Synthetic method of photoacid generator intermediate
By using ethyl bromide-2-fluoroacetic acid as a substrate and combining it with the synthetic route of Na2S2O4, triethylamine, hydrogen peroxide, sodium hydroxide, and concentrated sulfuric acid, the problems of highly toxic byproducts, high cost, and low yield in the synthesis of photo-induced acid-producing intermediates have been solved, and the large-scale production of high-purity, high-yield 2,2-difluoro-2-sulfonic acid has been achieved.
Patent Information
- Application Number
- CN202511924829.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-19
- Publication Date
- 2026-02-27
AI Technical Summary
The existing synthetic route for the photo-induced acid-producing intermediate 2,2-difluoro-2-sulfonic acid has problems such as highly toxic byproducts, difficulty in controlling the reaction, high cost, low yield, and difficulty in scaling up production.
Using ethyl bromide-2-fluoroacetic acid as the reaction substrate, 2,2-difluoro-2-sulfonic acid is synthesized via steps involving Na2S2O4, triethylamine, hydrogen peroxide, sodium hydroxide, and concentrated sulfuric acid. This method avoids highly toxic byproducts, employs reflux condensation and intermediate control, and results in a simple synthetic route with high yield.
A low-cost, high-yield synthesis without highly toxic byproducts was achieved, with high product purity, suitable for large-scale production.
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Abstract
Description
TECHNICAL FIELD
[0001] The application relates to the technical field of organic synthesis, in particular to a synthesis method of a photo-acid generator intermediate, in particular a synthesis method of 2,2-difluoro-2-sulfoacetic acid. BACKGROUND
[0002] The photo-acid generator is an important photosensitive material for semiconductor photoresist, and with the expansion of the production scale of KrF, ArF and other semiconductor photoresists, the market demand for the photo-acid generator will continue to release, and the industry development space is broad. As the photo-acid generator intermediate, the disclosed synthesis route of 2,2-difluoro-2-sulfoacetic acid is as follows: The route has the problems of toxic by-product hydrogen fluoride, great risk in scale production, uncontrollable reaction, unmonitorable reaction progress, insufficient reaction, residual raw materials which are difficult to separate, and great difficulty in purification. Another literature discloses a synthesis route as follows: The raw material of the route is expensive and difficult to purchase, needs to be customized, has high cost and is difficult to produce and scale.
[0003] Therefore, it is of great significance to develop a synthesis method of 2,2-difluoro-2-sulfoacetic acid which has a simple route, controllable reaction, no risk, low cost and high yield. SUMMARY
[0004] The application provides a synthesis method of a photo-acid generator intermediate, the raw material of the synthesis route is cheap bromo-difluoroacetic acid ethyl ester, the synthesis route is simple and risk-free, the reaction is controllable and complete, the yield is high, the purification is convenient, the product has high purity, and large-scale production can be realized; and the problems of toxic by-product, low yield, complex route, high cost and the like in the prior art are solved.
[0005] In order to solve the above technical problems, the application provides a synthesis method of a photo-acid generator intermediate, comprising the following steps:
[0006] S1, bromo-difluoroacetic acid ethyl ester is added into a mixed solution of Na2S2O4 and triethylamine, and stirring reaction is carried out, and the reaction formula is as follows:
[0007] ;
[0008] S2, hydrogen peroxide is added, stirring reaction is carried out, and the reaction formula is as follows:
[0009] ;
[0010] S3, after stirring reaction of sodium hydroxide, concentrated sulfuric acid is added for stirring reaction, and 2,2-difluoro-2-sulfoacetic acid is obtained, and the reaction formula is as follows:
[0011] .
[0012] The present application takes ethyl bromodifluoroacetate as a reaction substrate, which is cheap; the synthesis route is simple and there is no risk of toxic by-products; the reaction can be controlled and reacted completely, the yield is high, the purification is convenient, the product purity is high, and large-scale production can be realized; the problems of toxic by-products, low yield, complex route, high cost and the like in the prior art are solved.
[0013] Further, in S1, the adding of the ethyl bromodifluoroacetate into the mixed solution of Na2S2O4 and triethylamine is specifically: mixing Na2S2O4 with a solvent, placing in a cold bath, adding triethylamine, building a condensation reflux, and then adding ethyl bromodifluoroacetate. Preferably, the solvent is a mixed solvent of acetonitrile and water. Triethylamine base is easy to extract, avoiding the formation of sodium salt form by sodium hydroxide base, which is difficult to obtain and purify.
[0014] Further, the condensation reflux uses a -20℃~-10℃ condensation circulating pump.
[0015] Further, in S1, the reaction temperature is 50-60℃, and the reaction time is 4-5h.
[0016] Further, in S1, the equivalent ratio of the ethyl bromodifluoroacetate, Na2S2O4 and triethylamine is 1: (1.3-1.5): (1.3-1.5).
[0017] Further, in S2, the reaction temperature is 30-40℃, and the reaction time is 5-6h.
[0018] Further, the equivalent ratio of the ethyl bromodifluoroacetate and hydrogen peroxide is 1: (3-4).
[0019] Further, in S3, after adding sodium hydroxide, the reaction is carried out for 1-2h, and after adding concentrated sulfuric acid, the reaction is carried out for 1-2h.
[0020] Further, the equivalent ratio of the ethyl bromodifluoroacetate, sodium hydroxide and concentrated sulfuric acid is 1: (2-3): (9-10).
[0021] Further, in S1, after the reaction, the steps of adding water for dilution, ethyl acetate extraction, collecting organic phase and concentration are further included.
[0022] The beneficial effects of the present application are:
[0023] The present application takes ethyl bromodifluoroacetate as a reaction substrate, which is cheap; the synthesis route is simple and has no risk of toxic by-products; the reaction can be controlled and is complete, the yield is high, the product is easy to purify, the product purity is high, and large-scale production can be realized; and the problems of toxic by-products, low yield, complex route, high cost and the like in the prior art are solved. BRIEF DESCRIPTION OF DRAWINGS
[0024] In order to more clearly illustrate the technical solutions of the present application, the drawings needed in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor on the basis of these drawings.
[0025] Figure 1 is the carbon spectrum of the product 2,2-difluoro-2-sulfonic acid ethyl acetate obtained in Example 1 of the present application;
[0026] Figure 2 is the fluorine spectrum of the product 2,2-difluoro-2-sulfonic acid ethyl acetate obtained in Example 1 of the present application;
[0027] Figure 3 is the carbon spectrum of the product 2,2-difluoro-2-sulfonic acid ethyl acetate obtained in Example 2 of the present application;
[0028] Figure 4 is the fluorine spectrum of the product 2,2-difluoro-2-sulfonic acid ethyl acetate obtained in Example 2 of the present application;
[0029] Figure 5 is the fluorine spectrum of the product 2,2-difluoro-2-sulfonic acid ethyl acetate obtained in Comparative Example 1 of the present application. DETAILED DESCRIPTION
[0030] The technical solutions of the present application will be described below in conjunction with specific embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, not all. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of the present application.
[0031] The present embodiment relates to a synthesis method of a photoacid generator intermediate, comprising the following steps:
[0032] S1, adding ethyl bromodifluoroacetate into a mixed solution of Na2S2O4 and triethylamine, stirring and reacting, and the reaction formula is:
[0033] ;
[0034] S2, adding hydrogen peroxide, stirring and reacting, and the reaction formula is:
[0035] ;
[0036] S3, after adding sodium hydroxide and stirring the reaction, adding concentrated sulfuric acid and stirring the reaction to obtain 2, 2-difluoro-2-sulfonic acid ethyl acetate, the reaction formula is:
[0037] The embodiment uses bromo difluoroacetic acid ethyl ester as the reaction substrate, which is cheap; the synthesis route is simple and free of the risk of toxic by-products; the reaction can be controlled and completed completely, the yield is high, the purification is convenient, the product purity is high, and large-scale production can be realized; and the problems of toxic by-products, low yield, complex route, high cost and the like in the prior art are solved.
[0038] As a preferred embodiment, in S1, the adding of bromo difluoroacetic acid ethyl ester into the mixed solution of Na2S2O4 and triethylamine is specifically: mixing Na2S2O4 with a solvent, placing it in a cold bath, adding triethylamine, building a condensation reflux, and then adding bromo difluoroacetic acid ethyl ester; the condensation reflux uses a -20℃~-10℃ condensation circulating pump. Preferably, the solvent is a mixed solvent of acetonitrile and water. The use of triethylamine base is easy to extract, and avoids the formation of sodium salt in the form of sodium hydroxide base, which is difficult to obtain and purify in water.
[0039] As a preferred embodiment, in S1, the reaction temperature is 50-60℃, and the reaction time is 4-5h; the equivalent ratio of bromo difluoroacetic acid ethyl ester, Na2S2O4 and triethylamine is 1: (1.3-1.5): (1.3-1.5).
[0040] As a preferred embodiment, in S2, the reaction temperature is 30-40℃, and the reaction time is 5-6h; the equivalent ratio of bromo difluoroacetic acid ethyl ester and hydrogen peroxide is 1: (3-4).
[0041] As a preferred embodiment, in S3, after adding sodium hydroxide, the reaction is carried out for 1-2h, and after adding concentrated sulfuric acid, the reaction is carried out for 1-2h; the equivalent ratio of bromo difluoroacetic acid ethyl ester, sodium hydroxide and concentrated sulfuric acid is 1: (2-3): (9-10).
[0042] As a preferred embodiment, in S1, after the reaction, the steps of diluting with water, extracting with ethyl acetate, collecting the organic phase and concentrating are further included.
[0043] Example 1
[0044] The embodiment relates to a preparation method of 2, 2-difluoro-2-sulfonic acid ethyl acetate, comprising the following steps:
[0045] In a 1000 ml reaction flask, add (150 mmol, 1.5 eq, 25.95 g) Na2S2O4, 200 ml acetonitrile, 200 ml water, fully stir, put the system into ice water bath, add (150 mmol, 1.5 eq, 15.45 g) triethylamine, build condensation reflux (use -15°C condensation circulating pump), add (100 mmol, 1 eq, 20.19 g) ethyl bromodifluoroacetate, heat the system to 60°C, stir for 5h, and control the reaction by spotting on a plate.
[0046] After the reaction is completed, dilute with 200 ml water, extract with 200 ml ethyl acetate, separate the liquid, repeat three times, collect the organic phase, concentrate, and add the obtained product to (300 mmol, 3 eq, 34 ml) 30% hydrogen peroxide, heat to 40°C, react for 6h, and control by spotting on a plate.
[0047] After the reaction is completed, add (300 mmol, 3 eq, 12 g) sodium hydroxide, stir for 1h, add (1 mol, 10 eq, 98 g) concentrated sulfuric acid, stir for 1h, and distill the product (70 mmol, 12.32 g) 2,2-difluoro-2-sulfonic acid ethyl under reduced pressure. The yield is about 70.7%, and the product has the following properties: light yellow transparent liquid, the carbon spectrum of the product is shown in Figure 1 , and the fluorine spectrum of the product is shown in Figure 2 .
[0048] Example 2
[0049] This example relates to a method for scaling up the synthesis of 2,2-difluoro-2-sulfonic acid ethyl, comprising the following steps:
[0050] In a 5L reaction flask, add (750 mmol, 1.5 eq, 129.8 g) Na2S2O4, 1000 ml acetonitrile, 1000 ml water, fully stir, put the system into ice water bath, add (750 mmol, 1.5 eq, 77.25 g) triethylamine, build condensation reflux and flow water, add (500 mmol, 1 eq, 101 g) ethyl bromodifluoroacetate, heat the system to 60°C, stir for 5h, and control the reaction by spotting on a plate.
[0051] After the reaction is completed, dilute with 1000 ml water, extract with 2000 ml ethyl acetate, separate the liquid, repeat three times, collect the organic phase, concentrate, and add the obtained product to (1500 mmol, 3 eq, 170 ml) 30% hydrogen peroxide, heat to 40°C, react for 6h, and control by spotting on a plate.
[0052] The reaction was ended, sodium hydroxide (1500 mmol, 3 eq, 60 g) was added, stirred for 1 h, concentrated sulfuric acid (5 mol, 10 eq, 500 g) was added, stirred for 1 h, and the product (380 mmol, 67.26 g) 2,2-difluoro-2-sulfonic acid acetic acid was obtained by distillation under reduced pressure, with a yield of about 76%, and the product carbon spectrum was as shown in Figure 3 The product fluorine spectrum was as shown in Figure 4 .
[0053] Comparative Example 1
[0054] The comparative example relates to a preparation method of 2,2-difluoro-2-sulfonic acid acetic acid, comprising the following steps:
[0055] In a 1000 ml reaction bottle, 2-(fluorosulfonyl) difluoroacetyl fluoride (100 mmol, 18 g) and 200 ml formic acid were added, a condensation reflux was built, heated to 80℃, and reacted for 16 h (the byproduct hydrogen fluoride was absorbed with sodium hydroxide aqueous solution), until no gas was generated in the reaction, the reaction was ended, formic acid was removed by concentration under reduced pressure, and the product (500 mmol, 85 g) 2,2-difluoro-2-sulfonic acid acetic acid was obtained, with a yield of about 48%, and the product fluorine spectrum was as shown in Figure 5 HNMR results showed that the sulfonyl fluoride was not completely converted into sulfonic acid, and it was difficult to purify, because the reaction system contained a large amount of hydrogen fluoride, it was difficult to sample monitoring, and hydrogen fluoride was relatively dangerous in post-treatment, and it was difficult to scale up production.
[0056] The present application uses bromo difluoroacetic acid ethyl ester as a reaction substrate, which is cheap; the synthesis route is simple and has no risk of toxic byproducts; the reaction can be controlled and completely reacted, with high yield, convenient purification, high product purity, and large-scale production can be realized; and the problems of toxic byproducts, low yield, complex route, high cost and the like in the prior art are solved.
[0057] The present application has been described in detail in combination with the specific embodiments and exemplary examples, but these descriptions cannot be understood as limitations of the present application. Those skilled in the art understand that the technical solutions and embodiments of the present application can be variously replaced, modified or improved without departing from the spirit and scope of the present application, and these all fall within the scope of the present application. The protection scope of the present application is subject to the appended claims.
Claims
1. A method of synthesis of a photoacid generator intermediate, characterized in that, The method comprises the following steps: S1, adding ethyl bromodifluoroacetate into a mixed solution of Na2S2O4 and triethylamine, stirring and reacting, and the reaction formula is as follows: ； S2, adding hydrogen peroxide, stirring and reacting, and the reaction formula is as follows: ； S3, after adding sodium hydroxide and stirring and reacting, adding concentrated sulfuric acid and stirring and reacting, to obtain 2,2-difluoro-2-sulfonic acid ethyl, and the reaction formula is as follows: 。 2. The method of synthesis of a photoacid generator intermediate according to claim 1, wherein, In S1, the ethyl bromodifluoroacetate is added into the mixed solution of Na2S2O4 and triethylamine in the following manner: Na2S2O4 is mixed with a solvent and placed in a cold bath, triethylamine is added, a condensation reflux is built, and then ethyl bromodifluoroacetate is added.
3. The method of synthesis of photoacid generator intermediates as claimed in claim 2, wherein, The condensation reflux adopts a -20℃~-10℃ condensation circulating pump.
4. The method of synthesis of photoacid generator intermediates according to claim 1, wherein, In S1, the reaction temperature is 50-60℃, and the reaction time is 4-5h.
5. The method of synthesis of photoacid generator intermediates as claimed in claim 1 wherein, In S1, the equivalent ratio of ethyl bromodifluoroacetate, Na2S2O4 and triethylamine is 1:(1.3-1.5):(1.3-1.5).
6. The method of synthesis of photoacid generator intermediates as claimed in claim 1 wherein, In S2, the reaction temperature is 30-40℃, and the reaction time is 5-6h.
7. The method of synthesis of photoacid generator intermediates as claimed in claim 1 wherein, The equivalent ratio of ethyl bromodifluoroacetate and hydrogen peroxide is 1:(3-4).
8. The method of synthesis of photoacid generator intermediates as claimed in claim 1 wherein, In S3, after adding sodium hydroxide, the reaction is carried out for 1-2h, and after adding concentrated sulfuric acid, the reaction is carried out for 1-2h.
9. The method of synthesis of photoacid generator intermediates as claimed in claim 1 wherein, The equivalent ratio of ethyl bromodifluoroacetate, sodium hydroxide and concentrated sulfuric acid is 1:(2-3):(9-10).
10. The method of synthesis of photoacid generator intermediates as claimed in claim 1 wherein, In S1, after the reaction, the method further comprises the steps of adding water for dilution, ethyl acetate extraction, collecting the organic phase and concentration.