Synthesis method of methyl 4-formyl butyrate

Abstract

The invention discloses a synthesis method of methyl 4-formylbutyrate, and belongs to the technical field of chemical synthesis, methyl acrylate and nitromethane are subjected to a Michael addition reaction under the action of a catalyst to prepare methyl 4-nitrobutyrate, and the excessive undissolved catalyst can be recycled after being filtered; the method comprises the following steps: under the action of sodium tert-butoxide and potassium permanganate, carrying out hydrolytic oxidation reaction on methyl 4-nitrobutyrate, adding a sodium hydrogen sulfite aqueous solution and a sulfuric acid solution after the reaction is completed, consuming excessive potassium permanganate oxidant, reducing by-products, and carrying out purification treatment to obtain high-purity methyl 4-formyl butyrate. The synthesis method provided by the invention has the advantages of cheap and easily available raw materials, simple operation, easily controllable conditions, high total yield and easy realization of industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing 4-aldehyde butyric acid methyl ester. Background Art

[0002] Methyl 4-aldehyde butyrate is a 1,4-dicarbonyl compound with diverse chemical reactivity. It is mainly used as an organic synthesis intermediate and a raw material for pharmaceutical molecules. Literature reports show that this substance can be used for the preparation of quinazoline kinase inhibitors.

[0003] The structure of 4-formylbutyric acid methyl ester contains aldehyde units and ester structures, and has rich chemical reactivity. The aldehyde and ester units in its structure can undergo reduction reaction under the action of a reducing agent to obtain the corresponding 1,4-diol derivatives; it can also undergo olefination reaction (Wittig reaction) to obtain the corresponding olefin derivatives; in addition, it can also undergo condensation reaction with organic amine substances to obtain the corresponding imine derivatives. As a multifunctional compound, 4-formylbutyric acid methyl ester is widely used as an intermediate in organic synthesis. It can be used to synthesize various complex organic compounds, including functional materials such as drugs, pesticides and fragrances, through different reaction pathways, such as reduction, olefination, condensation, etc.

[0004] In the prior art, there are three main methods for synthesizing 4-formylbutyrate (methyl 4-oxobutyrate), the first of which is oxidation of 4-hydroxybutyrate, the second of which is reduction of 4-chloroformylbutyrate, and the third of which is hydrolysis or ozone oxidation of 4-nitrobutyrate. These methods are complicated to operate, require expensive catalysts or highly toxic and polluting chemical reagents, have high synthesis costs, and the yield still needs to be improved.

[0005] The patent application document with announcement number CN115385789B discloses a method for synthesizing methyl 4-oxobutyrate, which uses γ-butyrolactone as a starting material and sequentially undergoes hydrolysis and oxidation to obtain methyl 4-oxobutyrate. The reaction route of the method is as follows:

[0006]

[0007] This route first prepares 4-hydroxybutyric acid methyl ester by hydrolysis of γ-butyrolactone, and then oxidizes the 4-position alcohol to synthesize 4-oxobutyric acid methyl ester. The reaction conditions are mild, the solvent can be reused repeatedly, and the pollution to the environment is small. Its oxidant system is TEMPO / NaNO2. As a selective oxidant, TEMPO can oxidize alcohol to aldehyde with high selectivity, but TEMPO needs to be stored at low temperature and is expensive. It is only suitable for small-scale laboratory applications. It is costly in industrial production and requires additional storage and management costs.

[0008] Based on the above problems, the improvement of the industrial production process of 4-formylbutyric acid methyl ester is a major problem in medicinal chemistry. It is of great significance to design and develop a synthetic method with low production cost, simple operation, low environmental pollution, high yield and easy industrialization. Summary of the invention

[0009] The object of the present invention is to provide a method for synthesizing methyl 4-aldehyde butyrate, wherein the raw materials are cheap and readily available, the conditions are easily controlled, the product purity and yield are high, the method is green and environmentally friendly and easy to industrialize.

[0010] The purpose of the present invention can be achieved through the following technical solutions:

[0011] The present invention provides a method for synthesizing methyl 4-aldehyde butyrate, comprising the following steps:

[0012] Step 1, dissolving methyl acrylate in nitromethane, adding an inorganic solid base catalyst, stirring at room temperature for 24-72 hours, filtering potassium carbonate after the reaction is completed, concentrating under reduced pressure to recover nitromethane, and distilling under reduced pressure to obtain methyl 4-nitrobutyrate;

[0013] Step 2: Under nitrogen protection, heat sodium tert-butoxide and dissolve it in tert-butanol, add the methyl 4-nitrobutyrate, and stir at room temperature for 1-2 hours;

[0014] Step 3: After the stirring is completed, add n-heptane and stir evenly, cool to 0-5°C, add potassium permanganate aqueous solution dropwise, stir for 1-2h after the addition is completed, add sodium bisulfite aqueous solution and sulfuric acid solution, separate the organic layer, wash and dry it, filter it, concentrate it under reduced pressure to recover n-heptane to obtain a crude product, and distill the crude product under reduced pressure to obtain pure 4-aldehyde butyric acid methyl ester.

[0015] The target product methyl 4-nitrobutyrate is prepared by Michael addition reaction of methyl acrylate and nitromethane under the catalytic action of an inorganic solid base catalyst, and the sodium salt is obtained by removing active hydrogen at the ortho-carbon of the nitro group by sodium alcohol, and the aldehyde group is obtained by oxidation with potassium permanganate, and the excessive oxidation of potassium permanganate is inhibited by sodium bisulfite and sulfuric acid, so that the reaction prepares methyl 4-aldehyde butyrate with higher purity.

[0016] Furthermore, the volume ratio of the methyl acrylate to nitromethane is 1:10-20.

[0017] When the ratio of methyl acrylate to nitromethane is large, the amount of methyl acrylate is large, and di- and tri-substituted by-products will be produced. When the ratio is small, the amount of nitromethane is excessive, which can make methyl acrylate fully participate in the reaction, and the yield of the mono-substituted product 4-nitrobutyric acid methyl ester generated by the reaction is high.

[0018] Furthermore, the inorganic solid base catalyst is one of potassium carbonate and sodium bicarbonate. The inorganic solid base catalyst is an environmentally friendly catalyst and has the advantages of simple operation, no pollution and simple post-treatment.

[0019] Furthermore, the molar ratio of the inorganic solid base catalyst to methyl acrylate is 1-2:10, and an increase in the amount of the catalyst can improve the efficiency of the reaction.

[0020] Furthermore, the mass ratio of the sodium tert-butoxide to tert-butanol is 1:6-7.

[0021] Furthermore, in step 2, the heating temperature of sodium tert-butoxide to dissolve in tert-butanol is 30-45°C.

[0022] Furthermore, in step 2, the molar ratio of methyl 4-nitrobutyrate to sodium tert-butoxide is 1:2-2.2.

[0023] Furthermore, the volume ratio of n-heptane to tert-butanol is 1-3:1.

[0024] Furthermore, in step 3, the mass concentration of the potassium permanganate aqueous solution is 3-5%, and the potassium permanganate aqueous solution is added dropwise at a molar ratio of potassium permanganate to methyl 4-nitrobutyrate added in step 2 of 0.5-1:1. If the concentration of the potassium permanganate aqueous solution is too high, the oxidizing property will be too strong during the addition process, resulting in side reactions. Therefore, the concentration of the potassium permanganate aqueous solution needs to be controlled to reduce by-products.

[0025] Furthermore, in step 3, the potassium permanganate aqueous solution is added dropwise for 1-2 hours. The rate of addition should not be too fast, which will cause excessive potassium permanganate to produce byproducts locally.

[0026] Furthermore, the concentration of the sodium bisulfite aqueous solution is 0.5-1 mol / L, and the sodium bisulfite aqueous solution is added at a molar ratio of sodium bisulfite to potassium permanganate of 4:2-3.

[0027] Furthermore, the concentration of the sulfuric acid solution is 0.5-1 mol / L, and the sulfuric acid solution is added at a molar ratio of sulfuric acid to sodium bisulfite of 1:1-1.2.

[0028] The addition of sodium bisulfite and sulfuric acid can not only effectively remove excess potassium permanganate, but also improve the efficiency of the oxidation reaction and generate harmless by-products, playing an important auxiliary role.

[0029] Furthermore, the washing uses deionized water as a detergent, and the drying uses anhydrous sodium sulfate as a desiccant.

[0030] The reaction route of the above-mentioned synthesis method is as follows (taking potassium carbonate as a catalyst as an example):

[0031]

[0032] Beneficial effects of the present invention:

[0033] (1) In the synthesis method of methyl 4-formylbutyrate provided by the present invention, methyl acrylate and nitromethane, which are cheap and readily available, are used as raw materials, methyl 4-nitrobutyrate is prepared by Michael addition reaction under the catalytic action of an inorganic solid base catalyst, and the target product methyl 4-formylbutyrate is obtained by reaction in the presence of sodium alcoholate and potassium permanganate. The operation is simple, the conditions are easy to control, the total yield is high, the product is easy to purify, and industrial production is easy to achieve.

[0034] (2) The present invention uses an inorganic solid base catalyst (potassium carbonate or sodium bicarbonate) as a catalyst for the Michael addition reaction, potassium permanganate as an oxidant, and sodium bisulfite and sulfuric acid consume excess potassium permanganate, wherein the inorganic solid base catalyst is not completely dissolved in the reaction system, and the excess undissolved portion can be filtered and recovered for reuse. Potassium permanganate has strong oxidation selectivity, and after the oxidation reaction, the excess potassium permanganate can be consumed by adding sodium bisulfite and sulfuric acid. The formed product is non-toxic, which is convenient for controlling the degree of oxidation reaction and post-treatment. DETAILED DESCRIPTION

[0035] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0036] Example 1

[0037] Step 1, add 860g of methyl acrylate (10mol) into a 10L three-necked flask, then add 9L of nitromethane (the volume ratio of methyl acrylate to nitromethane is 1:10), stir and dissolve, then add 276g of potassium carbonate (2mol) into the flask, stir and react at room temperature (20°C-30°C) for 48h, filter after the reaction is completed, remove potassium carbonate, concentrate the filtrate under reduced pressure to recover nitromethane, and then perform reduced pressure distillation, use a high vacuum oil pump, set the external temperature to 120°C, collect the fraction with a boiling point of 95-100°C / 8mmHg, and obtain 1146g of methyl 4-nitrobutyrate, with a yield of 78%;

[0038] Step 2: Under nitrogen protection, 192 g of sodium tert-butoxide (2 mol) and 1500 mL of tert-butanol (1163 g) were added to a three-necked flask, and the temperature was raised to 45 ° C. while stirring, and the stirring was continued at a constant temperature until it was completely dissolved. 147 g of methyl 4-nitrobutyrate (1.0 mol) prepared in step 1 was added to the three-necked flask, and stirred at room temperature for 2 h;

[0039] Step 3, after stirring, add 3L of n-heptane to stir evenly, cool to 3 ° C, potassium permanganate aqueous solution (mass concentration is 5%, 118g potassium permanganate, 2240g water) is added dropwise according to the addition amount of potassium permanganate 0.75mol, constant temperature 3 ° C stirring condition 1.5h dropwise addition is completed, after dropping, continue to stir for 1h, add 1L sodium bisulfite aqueous solution (1mol / L) and 1L sulfuric acid solution (1mol / L), stir evenly, take the organic layer after standing and stratifying, adopt 1L deionized water washing, after washing, use anhydrous sulfuric acid drying, filter, filtrate decompression concentration recovery n-heptane, obtain 4-aldehyde group butyric acid methyl ester crude product, crude product is distilled under reduced pressure with a thorn-shaped fractionating column, collects the fraction of boiling point 103 ° C / 20mmHg, obtains light yellow liquid, i.e. 4-aldehyde group butyric acid methyl ester pure product. After weighing, its mass is 103g, and the yield is 86%, and GC detects that its purity is 97%. The data of the H NMR spectrum are as follows: 0.67

[0040] 1 H-NMR (300MHz, CDCl3) δ: 9.78 (s, 1H), 3.67 (s, 3H), 2.76 (t, 2H), 2.62 (t, 2H).

[0041] Example 2

[0042] The only difference from Example 1 is that in step 1, the amount of nitromethane added is increased, and 9 L is adjusted to 13.5 L, and the volume ratio of methyl acrylate to nitromethane is 1:15. Step 1 is as follows, and the other steps and conditions are the same as in Example 1.

[0043] Step 1: Add 860g of methyl acrylate (10mol) to a 10L three-necked flask, then add 13.5L of nitromethane (the volume ratio of methyl acrylate to nitromethane is 1:15), stir and dissolve, then add 276g of potassium carbonate (2mol) to the flask, stir and react at room temperature (20℃-30℃) for 48h, filter after the reaction is completed, remove potassium carbonate, concentrate the filtrate under reduced pressure to recover nitromethane, and then perform reduced pressure distillation, use a high vacuum oil pump, set the external temperature to 120℃, collect the fraction with a boiling point of 95-100℃ / 8mmHg, and obtain 1265g of methyl 4-nitrobutyrate, with a yield of 86%. 0.74

[0044] Example 3

[0045] The only difference from Example 1 is that in step 1, the amount of nitromethane added is increased, and 9L is adjusted to 18L, and the volume ratio of methyl acrylate to nitromethane is 1:20. Step 1 is as follows, and the other steps and conditions are the same as in Example 1.

[0046] Step 1: Add 860g of methyl acrylate (10mol) to a 10L three-necked flask, then add 18L of nitromethane (the volume ratio of methyl acrylate to nitromethane is 1:20), stir and dissolve, then add 276g of potassium carbonate (2mol) to the flask, stir and react at room temperature (20℃-30℃) for 48h, filter after the reaction is completed, remove potassium carbonate, concentrate the filtrate under reduced pressure to recover nitromethane, and then perform reduced pressure distillation, use a high vacuum oil pump, set the external temperature to 120℃, collect the fraction with a boiling point of 95-100℃ / 8mmHg, and obtain 1295g of methyl 4-nitrobutyrate, with a yield of 88%. 0.76

[0047] Example 4

[0048] The only difference from Example 2 is that the potassium permanganate aqueous solution is added dropwise at a molar ratio of potassium permanganate to 4-nitrobutyric acid methyl ester added in step 2 of 0.5:1, and 0.75 mol of potassium permanganate in step 3 is adjusted to 0.5 mol. Step 3 is as follows, and the other steps and conditions are the same as in Example 2.

[0049] Step 3: After the stirring is completed, add 3L of n-heptane and stir evenly, cool to 3°C, add potassium permanganate aqueous solution (mass concentration is 5%, 79g potassium permanganate, 1501g water) according to the addition amount of 0.5mol of potassium permanganate, and complete the addition under constant temperature and stirring at 3°C ​​for 1.5h. After the addition is completed, continue to stir for 1h, add 667mL of sodium bisulfite aqueous solution (1mol / L) and 667mL of sulfuric acid solution (1mol / L), stir evenly, let stand and stratify, take the organic layer, wash with 1L of deionized water, dry with anhydrous sulfuric acid after washing, filter, and concentrate the filtrate under reduced pressure to recover n-heptane to obtain crude 4-aldehyde butyric acid methyl ester. The crude product is distilled under reduced pressure using a thorn-shaped fractionating column, and the fraction with a boiling point of 103°C / 20mmHg is collected to obtain a light yellow liquid, i.e., pure 4-aldehyde butyric acid methyl ester. After weighing, its mass is 99g, the yield is 82%, and its purity is 96% detected by GC. 0.71

[0050] Example 5

[0051] The only difference from Example 2 is that the potassium permanganate aqueous solution is added dropwise at a molar ratio of potassium permanganate to methyl 4-nitrobutyrate added in step 2 of 1:1, and 0.75 mol of potassium permanganate in step 3 is adjusted to 1.0 mol. Step 3 is as follows, and the other steps and conditions are the same as in Example 2.

[0052] Step 3, after stirring, add 3L of n-heptane to stir evenly, cool to 3 ° C, potassium permanganate aqueous solution (mass concentration is 5%, 158g potassium permanganate, 3002g water) is added dropwise according to the addition amount of potassium permanganate 1.0mol, constant temperature 3 ° C stirring condition 1.5h dropwise addition is completed, after the dropwise addition is completed, continue to stir for 1h, add 1333mL sodium bisulfite aqueous solution (1mol / L) and 1333mL sulfuric acid solution (1mol / L), stir evenly, take the organic layer after standing and stratifying, adopt 1L deionized water washing, after washing, use anhydrous sulfuric acid drying, filter, filtrate decompression concentration recovery n-heptane, obtain 4-aldehyde group butyric acid methyl ester crude product, crude product is distilled under reduced pressure with a thorn-shaped fractionating column, collects the fraction with a boiling point of 103 ° C / 20mmHg, obtains a light yellow liquid, i.e. 4-aldehyde group butyric acid methyl ester pure product. Its mass is 101g after weighing, and the yield is 84%, and GC detects that its purity is 96%. 0.72

[0053] Example 6

[0054] The only difference from Example 2 is that the catalyst in step 1 is replaced by sodium bicarbonate instead of potassium carbonate. Step 1 is as follows, and the other conditions and steps are the same as in Example 2.

[0055] Step 1: Add 860g of methyl acrylate (10mol) to a 10L three-necked flask, then add 13.5L of nitromethane (the volume ratio of methyl acrylate to nitromethane is 1:15), stir and dissolve, then add 168g of sodium bicarbonate (2mol) to the flask, stir and react at room temperature (20℃-30℃) for 48h, filter after the reaction is completed, remove potassium carbonate, concentrate the filtrate under reduced pressure to recover nitromethane, and then perform reduced pressure distillation, use a high vacuum oil pump, set the external temperature to 120℃, collect the fraction with a boiling point of 95-100℃ / 8mmHg, and obtain 1221g of methyl 4-nitrobutyrate, with a yield of 83%. 0.71

[0056] Comparative Example 1

[0057] According to Example 2 in the patent application document with publication number CN115385789A, methyl 4-oxobutyrate was prepared with a total yield of 62%.

[0058] Comparative Example 2

[0059] Compared with Example 1, in step 3 of this comparative example, no sodium bisulfite aqueous solution and sulfuric acid solution are added. Step 3 is as follows, and other conditions and steps are the same as in Example 1.

[0060] After step 3 and stirring were completed, 3L of normal heptane was added and stirred evenly, cooled to 3°C, potassium permanganate aqueous solution (mass concentration was 5%, 118g potassium permanganate, 2240g water) was added dropwise according to the addition amount of 0.75mol of potassium permanganate, and the addition was completed for 1.5h under constant temperature 3°C stirring conditions, and the addition was continued to stir for 1h, and the organic layer was taken after standing and stratification, and 1L of deionized water was used for washing, and anhydrous sulfuric acid was dried after washing, and filtered, and the filtrate was concentrated and recovered under reduced pressure. Normal heptane was obtained to obtain a crude product of 4-aldehyde butyric acid methyl ester, and the crude product was distilled under reduced pressure with a thorn-shaped fractionating column, and a fraction with a boiling point of 103°C / 20mmHg was collected to obtain a light yellow liquid, i.e., pure 4-aldehyde butyric acid methyl ester. Its mass after weighing was 96g, and the yield was 78%, and it was 94% when GC detected its purity.

[0061] It can be seen from Examples 1 to 3 that when nitromethane is excessive, there are few by-products, and the yield of 4-nitrobutyric acid methyl ester is high. It can be seen from Examples 4 and 5 that the amount of potassium permanganate will affect the yield of 4-formylbutyric acid methyl ester. The potassium permanganate addition amount of Example 1 is the optimal condition. When sodium bicarbonate is used as an alkaline catalyst in Example 6, due to its weak alkalinity compared to potassium carbonate, the reaction activity is low. Under the same dosage, the yield of 4-nitrobutyric acid methyl ester is slightly reduced. Combining the comparative examples and the results of the embodiments, it can be seen that the synthesis method of 4-formylbutyric acid methyl ester provided by the present invention, methyl acrylate and catalyst are both cheap and easy to obtain, simple to operate, and mild conditions. In Example 3, the total yield can reach 76%, and it is easy to realize industrial production. Using the prior art as Comparative Example 1, its total yield is obviously not as good as that of the embodiment. When sodium bisulfite aqueous solution and sulfuric acid solution are not added in Comparative Example 2, due to the excessive potassium permanganate, oxidation will continue to be provided, and by-products will be produced, resulting in a reduction in the yield and purity of the pure product of 4-formylbutyric acid methyl ester.

[0062] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.

[0063] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing methyl 4-aldehyde butyrate, characterized in that: The following steps are involved: Step 1, dissolving methyl acrylate in nitromethane, adding an inorganic solid base catalyst, stirring at room temperature for 24-72 hours, filtering potassium carbonate after the reaction is completed, concentrating under reduced pressure to recover nitromethane, and distilling under reduced pressure to obtain methyl 4-nitrobutyrate; Step 2: Under nitrogen protection, heat sodium tert-butoxide and dissolve it in tert-butanol, add the methyl 4-nitrobutyrate, and stir at room temperature for 1-2 hours; Step 3: After the stirring is completed, add n-heptane and stir evenly, cool to 0-5°C, add potassium permanganate aqueous solution dropwise, stir for 1-2h after the addition is completed, add sodium bisulfite aqueous solution and sulfuric acid solution, separate the organic layer, wash and dry it, filter it, concentrate it under reduced pressure to recover n-heptane to obtain a crude product, and distill the crude product under reduced pressure to obtain pure 4-aldehyde butyric acid methyl ester.

2. A method for synthesizing 4-aldehyde butyric acid methyl ester according to claim 1, characterized in that, The volume ratio of the methyl acrylate to nitromethane is 1:10-20.

3. A method for synthesizing methyl 4-aldehyde butyrate according to claim 1, characterized in that, The inorganic solid base catalyst is one of potassium carbonate and sodium bicarbonate.

4. A method for synthesizing 4-aldehyde butyric acid methyl ester according to claim 1, characterized in that, The molar ratio of the inorganic solid base catalyst to methyl acrylate is 1-2:

10.

5. A method for synthesizing methyl 4-aldehyde butyrate according to claim 1, characterized in that, The mass ratio of the sodium tert-butoxide to tert-butanol is 1:6-7.

6. A method for synthesizing methyl 4-aldehyde butyrate according to claim 1, characterized in that, In step 2, the molar ratio of methyl 4-nitrobutyrate to sodium tert-butoxide is 1:2-2.

2.

7. A method for synthesizing methyl 4-aldehyde butyrate according to claim 1, characterized in that, The volume ratio of n-heptane to tert-butanol is 1-3:

1.

8. A method for synthesizing methyl 4-aldehyde butyrate according to claim 1, characterized in that, In step 3, the mass concentration of the potassium permanganate aqueous solution is 3-5%, and the potassium permanganate aqueous solution is added dropwise at a molar ratio of potassium permanganate to methyl 4-nitrobutyrate of 0.5-1:

1.

9. A method for synthesizing methyl 4-aldehyde butyrate according to claim 1, characterized in that, The concentration of the sodium bisulfite aqueous solution is 0.5-1 mol / L, and the sodium bisulfite aqueous solution is added at a molar ratio of sodium bisulfite to potassium permanganate of 4:2-3.

10. A method for synthesizing methyl 4-aldehyde butyrate according to claim 1, characterized in that: The concentration of the sulfuric acid solution is 0.5-1 mol / L, and the sulfuric acid solution is added at a molar ratio of sulfuric acid to sodium bisulfite of 1:1-1.2.

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