4. A process for the preparation of 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine.

Abstract

The application discloses a preparation method of 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine, which comprises two steps of reactions: in the first step, triethanolamine is used as a starting material, and intramolecular dehydration and ring formation reaction occur under the action of a catalyst iron trichloride, so that an intermediate N-hydroxyethyl morpholine is obtained after rectification; in the second step, nucleophilic substitution reaction occurs between the intermediate and 2-methoxyethoxymethyl chloride in an organic solvent under the action of an acid binding agent, so that 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine crude product is obtained after extraction, water removal and solvent rotary evaporation, and the crude product is purified to obtain 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine product; the use amount of the catalyst iron trichloride in the first step is 2% to 4% of the mass of the triethanolamine; and the mass ratio of the intermediate to the 2-methoxyethoxymethyl chloride is 1:1.2 to 1.4; the product prepared by the method has a purity meeting the demand of electronic chemicals, provides a raw material basis for subsequent research in the photoresist field, and has high industrial popularization value.

Description

Technical Field

[0001] This invention belongs to the field of electronic chemistry technology and relates to a method for preparing morpholine substances, particularly a method for preparing 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine. Background Technology

[0002] Morpholine, N-methylmorpholine, N-ethylmorpholine, etc. are a large class of heterocyclic tertiary amines, which have the properties of ethers and amines. They are widely used in the fields of medicine, pesticides, and chemical industry. More traditional applications include insecticides, plant growth regulators, and surfactants.

[0003] With the in-depth research on photoresist in China in recent years, there have been reports of applying morpholine substances to the preparation of photoresist stripping solutions. For example, Chinese invention patent application No. 202210374548.7 discloses "A photoresist stripping solution and its preparation method". The cyclic organic amine substances in the raw materials involve a variety of morpholine substances. The photoresist stripping solution disclosed in this invention has good stability and good stripping effect, and will not corrode the substrate such as aluminum gate, especially copper gate.

[0004] As an electronic chemical, it requires even higher purity and more sophisticated preparation processes. Currently, commercially available 4-(2-methoxyethyl)morpholine products with a purity of over 98% are expensive, costing two to three thousand yuan per hundred grams. The 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine product studied in this invention has a similar structure to 4-(2-methoxyethyl)morpholine, but it has a higher boiling point, is more stable, and has lower acidity, thus possessing greater application value.

[0005] However, reports on the preparation process of 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine are rare, and correspondingly, there are very few domestic suppliers that can provide this product. Summary of the Invention

[0006] The purpose of this invention is to develop a 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine product that meets the requirements for use in electronic chemicals, and its synthetic route and preparation method have been studied in depth.

[0007] The technical solution adopted in this invention is a method for preparing 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine. The key point is that the synthetic route of the above preparation method is as follows:

[0008]

[0009] The above preparation method includes two steps: the first step involves intramolecular dehydration and cyclization of triethanolamine as a starting material under the action of ferric chloride catalyst, followed by distillation to obtain the intermediate N-hydroxyethylmorpholine; the second step involves nucleophilic substitution of the intermediate with 2-methoxyethoxymethyl chloride in an organic solvent under the action of an acid-binding agent, followed by extraction, dehydration, and solvent drying to obtain crude 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine, which is then purified to obtain the 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine product; the amount of ferric chloride catalyst used in the first step is 2% to 4% of the mass of triethanolamine; the mass ratio of the intermediate to 2-methoxyethoxymethyl chloride is 1:1.2 to 1.4.

[0010] Specifically, the aforementioned catalyst, ferric chloride, requires dissolving solid ferric chloride in an equal mass of concentrated hydrochloric acid to prepare a ferric chloride hydrochloric acid solution for use as a catalyst.

[0011] Specifically, the reaction temperature of the first step reaction is 200℃~250℃, and the reaction time is 6h~8h; the reaction temperature of the second step reaction is 0℃~5℃, and the reaction time is 2h~4h.

[0012] Furthermore, the acid-binding agent mentioned above is any one of pyridine, triethylamine, and diethylamine; the mass ratio of the acid-binding agent to the intermediate N-hydroxyethylmorpholine is 1:0.5 to 1.0.

[0013] Furthermore, the aforementioned organic solvent is any one of acetonitrile, tetrahydrofuran, and N,N-dimethylformamide; the amount of organic solvent used per 100 grams of intermediate N-hydroxyethylmorpholine is 0.8L to 1.2L.

[0014] It should be noted that the second step of the above reaction needs to be carried out under the protection of an inert gas. The feeding method for the second step is to add 2-methoxyethoxymethyl chloride dropwise to the reactor containing the intermediate N-hydroxyethylmorpholine and the acid-binding agent, and control the dropping time and dropping temperature.

[0015] Preferably, the dropping time is 30 min to 60 min and the dropping temperature is -5℃ to 10℃.

[0016] It should also be noted that the crude 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine is purified by distillation. The fraction at the top of the column at 110°C is collected by vacuum distillation to obtain the 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine product.

[0017] Compared with the prior art, the present invention has the following advantages:

[0018] This invention studies a method for preparing morpholine-based products, specifically 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine. Suppliers of similar products are limited, and their market prices are relatively high. The product of this invention has a higher boiling point, greater stability, and lower acidity, thus possessing greater application value. The research on the preparation process of this invention enriches the diversity of similar products and market choices, providing a raw material foundation for subsequent research in the field of photoresists.

[0019] This invention uses triethanolamine, a commonly used chemical raw material, as a starting material to prepare 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine with a purity of over 99% through a two-step reaction. This product meets the purity requirements for use as an electronic chemical raw material (the purity requirement for this type of product is over 98%). The raw materials used in this invention are inexpensive, and no expensive precious metal catalysts are used. The process steps are also relatively simple, and the overall product yield can reach over 50%, making it highly valuable for industrial application. Attached Figure Description

[0020] Figure 1 This is the NMR spectrum of sample 1 of the present invention.

[0021] Figure 2 This is the gas chromatography spectrum of sample 1 of the present invention.

[0022] Figure 3 This is the high-performance gas phase spectrum of sample 1 of the present invention. Detailed Implementation

[0023] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0024] Unless otherwise specified in the examples, the procedures can be followed according to conventional conditions; unless the manufacturers of the reagents or instruments used are specified, they are all conventional products that can be purchased commercially.

[0025] Examples 1 to 4

[0026] In this embodiment, the synthetic route used is as follows:

[0027]

[0028] 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine was prepared by the following steps:

[0029] S1. Preparation of intermediate N-hydroxyethylmorpholine:

[0030] S1-1. Preparation of catalyst solution:

[0031] Dissolve ferric chloride crystals in an equal mass of concentrated hydrochloric acid, with a mass concentration of approximately 37%. The preparation process can be appropriately heated to facilitate complete dissolution of the solid.

[0032] S1-2, Synthetic Intermediate:

[0033] Add 150g of triethanolamine to the reactor, heat and stir, and add the catalyst solution prepared in step S1-1 dropwise. After the addition is complete, gradually raise the temperature to 200℃~250℃ and react for 6h~8h. During the reaction, intermediates and water are continuously distilled out and collected after condensation.

[0034] The collected liquid was distilled to obtain the intermediate N-hydroxyethylmorpholine, which was denoted as the intermediate sample.

[0035] Preparation of S2,4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine:

[0036] S2-1, Synthesis of 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine:

[0037] Add a certain volume of organic solvent, 130g of intermediate N-hydroxyethylmorpholine and a certain mass of acid-binding agent to the reactor, cool down under nitrogen protection, and add 2-methoxyethoxymethyl chloride dropwise, controlling the dropwise addition time. After the dropwise addition is completed, keep the temperature low for the reaction.

[0038] Purification of S2-2,4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine product:

[0039] After the reaction was completed, the reaction solution was quenched with water, extracted with ethyl acetate, the organic phases were combined, anhydrous magnesium sulfate and molecular sieve were added to remove water, and the solvent was evaporated under vacuum to collect the crude product.

[0040] The crude product was purified by distillation. 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine product sample was obtained by vacuum distillation at a top temperature of 110℃.

[0041] The specific types and amounts of raw materials and reaction parameters in Examples 1 to 4 are shown in Table 1. Intermediate samples 1 to 4 and product samples 1 to 4 were prepared respectively.

[0042] Table 1: Comparison of specific raw materials, dosages, and reaction parameters in the examples

[0043]

[0044]

[0045] Continued from Table 1: Comparison of specific raw materials, dosage ratios, and reaction parameters in the examples.

[0046]

[0047] Comparative Example 1

[0048] The specific implementation process is the same as in Example 1, except that in step S1-1, concentrated hydrochloric acid is not used to prepare the catalyst solution, but an equal mass of concentrated sulfuric acid is used as the catalyst preparation solution. The subsequent preparation process is the same as in Example 1, and intermediate reference standard 1 is prepared, and then product reference standard 1 is prepared.

[0049] Comparative Example 2

[0050] The specific implementation process is the same as in Example 1, except that in step S1-1, ferric chloride is not used as a catalyst, but an equimolar amount of aluminum chloride is used as a catalyst and mixed with concentrated hydrochloric acid to form an aluminum chloride solution. The subsequent preparation process is the same as in Example 1, and intermediate reference standard 2 is prepared, which in turn prepares product reference standard 2.

[0051] Comparative Example 3

[0052] The specific implementation process is the same as in Example 1, except that in step S1-1, concentrated hydrochloric acid is not used to prepare the catalyst solution, but an equal mass of water is used as the catalyst preparation solution. The subsequent preparation process is the same as in Example 1, and intermediate reference standard 3 is prepared, and then product reference standard 3 is prepared.

[0053] Comparative Example 4

[0054] The specific implementation process is the same as in Example 1, except that in step S2-1, the acid-binding agent used in this invention is not used, but an equimolar amount of sodium hydroxide is used as the acid-binding agent to prepare product reference standard 4.

[0055] Comparative Example 5

[0056] The specific implementation process is the same as in Example 1, except that in step S2-1, the time for adding 2-methoxyethoxymethyl chloride is controlled at 20 min, while the addition temperature, reaction time, and reaction temperature remain unchanged, and product reference standard 5 is prepared.

[0057] Analysis and Testing

[0058] The product samples prepared by this invention were analyzed by 1H NMR and HPLC-MS / MS, confirming that the obtained samples conform to the structural characteristics of 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine. The test chromatograms of some product samples are shown in the appendix. Figures 1-2 .

[0059] The purity of the samples and reference standards was determined by high-performance gas chromatography (HPLC), and the yield was calculated using the following formula. The results are shown in Table 2. For the chromatograms of some product samples, please refer to the appendix. Figure 3 .

[0060] The yield calculation formula is:

[0061] Formula 1: Intermediate yield = Actual weight of the intermediate obtained (g) / Theoretical yield calculated based on the amount of triethanolamine used (g) × 100%.

[0062] Formula 2: Product yield = Actual weight of the product obtained (g) / Theoretical yield calculated based on the amount of intermediate used (g) × 100%.

[0063] Formula 3: Overall yield = Intermediate yield × Product yield / 100%

[0064] Table 2: Summary of Purity and Yield Results

[0065]

[0066]

[0067] As shown in Table 2, the intermediate prepared by this invention achieves a purity of over 98.2%, an intermediate yield of over 75%, and a product purity of over 99.2%, meeting the purity requirements for electronic chemicals. In the study of the first-step reaction, it was found that using a metal catalyst with properties similar to ferric chloride, such as aluminum trichloride, also has a certain catalytic effect on the intramolecular dehydration and cyclization reaction of triethanolamine, but its catalytic effect is not as good as that of ferric chloride used in this invention. Furthermore, the catalytic effect is also related to the method of catalyst application. Generally, concentrated sulfuric acid is considered to promote dehydration reactions; however, in this invention, the effect of using concentrated sulfuric acid to prepare the catalyst is actually less than that of concentrated hydrochloric acid. This may be because triethanolamine reacts with concentrated hydrochloric acid to form triethanolamine hydrochloride. As the reaction proceeds, the triethanolamine hydrochloride gradually dissolves, releasing the hydrochloric acid and completing the intramolecular dehydration. The salt formed by the reaction of triethanolamine with concentrated sulfuric acid is relatively stable in the later stages of the reaction, thus forming impurities that are carried into the intermediate, reducing the yield and purity of the intermediate. Catalysts prepared without acidic solvents, such as using only water in Comparative Example 3, can avoid introducing some triethanolamine salt impurities, but the yield of intermediates is very low. This shows that choosing a suitable acidic solvent can also play a certain role as a phase transfer catalyst, which helps to improve catalytic efficiency and thus improve the yield of intermediates.

[0068] As for the second step reaction, the catalytic effect of using strong inorganic bases as acid-binding agents is far less than that of weak inorganic base catalysts. However, the yield of this step reaction is not particularly high, and there is still room for further research.

[0069] Impurity analysis of the product samples prepared according to this invention revealed that there were few types of impurities and their contents were low. Taking product sample 1 as an example, the impurity analysis results are shown in Table 3.

[0070] Table 3: Impurity analysis results of sample 1

[0071]

[0072] As shown in Table 3, the samples prepared by this invention contain few types of impurities, only four, and only one impurity with a content exceeding 0.2%. The study also found that excessive impurities carried by intermediates hinder product purification and increase its difficulty. The fewer the types and the lower the content of impurities carried by the intermediates, the more beneficial it is to preparing high-purity products. Therefore, improving the controllability of the intermediate preparation process, and thus improving the purity of the intermediates, is essential for preparing products that meet quality requirements.

Claims

A method for preparing 1,4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine, characterized in that, The synthetic route of the preparation method is as follows: The preparation method comprises two steps: the first step involves intramolecular dehydration and cyclization of triethanolamine as a starting material under the catalysis of ferric chloride, followed by distillation to obtain the intermediate N-hydroxyethylmorpholine; the second step involves a nucleophilic substitution reaction between the intermediate and 2-methoxyethoxymethyl chloride in an organic solvent under the action of an acid-binding agent, followed by extraction, dehydration, and solvent drying to obtain crude 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine, which is then purified to obtain the 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine product; the amount of ferric chloride catalyst used in the first step is 2% to 4% of the mass of triethanolamine; the mass ratio of the intermediate to 2-methoxyethoxymethyl chloride is 1:1.2 to 1.

4.

2. The method for preparing 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine according to claim 1, characterized in that, The catalyst, ferric chloride, needs to be prepared by dissolving solid ferric chloride in an equal mass of concentrated hydrochloric acid to form a ferric chloride hydrochloric acid solution for use as a catalyst.

3. The method for preparing 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine according to claim 1, characterized in that, The reaction temperature of the first step is 200℃~250℃, and the reaction time is 6h~8h; the reaction temperature of the second step is 0℃~5℃, and the reaction time is 2h~4h.

4. The method for preparing 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine according to claim 1, characterized in that, The acid-binding agent is any one of pyridine, triethylamine, and diethylamine; the mass ratio of the acid-binding agent to the intermediate N-hydroxyethylmorpholine is 1:0.5 to 1.

0.

5. The method for preparing 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine according to claim 1, characterized in that, The organic solvent is any one of acetonitrile, tetrahydrofuran, and N,N-dimethylformamide; the amount of organic solvent used is 0.8L to 1.2L per 100g of intermediate N-hydroxyethylmorpholine.

6. The method for preparing 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine according to claim 1, characterized in that, The second step reaction needs to be carried out under inert gas protection. The feeding method for the second step reaction is to add 2-methoxyethoxymethyl chloride dropwise to a reactor containing the intermediate N-hydroxyethylmorpholine and the acid-binding agent, and control the dropping time and dropping temperature.

7. The method for preparing 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine according to claim 6, characterized in that, The dripping time is 30 min to 60 min, and the dripping temperature is -5℃ to 10℃.

8. The method for preparing 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine according to claim 1, characterized in that, The crude 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine was purified by distillation. The fraction at the top of the column at 110°C was collected by vacuum distillation to obtain the 4-[2-[(2-methoxyethoxy)methoxy]ethyl]morpholine product.

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