A method for preparing high purity 2-(2-methoxycarbonyl ethyl)-2-oxazoline

Abstract

The application discloses a preparation method of high-purity 2-(2-methoxycarbonyl ethyl)-2-oxazoline. The 2-(2-methoxycarbonyl ethyl)-2-oxazoline is purified through the following steps: blending and extracting 2-(2-methoxycarbonyl ethyl)-2-oxazoline crude products with a solvent, and then performing three-stage vacuum distillation, so that the purity of the 2-(2-methoxycarbonyl ethyl)-2-oxazoline can reach 99.9%, and the problems that methylation is prone to occur and by-products exist when 2-(2-methoxycarbonyl ethyl)-2-oxazoline itself is ring-closed are solved, thereby meeting the use requirements of medical adhesives.

Description

Technical Field

[0001] This invention relates to a method for preparing high-purity 2-(2-methoxycarbonylethyl)-2-oxazoline, belonging to the field of biomedical materials. Specifically, this invention relates to a multi-stage distillation purification method for 2-(2-methoxycarbonylethyl)-2-oxazoline, and the resulting high-purity compound can be used in the subsequent preparation of medical adhesives. Background Technology

[0002] In modern medicine, controlling bleeding is one of the major challenges during surgical procedures on solid organs. Common methods such as suturing, electrocautery, and ultrasonic sealing are often insufficient for surgeries involving the liver or kidneys. Therefore, alternative methods are needed to control bleeding in procedures like liver resection and nephrectomy, making the development of local hemostatic agents a superior alternative.

[0003] Currently, most hemostatic products have certain drawbacks: biologically derived polymeric materials such as starch, chitosan, collagen, or gelatin, although these biocompatible and biodegradable products can accelerate the natural coagulation cross-linking reaction, usually have limited hemostatic effects and are difficult to apply to actual cases of large-area bleeding. In addition, animal-derived products also pose a risk of viral or prion transmission. Recent approaches combine the beneficial properties of natural and synthetic polymers. For example, Hemopatch, a porous collagen carrier coated with 4arm-PEG-NHS, exhibits better hemostatic effects compared to other commercially available products. However, the inherent rapid cross-linking mechanism of 4arm-PEG-NHS can lead to irregular sealing of the wound site or poor fixation with tissue. Furthermore, the hydrophilicity of PEG can cause the polymer to detach from the carrier during bleeding. These potential drawbacks need to be addressed by modifying the polymer structure. However, PEG has limited options in terms of customized functionalization and polarity. Therefore, poly(2-oxazoline) has been developed as an alternative. Its cationic ring-opening polymerization process can introduce functional side chains and end groups, and can also synthesize a series of copolymers, thereby precisely controlling the polymer polarity and the degree of side chain functionalization.

[0004] Commonly used medical adhesives containing poly(2-oxazoline) components primarily utilize poly(2-oxazoline) copolymers, with monomers including 2-ethyl-2-oxazoline and 2-(2-methoxycarbonylethyl)-2-oxazoline. While 2-ethyl-2-oxazoline is commercially available, 2-(2-methoxycarbonylethyl)-2-oxazoline requires a designed reaction for synthesis. Patents CN108939174A and CN118546102A each propose a synthetic method for 2-(2-methoxycarbonylethyl)-2-oxazoline. However, due to the tendency for methylation or the presence of byproducts during cyclization of 2-(2-methoxycarbonylethyl)-2-oxazoline, its NMR spectra exhibit significant impurity peaks at 2.5-2.75 ppm, resulting in purity levels insufficient for the synthesis of medical adhesives. Summary of the Invention

[0005] Technical Problem: The purpose of this invention is to provide a method for preparing high-purity 2-(2-methoxycarbonylethyl)-2-oxazoline. Starting from the crude product of 2-(2-methoxycarbonylethyl)-2-oxazoline, a three-stage vacuum distillation is performed on it, so that the purity of 2-(2-methoxycarbonylethyl)-2-oxazoline meets the requirements for the synthesis of medical adhesives.

[0006] Technical solution:

[0007] The present invention provides a technical solution for preparing high-purity 2-(2-methoxycarbonylethyl)-2-oxazoline, as follows:

[0008] A high-purity 2-(2-methoxycarbonylethyl)-2-oxazoline, characterized in that: the compound has the following structural formula:

[0009] .

[0010] A method for preparing high-purity 2-(2-methoxycarbonylethyl)-2-oxazoline as described in claim 1, comprising the following specific steps:

[0011] Step 1: Extraction with 2-(2-methoxycarbonylethyl)-2-oxazoline and extractant;

[0012] Step 2: 2-(2-methoxycarbonylethyl)-2-oxazoline is subjected to first-stage vacuum distillation;

[0013] Step 3: 2-(2-methoxycarbonylethyl)-2-oxazoline is mixed with a solvent and then subjected to two-stage vacuum distillation;

[0014] Step 4: 2-(2-methoxycarbonylethyl)-2-oxazoline is subjected to three-stage vacuum distillation.

[0015] In step one, the specific extractant can be ethyl acetate, dichloromethane, dichloroethane, or water. The mass-to-volume ratio of the crude compound to the extractant is 500 g: 10 L, and the volume ratio of the aqueous phase to the organic phase in the extractant is 4:1. The extraction is repeated three times, the organic phases are combined, and the organic phase is concentrated.

[0016] In step two, the concentrated organic phase is subjected to first-stage distillation under reduced pressure at a temperature of 140~170°C.

[0017] In step three, the first-stage fraction is mixed with dichloroethane solvent at a temperature of 110~140℃ and then subjected to secondary vacuum distillation.

[0018] In step four, the secondary fraction is mixed with a specific solvent at a temperature of 70~110℃ and then subjected to tertiary vacuum distillation.

[0019] The obtained final product is subjected to nuclear magnetic resonance detection to obtain the corresponding spectrum, and its purity is calculated.

[0020] Beneficial effects: This invention improves the purity of 2-(2-methoxycarbonylethyl)-2-oxazoline. The purity of 2-(2-methoxycarbonylethyl)-2-oxazoline purified using the method of this application can reach 99.9%, which meets the requirements of medical-grade raw materials. Attached Figure Description

[0021] Figure 1 The image shows the 1H NMR spectrum of 2-(2-methoxycarbonylethyl)-2-oxazoline obtained in Comparative Example 1.

[0022] Figure 2 The 1H NMR spectrum of 2-(2-methoxycarbonylethyl)-2-oxazoline obtained in Example 1.

[0023] Figure 3 The image shows the 1H NMR spectrum of 2-(2-methoxycarbonylethyl)-2-oxazoline obtained in Example 2.

[0024] Figure 4 The image shows the 1H NMR spectrum of 2-(2-methoxycarbonylethyl)-2-oxazoline obtained in Example 3.

[0025] Figure 5 The image shows the 1H NMR spectrum of 2-(2-methoxycarbonylethyl)-2-oxazoline obtained in Example 4.

[0026] Figure 6 The 1H NMR spectrum of 2-(2-methoxycarbonylethyl)-2-oxazoline obtained in Example 5. Detailed Implementation

[0027] The technical solutions described in this invention will be further described in detail below through specific embodiments, so that the advantages and features of this invention can be more easily understood by those skilled in the art, thereby making a clearer and more explicit definition of the scope of protection of this invention.

[0028] Simultaneously, by nuclear magnetic resonance hydrogen spectroscopy 1 H-NMR was used to identify the structure and calculate the purity of the final product obtained in step four.

[0029] Comparative Example 1

[0030] 2-(2-methoxycarbonylethyl)-2-oxazoline was synthesized according to the synthesis method described in patent CN118546102A.

[0031] In this comparative example, the purity of 2-(2-methoxycarbonylethyl)-2-oxazoline was 78.2%, and the results... Figure 1 middle 1 Calculated by H NMR.

[0032] Example 1

[0033] A method for preparing high-purity 2-(2-methoxycarbonylethyl)-2-oxazoline, comprising the following specific steps:

[0034] Step 1: Take 100 g of 2-(2-methoxycarbonylethyl)-2-oxazoline synthesized in Comparative Example 1, add 2 L of ethyl acetate in batches and extract three times, then combine the organic phases.

[0035] Step 2: Distill the extract under reduced pressure at 150°C.

[0036] Step 3: Take 75 g of the first-stage distillate, add 50 mL of dichloroethane, and distill under reduced pressure at 130 °C.

[0037] Step 4: Take 50 g of the second distillation fraction and distill it under reduced pressure at 70 °C.

[0038] The purity of the purified 2-(2-methoxycarbonylethyl)-2-oxazoline in this embodiment is based on... Figure 2 middle 1 Calculated by H NMR.

[0039] Example 2

[0040] The difference from Example 1 lies in the choice of organic phase for extraction; all other steps are the same, and the specific steps include the following:

[0041] Step 1: Take 100 g of 2-(2-methoxycarbonylethyl)-2-oxazoline synthesized in Comparative Example 1, add 2 L of dichloroethane in batches and extract three times, then combine the organic phases.

[0042] Step 2: Distill the extract under reduced pressure at 150 °C.

[0043] Step 3: Take 75 g of the first-stage distillate, add 50 mL of dichloroethane, and distill under reduced pressure at 130 °C.

[0044] Step 4: Take 50 g of the second distillation fraction and distill it under reduced pressure at 70 °C.

[0045] Example 3

[0046] The difference from Example 1 lies in the temperature selected for the first-stage distillation; all other steps are the same. The specific steps include the following:

[0047] Step 1: Take 100 g of 2-(2-methoxycarbonylethyl)-2-oxazoline synthesized in Comparative Example 1, add 2 L of ethyl acetate in batches and extract three times, then combine the organic phases.

[0048] Step 2: Distill the extract under reduced pressure at 165 °C.

[0049] Step 3: Take 75 g of the first-stage distillate, add 50 mL of dichloroethane, and distill under reduced pressure at 130 °C.

[0050] Step 4: Take 50 g of the second distillation fraction and distill it under reduced pressure at 70 °C.

[0051] Example 4

[0052] The difference from Example 1 lies in the temperature selected for the second-stage distillation; all other steps are the same. The specific steps include the following:

[0053] Step 1: Take 100 g of 2-(2-methoxycarbonylethyl)-2-oxazoline synthesized in Comparative Example 1, add 2 L of ethyl acetate in batches and extract three times, then combine the organic phases.

[0054] Step 2: Distill the extract under reduced pressure at 150 °C.

[0055] Step 3: Take 75 g of the first-stage distillate, add 50 mL of dichloroethane, and distill under reduced pressure at 110 °C.

[0056] Step 4: Take 50 g of the second distillation fraction and distill it under reduced pressure at 70 °C.

[0057] Example 5

[0058] The difference from Example 1 lies in the temperature selected for the three-stage distillation; all other steps are the same. The specific steps include the following:

[0059] Step 1: Take 100 g of 2-(2-methoxycarbonylethyl)-2-oxazoline synthesized in Comparative Example 1, add 2 L of ethyl acetate in batches and extract three times, then combine the organic phases.

[0060] Step 2: Distill the extract under reduced pressure at 150 °C.

[0061] Step 3: Take 75 g of the first-stage distillate, add 50 mL of dichloroethane, and distill under reduced pressure at 110 °C.

[0062] Step 4: Take 50 g of the second distillation fraction and distill it under reduced pressure at 90 ℃.

[0063] Table 1 shows the experimental results of the purity of 2-(2-methoxycarbonylethyl)-2-oxazoline purified in Examples 1 to 5. As can be seen from the purity data in the table and the examples, compared with the purity of the crude 2-(2-methoxycarbonylethyl)-2-oxazoline in Comparative Example 1, the purity of 2-(2-methoxycarbonylethyl)-2-oxazoline can be significantly improved by the operating method of the present invention. Compared with Example 1, Example 2 changed the extractant, Example 3 changed the temperature of the first-stage distillation, Example 4 changed the temperature of the second-stage distillation, and Example 5 changed the temperature of the third-stage distillation; the purity decreased in all these cases.

[0064] Table 1. Purity of 2-(2-methoxycarbonylethyl)-2-oxazoline under different conditions

[0065] sample Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 purity 99.97% 94.2% 88.5% 86.6% 95.3% 78.2%

[0066] The above examples are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and to apply it accordingly. They should not be used to limit the scope of protection of the present invention. All equivalent changes or modifications made according to the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A high-purity 2-(2-methoxycarbonylethyl)-2-oxazoline, characterized in that: The structural formula of the compound is: 。 2. A method for preparing high-purity 2-(2-methoxycarbonylethyl)-2-oxazoline as described in claim 1, characterized in that... The specific steps include the following: Step 1: Extraction with 2-(2-methoxycarbonylethyl)-2-oxazoline and extractant; Step 2: 2-(2-methoxycarbonylethyl)-2-oxazoline is subjected to first-stage vacuum distillation; Step 3: 2-(2-methoxycarbonylethyl)-2-oxazoline is mixed with a solvent and then subjected to two-stage vacuum distillation; Step 4: 2-(2-methoxycarbonylethyl)-2-oxazoline is subjected to three-stage vacuum distillation.

3. The method for preparing high-purity 2-(2-methoxycarbonylethyl)-2-oxazoline according to claim 2, characterized in that: In step one, the specific extractant can be ethyl acetate, dichloromethane, dichloroethane, or water. The mass-to-volume ratio of the crude compound to the extractant is 500 g: 10 L, and the volume ratio of the aqueous phase to the organic phase in the extractant is 4:

1. The extraction is repeated three times, the organic phases are combined, and the organic phase is concentrated.

4. The method for preparing high-purity 2-(2-methoxycarbonylethyl)-2-oxazoline according to claim 3, characterized in that: In step two, the concentrated organic phase is subjected to first-stage distillation under reduced pressure at a temperature of 140~170°C.

5. The method for preparing high-purity 2-(2-methoxycarbonylethyl)-2-oxazoline according to claim 4, characterized in that: In step three, the first-stage fraction is mixed with dichloroethane solvent at a temperature of 110~140℃ and then subjected to secondary vacuum distillation.

6. The method for preparing high-purity 2-(2-methoxycarbonylethyl)-2-oxazoline according to claim 5, characterized in that: In step four, the secondary fraction is mixed with a specific solvent at a temperature of 70~110℃ and then subjected to tertiary vacuum distillation.

7. The purity of the final product obtained according to claim 6 is calculated by obtaining the corresponding spectrum through nuclear magnetic resonance detection.

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