-1, 2-propylene glycol, which comprises the following steps: S1, reacting (S)-3-chloro-1, 2-propylene glycol to be detected with a transforming agent to generate a derivative capable of absorbing ultraviolet rays; step S2, carrying out liquid chromatography detection on the derivative to obtain a liquid chromatogram; and S3, determining the chiral purity of the derivative based on the liquid chromatogram, and taking the chiral purity of the derivative as the chiral purity of the (S)-3-chloro-1, 2-propylene glycol to be detected. According to the chiral purity detection method of the (S)-3-chloro-1, 2-propylene glycol provided by the embodiment of the invention, the ultraviolet absorption group is derived and introduced into the (S)-3-chloro-1, 2-propylene glycol, so that the isomer can be detected and separated by using low-cost liquid chromatography, and the chiral purity of the (S)-3-chloro-1, 2-propylene glycol can be accurately determined on the basis.

Description

Technical Field

[0001] This invention belongs to the field of organic matter detection technology, and more specifically, relates to a method for detecting the chiral purity of (S)-3-chloro-1,2-propanediol. Background Technology

[0002] (S)-3-chloro-1,2-propanediol is an important pharmaceutical intermediate and a chiral raw material for many drugs, such as the migraine drug timolol and the fungal infection treatment drug itraconazole. Its chiral purity significantly affects drug synthesis and purification. Therefore, accurate and convenient detection of the chiral purity of (S)-3-chloro-1,2-propanediol is fundamental to the synthesis of many drugs.

[0003] (S)-3-chloro-1,2-propanediol presents significant challenges in directly determining its chiral purity due to its numerous polar functional groups. Currently, the common method involves derivatizing (S)-3-chloro-1,2-propanediol before detection. However, the weak UV absorption of (S)-3-chloro-1,2-propanediol and its derivatives makes it difficult to separate isomers using liquid chromatography. Current methods primarily rely on polarimetry (which carries significant errors) to determine specific rotation and chiral gas chromatography (GC) to assess the chiral purity of derivatives. However, GC typically requires high temperatures, and the availability and cost of chiral GC columns are limited, resulting in high experimental and detection costs. Summary of the Invention

[0004] In view of this, the purpose of this invention is to provide a convenient and reliable method for detecting the chiral purity of (S)-3-chloro-1,2-propanediol.

[0005] The method for determining the chiral purity of (S)-3-chloro-1,2-propanediol according to embodiments of the present invention includes: Step S1 involves reacting the (S)-3-chloro-1,2-propanediol to be tested with a conversion agent to generate a derivative capable of absorbing ultraviolet light. Step S2: Perform liquid chromatography detection on the derivative to obtain a liquid chromatogram; Step S3: Determine the chiral purity of the derivative based on the liquid chromatogram, and use it as the chiral purity of the (S)-3-chloro-1,2-propanediol to be tested.

[0006] In some embodiments of the present invention, the converting agent is a benzophenone-based ultraviolet absorber, which includes one or more of benzophenone, 2,4-dihydroxybenzophenone, 2,2',4,4'-tetrahydroxybenzophenone, 2,4,4'-trihydroxybenzophenone, and 2,2',4-trihydroxybenzophenone.

[0007] Furthermore, the converting agent is benzophenone, and the derivative is (S)-4-chloromethyl-2,2-diphenyl-1,3-dioxane.

[0008] Furthermore, in step S1, the reaction is carried out under acid catalysis, wherein the acid is one or more of p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, pyridine p-toluenesulfonate, and 2,4,6-trimethylpyridine p-toluenesulfonate.

[0009] Further, in step S1, the molar ratio of (S)-3-chloro-1,2-propanediol:benzophenone:acid is 2.0:1.0:(0.02-0.5).

[0010] Further, step S1 includes: In a reaction flask, toluene, (S)-3-chloro-1,2-propanediol and benzophenone were added, followed by the addition of p-toluenesulfonic acid monohydrate, and the mixture was refluxed to produce the (S)-4-chloromethyl-2,2-diphenyl-1,3-dioxane.

[0011] Furthermore, step S1 also includes: The reaction solution was washed successively with water, saturated sodium bicarbonate aqueous solution, and saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the (S)-4-chloromethyl-2,2-diphenyl-1,3-dioxane.

[0012] In some embodiments of the present invention, in step S2, the liquid chromatography detection conditions are as follows: the sample chamber temperature is room temperature, the chromatographic column is a chiral chromatographic column, the mobile phase A is chromatographically pure isopropanol, the mobile phase B is chromatographically pure n-hexane, and an isocratic elution program is used.

[0013] Furthermore, in the isocratic elution program, the ratio of mobile phase A to mobile phase B is 10:90, and the running time is 20 min.

[0014] Furthermore, the chiral chromatographic column is one of Thermo Fisher Scientific Hypersil Chiral OT, Daicel CHIRALPAK IK, or Daicel CHIRALPAK AY-H. The column dimensions can be 250 mm in length × 4.6 mm in inner diameter, with a packing particle diameter of 5 μm.

[0015] The above-described technical solution of the present invention has at least one of the following beneficial effects: This invention provides a convenient and reliable method for detecting the chiral purity of (S)-3-chloro-1,2-propanediol by introducing (S)-3-chloro-1,2-propanediol into a UV-absorbing group, thereby enabling detection by low-cost liquid chromatography. According to the detection method of the present invention, isomers can be well separated by using a suitable chiral chromatographic column, thereby enabling accurate determination of the chiral purity of (S)-3-chloro-1,2-propanediol; Furthermore, the method for obtaining the derivative (S)-4-chloromethyl-2,2-diphenyl-1,3-dioxane from (S)-3-chloro-1,2-propanediol is simple and easy to operate. Attached Figure Description

[0016] Figure 1 The chiral liquid chromatogram of the derivatized sample 4-chloromethyl-2,2-diphenyl-1,3-dioxane obtained in the experimental example is shown. Figure 2 The chiral liquid chromatogram of the derivative (S)-4-chloromethyl-2,2-diphenyl-1,3-dioxane obtained in Example 1 is shown. Detailed Implementation

[0017] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions 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 some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the described embodiments of the present invention are within the scope of protection of the present invention.

[0018] The following describes in detail the method for detecting the chiral purity of (S)-3-chloro-1,2-propanediol according to embodiments of the present invention.

[0019] The method for determining the chiral purity of (S)-3-chloro-1,2-propanediol according to embodiments of the present invention includes: Step S1 involves reacting the (S)-3-chloro-1,2-propanediol to be tested with a conversion agent to generate a derivative capable of absorbing ultraviolet light. Step S2: Perform liquid chromatography detection on the derivative to obtain a liquid chromatogram; Step S3: Determine the chiral purity of the derivative based on the liquid chromatogram, and use it as the chiral purity of the (S)-3-chloro-1,2-propanediol to be tested.

[0020] According to the method for determining the chiral purity of (S)-3-chloro-1,2-propanediol of the present invention (hereinafter sometimes referred to as the detection method), (S)-3-chloro-1,2-propanediol is first converted into a derivative capable of absorbing ultraviolet light. Then, its chiral purity can be determined by measuring its spectrum by liquid chromatography. Compared with gas chromatography, liquid chromatography has a lower operating temperature and a lower cost of gas chromatography columns, which can greatly reduce the detection cost.

[0021] The detection method will now be described in detail. (I) Derivative conversion (i.e., step S1: reacting the analyte (S)-3-chloro-1,2-propanediol with a converting agent to generate a derivative that can absorb ultraviolet light) According to the detection method of the present invention, the objective is to convert (S)-3-chloro-1,2-propanediol into a derivative capable of absorbing ultraviolet light, thereby determining the chiral purity of (S)-3-chloro-1,2-propanediol by testing the chiral purity of the derivative using liquid chromatography.

[0022] To this end, the test (S)-3-chloro-1,2-propanediol is first reacted with a conversion agent to generate a derivative that can absorb ultraviolet light.

[0023] In some embodiments of the present invention, as a conversion agent, a benzophenone-based ultraviolet absorber may be selected, specifically one or more of benzophenone, 2,4-dihydroxybenzophenone, 2,2',4,4'-tetrahydroxybenzophenone, 2,4,4'-trihydroxybenzophenone, and 2,2',4-trihydroxybenzophenone may be selected.

[0024] On the one hand, these absorbers can react with (S)-3-chloro-1,2-propanediol to introduce ultraviolet absorbing groups; on the other hand, these absorbers can form stable derivatives with (S)-3-chloro-1,2-propanediol without changing the chiral properties of (S)-3-chloro-1,2-propanediol.

[0025] The preferred converting agent is benzophenone. Benzophenone reacts with (S)-3-chloro-1,2-propanediol to obtain a derivative, namely (S)-4-chloromethyl-2,2-diphenyl-1,3-dioxane.

[0026] In some embodiments of the present invention, the reaction is carried out under acid catalysis. Acid catalysis allows proton transfer from the acid to the substrate, thereby accelerating the reaction and shortening the reaction time. The acid used may be one or more of p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, pyridine p-toluenesulfonate, and 2,4,6-trimethylpyridine p-toluenesulfonate.

[0027] Further, the molar ratio of (S)-3-chloro-1,2-propanediol:benzophenone:acid is 2.0:1.0:(0.02-0.5).

[0028] In one specific embodiment of the present invention, the derivative conversion process specifically includes: In a reaction flask, toluene, (S)-3-chloro-1,2-propanediol and benzophenone were added, followed by the addition of p-toluenesulfonic acid monohydrate, and the mixture was refluxed to produce the (S)-4-chloromethyl-2,2-diphenyl-1,3-dioxane.

[0029] The derivative, (S)-4-chloromethyl-2,2-diphenyl-1,3-dioxane, has strong ultraviolet absorption properties. Without changing the chiral purity of the analyte (S)-3-chloro-1,2-propanediol, the derivative can be used to detect and separate isomers in liquid chromatography.

[0030] Specifically, its reaction formula is shown in equation (1) below: (1) In other words, the derivative is converted in toluene solvent and reacted under acid catalysis using p-toluenesulfonic acid monohydrate under reflux conditions to produce the derivative, (S)-4-chloromethyl-2,2-diphenyl-1,3-dioxane. These conditions are simple and easy to operate.

[0031] Furthermore, it may also include: The reaction solution was washed successively with water, saturated sodium bicarbonate aqueous solution, and saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the (S)-4-chloromethyl-2,2-diphenyl-1,3-dioxane.

[0032] In other words, after the conversion is complete, only simple washing and post-treatment are needed to obtain the derivative (S)-4-chloromethyl-2,2-diphenyl-1,3-dioxane.

[0033] (ii) Liquid chromatography detection (i.e., step S2: perform liquid chromatography detection on the derivative to obtain a high performance liquid chromatogram) In other words, after converting (S)-3-chloro-1,2-propanediol into a derivative that can absorb ultraviolet light, namely (S)-4-chloromethyl-2,2-diphenyl-1,3-dioxane, its chiral purity needs to be determined by liquid chromatography.

[0034] In some embodiments of the present invention, in step S2, the liquid chromatography detection conditions are as follows: the sample chamber temperature is room temperature, the chromatographic column is a chiral chromatographic column, the mobile phase A is chromatographically pure isopropanol, the mobile phase B is chromatographically pure n-hexane, and an isocratic elution program is used.

[0035] In some embodiments of the present invention, in the isocratic elution program, the ratio of mobile phase A to mobile phase B is 10:90, and the running time is 20 min.

[0036] In some embodiments of the present invention, the chiral chromatographic column is a Thermo Fisher Hypersil Chiral OT or a Daicel CHIRALPAK. ® IK, CeraVe CHIRALPAK ®One of the AY-H series. Among them, using a Thermo Fisher Hypersil ChiralOT chiral column allows for better separation of the R and S isomers in the derivative.

[0037] In some embodiments of the invention, for example, the Thermo Fisher chiral column used is the Hypersil Chiral OT. As an example, the column size is, for example, 250 mm × 4.6 mm, 5 μm.

[0038] The liquid chromatogram can be obtained through the above detection.

[0039] (iii) Calculation of chiral purity (i.e., step S3: determine the chiral purity of the derivative based on the liquid chromatogram, and use it as the chiral purity of the (S)-3-chloro-1,2-propanediol to be tested) In other words, after obtaining the liquid chromatogram, the chiral purity of the derivative can be determined based on the liquid chromatogram, and the chiral purity of the (S)-3-chloro-1,2-propanediol to be tested can be determined accordingly.

[0040] Determining the purity of isomers based on liquid chromatography is common knowledge well known to those skilled in the art, and will not be elaborated upon here.

[0041] The detection method of the present invention will be further described in detail below through specific embodiments.

[0042] First, it was determined whether the isomers of 4-chloromethyl-2,2-diphenyl-1,3-dioxane with the R,S configuration could be separated by chiral liquid chromatography. Simultaneously, to eliminate the influence of derivatization on chirality, racemic 3-chloro-1,2-propanediol was used for derivatization using the method described in this application, and the resulting product was analyzed by chiral liquid chromatography. Racemic 3-chloro-1,2-propanediol derivatization and chiral liquid chromatography detection were performed in the experiment.

[0043] Add 80 mL of toluene, 8.5 g of racemic 3-chloro-1,2-propanediol, 7 g of benzophenone and 0.17 g of p-toluenesulfonic acid monohydrate to a 250 mL three-necked flask, and reflux for 12 h.

[0044] After the HPLC detection of benzophenone is completed, post-processing is performed.

[0045] Post-processing: The reaction solution was washed twice with 30 mL of water, once with 40 mL of saturated sodium bicarbonate aqueous solution, and once with 30 mL of saturated brine. After drying with anhydrous sodium sulfate, the solution was filtered and concentrated to obtain 9.08 g of the derivatized sample 4-chloromethyl-2,2-diphenyl-1,3-dioxane, with a yield of 86%.

[0046] The NMR results of the derivatized samples are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.47-7.52 (m, 4ArH), 7.28-7.35 (m, 6ArH), 4.38-4.44 (m, 1H), 4.10-4.12 (m, 1H), 3.98-4.08 (m, 1H), 3.63-3.67 (m, 1H),3.43-3.48 (m, 1H). The detection results are consistent with the structure of 4-chloromethyl-2,2-diphenyl-1,3-dioxane.

[0047] The product 4-chloromethyl-2,2-diphenyl-1,3-dioxane obtained in the experiment was subjected to chiral liquid chromatography detection. The liquid chromatography detection conditions are shown in Table 1 below:

[0048] Test results as follows Figure 1 As shown.

[0049] Depend on Figure 1 It can be seen that the R-type and S-type can be separated well.

[0050] In other words, based on this chiral liquid chromatogram, the content of each isomer can be determined by calculating the area ratio. Figure 1 The spectrum indicates that the S-isomer accounts for 50%, which corresponds to the racemic 3-chloro-1,2-propanediol.

[0051] This demonstrates that the derivatization method and chiral liquid chromatography detection method of this application can determine the chiral purity of the analyte (S)-3-chloro-1,2-propanediol. Example 1: (S)-3-chloro-1,2-propanediol derivatization and chiral liquid chromatography detection

[0052] Add 80 mL of toluene, 8.5 g of (S)-3-chloro-1,2-propanediol, 7 g of benzophenone and 0.17 g of p-toluenesulfonic acid monohydrate to a 250 mL three-necked flask, and reflux for 12 h.

[0053] After the HPLC detection of benzophenone is completed, post-processing is performed.

[0054] Post-processing: The reaction solution was washed twice with 30 mL of water, once with 40 mL of saturated sodium bicarbonate aqueous solution, and once with 30 mL of saturated brine. After drying with anhydrous sodium sulfate, the solution was filtered and concentrated to obtain 8.97 g of the derivatized sample (S)-4-chloromethyl-2,2-diphenyl-1,3-dioxane, with a yield of 85%.

[0055] The derivatized sample (S)-4-chloromethyl-2,2-diphenyl-1,3-dioxane obtained in Example 1 was subjected to chiral liquid chromatography detection under the same chiral liquid chromatography detection conditions as described above. The detection results are as follows: Figure 2 As shown.

[0056] based on Figure 2 The purity of the S isomer of the derivatized sample in Example 1 was 99.7% as obtained from the liquid chromatography detection chromatogram. Therefore, it can be inferred that the chiral purity of the (S)-3-chloro-1,2-propanediol to be detected is 99.7%.

[0057] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles 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 kind of ( S A method for determining the chiral purity of 3-chloro-1,2-propanediol, characterized in that, include: Step S1 involves reacting the (S)-3-chloro-1,2-propanediol to be tested with a conversion agent to generate a derivative capable of absorbing ultraviolet light. Step S2: Perform liquid chromatography detection on the derivative to obtain a liquid chromatogram; Step S3: Determine the chiral purity of the derivative based on the liquid chromatogram, and use it as the chiral purity of the (S)-3-chloro-1,2-propanediol to be tested.

2. The method for determining the chiral purity of (S)-3-chloro-1,2-propanediol according to claim 1, characterized in that, The converter is a benzophenone-based ultraviolet absorber, which includes one or more of benzophenone, 2,4-dihydroxybenzophenone, 2,2',4,4'-tetrahydroxybenzophenone, 2,4,4'-trihydroxybenzophenone, and 2,2',4-trihydroxybenzophenone.

3. The method for determining the chiral purity of (S)-3-chloro-1,2-propanediol according to claim 2, characterized in that, The converting agent is benzophenone, and the derivative is (S)-4-chloromethyl-2,2-diphenyl-1,3-dioxane.

4. The method for determining the chiral purity of (S)-3-chloro-1,2-propanediol according to claim 3, characterized in that, In step S1, the reaction is carried out under acid catalysis, wherein the acid is one or more of p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, pyridine p-toluenesulfonate, and 2,4,6-trimethylpyridine p-toluenesulfonate.

5. The method for determining the chiral purity of (S)-3-chloro-1,2-propanediol according to claim 3, characterized in that, In step S1, the molar ratio of (S)-3-chloro-1,2-propanediol:benzophenone:acid is 2.0:1.0:(0.02-0.5).

6. The method for determining the chiral purity of (S)-3-chloro-1,2-propanediol according to claim 3, characterized in that, Step S1 includes: In a reaction flask, toluene, (S)-3-chloro-1,2-propanediol and benzophenone were added, followed by the addition of p-toluenesulfonic acid monohydrate, and the mixture was refluxed to produce the (S)-4-chloromethyl-2,2-diphenyl-1,3-dioxane.

7. The method for determining the chiral purity of (S)-3-chloro-1,2-propanediol according to claim 6, characterized in that, Step S1 further includes: The reaction solution was washed successively with water, saturated sodium bicarbonate aqueous solution, and saturated brine, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the (S)-4-chloromethyl-2,2-diphenyl-1,3-dioxane.

8. The method for determining the chiral purity of (S)-3-chloro-1,2-propanediol according to claim 1, characterized in that, In step S2, the detection conditions for liquid chromatography are as follows: the sample chamber temperature is room temperature, the chromatographic column is a chiral chromatographic column, the mobile phase A is chromatographically pure isopropanol, the mobile phase B is chromatographically pure n-hexane, and an isocratic elution program is used.

9. The method for determining the chiral purity of (S)-3-chloro-1,2-propanediol according to claim 8, characterized in that, In the isocratic elution program, the ratio of mobile phase A to mobile phase B is 10:90, and the running time is 20 minutes.

10. The method for determining the chiral purity of (S)-3-chloro-1,2-propanediol according to claim 8, characterized in that, The chiral chromatographic column is one of Thermo Fisher Hypersil Chiral OT, Daicel CHIRALPAK IK, or Daicel CHIRALPAKAY-H.

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