CN116903457A - Synthesis method of 2-hydroxy-5-isopropylbenzoic acid - Google Patents

Abstract

The invention provides a synthesis method of 2-hydroxy-5-isopropylbenzoic acid. The method is as follows: using 4-isopropylphenol as raw material, 4-isopropylphenol, TEA, MgCl ₂ and (CH ₂ O)n are mixed and reacted in MeCN, the reaction temperature is 60-80°C, and post-processing Obtain compound 2; dissolve compound 2 in dioxane and water, then add sulfamic acid, sodium dihydrogen phosphate, sodium chlorite and sodium sulfite to react. The reaction temperature is 0-4°C. After post-treatment, compound 3 is obtained. That is 2-hydroxy-5-isopropylbenzoic acid. By optimizing the reaction process conditions, the present invention achieves a total yield of 88.1%. The raw material reagents of the two-step reaction method are cheap and easy to obtain, have strong operability, mild reaction conditions, and very simple post-processing, which is convenient for industrial scale-up production. And the use of sulfamic acid can shorten the reaction time and improve work efficiency.

Description

A kind of synthesis method of 2-hydroxy-5-isopropylbenzoic acid

Technical field

The invention belongs to the field of organic pharmaceutical synthesis, and specifically relates to a synthesis method of pharmaceutical intermediate 2-hydroxy-5-isopropylbenzoic acid.

Background technique

2-Hydroxy-5-isopropylbenzoic acid (CAS number: 31589-71-6) is a new and effective key intermediate for disulfide compound capture and recognition of chemical probes that act on the activation core, hereinafter referred to as compound 3. Pfizer has active intermediates available for fluoropyridine-based Vlla/TF complex inhibitors and PDE4 inhibitors. The yield inherent to its synthetic method is very low.

The structural formula of compound 3 is:

Currently, the existing synthetic route of compound 3 is as follows:

The synthesis route of compound 3 reported in the literature seems simple and only requires one step to complete the reaction, but the actual operation is very difficult. This reaction requires mixing compound 1 and potassium carbonate without a solvent, passing in carbon dioxide gas, and maintaining a high temperature reaction of 150°C. It can be seen that this is a high temperature and high pressure reaction. It is very difficult to implement the reaction and is very dangerous. , and it is not easy to enlarge. We basically did not replicate the reactions reported in this literature in our laboratory. Therefore, it is urgent to develop a new route to obtain the target molecule compound 3.

Contents of the invention

The object of the present invention is to provide a synthesis method of intermediates. The present invention has successfully screened out a two-step synthesis method, which is simple to operate, has a mild reaction, and its yield has been greatly improved. It is also convenient for industrial scale-up production and provides good support for the application of this product in the field of new drug development.

The technical solutions adopted by the present invention to solve the above technical problems are as follows:

The synthetic route adopted in the present invention is as follows:

The invention provides a synthesis method of 2-hydroxy-5-isopropylbenzoic acid, which uses 4-isopropylphenol as raw material and undergoes a two-step reaction to obtain compound 3, that is, 2-hydroxy-5-isopropylbenzoic acid. Formic acid; the synthesis method includes the following steps:

S1. Synthesis of compound 2:

4-Isopropylphenol, TEA, MgCl ₂ and (CH ₂ O)n were mixed and reacted in MeCN. The reaction temperature was 60-80°C. After post-treatment, compound 2 was obtained;

S2. Synthesis of compound 3:

Compound 2 is dissolved in dioxane and water, and then sulfamic acid, sodium dihydrogen phosphate, sodium chlorite and sodium sulfite are added to react. The reaction temperature is -5 to 5°C. After post-treatment, compound 3 is obtained.

As a preferred embodiment, the reaction temperature in step S1 is 65-75°C, and the reaction time is 2-5 hours.

As a preferred embodiment, the reaction temperature in step S1 is 70°C and the reaction time is 2 hours.

As a preferred embodiment, in step S1, after the raw materials are added to the reaction bottle, the air in the reaction bottle is replaced with inert gas, and then the reaction is carried out at the temperature.

As a preferred embodiment, in step S2, compound 2 is added to 1,4-dioxane and water, and at 0-5°C, an aqueous solution of sulfamic acid, sodium dihydrogen phosphate and sodium chlorite is added, and stirred After 0.5-1h, sodium sulfite is then added for reaction.

As a preferred embodiment, in step S2, compound 2 is added to 1,4-dioxane and water, followed by adding sulfamic acid and sodium dihydrogen phosphate to completely dissolve it, and then adding chlorous acid at 0-5°C. Sodium aqueous solution, stir for 0.5-1h, then add sodium sulfite and stir for 0.5-1h to react.

As a preferred embodiment, the post-treatment in steps S1 and S2 includes: using a mixture of petroleum ether and ethyl acetate for chromatographic detection, HCl acidification, extraction with a mixed solvent of ethyl acetate and water, washing the organic layer, drying and concentration, Wherein, the ratio of ethyl acetate to water is 2:1-6:1, preferably 3:1, and the extraction is performed twice.

As a preferred embodiment, after concentration in the post-treatment of step S2, use n-hexane to titrate and filter to obtain compound 3; wherein, the temperature of the titration is 15-25°C, preferably 20°C; the time of the titration is 1 -3h, preferably 2h.

As a preferred embodiment, in step S1, the ratio of petroleum ether to ethyl acetate is 9:1-11:1, preferably 10:1; the concentration of HCl is 1-3M, preferably 1M; Acidify to pH=1-4, preferably pH=2-3.

As a preferred embodiment, in step S2, the ratio of petroleum ether to ethyl acetate is 2:1-4:1, preferably 3:1; the concentration of HCl is 5-7M, preferably 6M; Acidify to pH=1-4, preferably pH=1-2.

As a preferred embodiment, the molar concentration of 4-isopropylphenol in the reaction solution in step S1 is 0.4-0.6mol/L, preferably 0.55mol/L; the molar concentration of TEA in the reaction solution is 1.0 -3.0mol/L, preferably 2.05mol/L; the molar concentration of MgCl ₂ in the reaction solution is 0.6-1.0mol/L, preferably 0.83mol/L; the (CH ₂ O)n in the reaction solution The molar concentration is 1.0-3.0mol/L, preferably 2.03mol/L; the volume ratio of MeCN to the reaction solution is 0.5:1-0.8:1, preferably 0.68:1;

In step S2, the molar concentration of compound 2 in the reaction solution is 0.1-0.3mol/L, preferably 0.12mol/L; the volume ratio of 1,4-dioxane to the reaction solution is 0.6:1- 0.8:1, preferably 0.7:1; the molar concentration of the sulfamic acid in the reaction solution is 0.1-0.3mol/L, preferably 0.18mol/L; the molar concentration of the disodium hydrogen phosphate in the reaction solution It is 0.3-0.6mol/L, preferably 0.48mol/L; the molar concentration of sodium chlorite in the reaction solution is 0.1-0.2mol/L, preferably 0.16mol/L; the sodium sulfite is in the reaction solution The molar concentration is 0.1-0.2mol/L, preferably 0.16mol/L.

The invention also provides a method for synthesizing pharmaceutical intermediates, using 4-isopropylphenol as raw material to synthesize pharmaceutical intermediate compound 2; the structural formula of compound 2 is as follows:

4-Isopropylphenol, TEA, MgCl ₂ and (CH ₂ O)n were mixed in MeCN, the reaction temperature was 60-80°C, and compound 2 was obtained after post-treatment.

The invention also provides a method for synthesizing pharmaceutical intermediates, which synthesizes compound 3 from compound 2. The structural formula of compound 3 is as follows:

Compound 2,1,4-dioxane, water, sulfamic acid, sodium dihydrogen phosphate, sodium chlorite and sodium sulfite are reacted at a reaction temperature of -5 to 5°C, and compound 3 is obtained after post-treatment.

Compared with the prior art, the beneficial effects of the present invention are as follows:

The present invention uses commercially available 4-isopropylphenol as raw material, uses reagents such as paraformaldehyde and sulfamic acid respectively, and introduces carboxyl groups in a two-step reaction. The two-step yield of this method is 88.1%. The raw material reagents of the two-step reaction method are cheap and easy to obtain, have strong operability, mild conditions, very simple post-processing, and do not require complicated purification methods. Finally, you can get a product with high quality properties by beating with n-hexane, and use sulfamate. Acid can shorten reaction time and improve work efficiency.

Detailed ways

The technical solution of the present invention will be described in detail below with reference to examples. However, the protection scope of the present invention is not limited to this: the reagents and materials used below are all commercial products unless otherwise specified.

Example 1: Synthesis of Compound 2

4-Isopropylphenol (20g, 146mmol), TEA (54.9g, 543mmol, 75.6mL), MgCl ₂ (20.9g, 220mmol, 9.04mL) and (CH ₂ O)n ( 27.5g, 538mmol), nitrogen replacement 3 times, reaction at 70°C for 2 hours, TLC (PE: EtOAC=10:1, R _f product=0.8) showed that the reaction was completed. The reaction mixture was acidified with 1M HCl to pH=2-3, the reaction mixture was diluted with 100mL water, and extracted with ethyl acetate (300mL*2); the combined organic layer was washed twice with 500mL water, dried with Na ₂ SO ₄ , and filtered , concentrated under reduced pressure to obtain 2-hydroxy-5-isopropylbenzaldehyde (25g, crude) as yellow oil, which is compound 2. The yield of compound 2 was 86%.

¹ H NMR: EB7512-182-P1A (400MHz, CDCl ₃ ) δ10.9 (s, 1H), 9.89 (s, 1H), 7.42 (dd, J = 2.4, 8.4Hz, 1H), 7.39 (d, J ＝2.4Hz,1H),6.94(d,J＝8.4Hz,1H),2.85-2.99(m,1H),1.26(d,J＝6.8Hz,6H)

Example 2: Synthesis of Compound 3

Compound 2 (17.0g, 103mmol) obtained in Example 1 was dissolved in a solution of 1,4-dioxane (600mL) and water (200mL), and sulfamic acid (15.1g, 155mmol, 7.01mL) was added successively. ), sodium dihydrogen phosphate (49.7g, 414mmol), after it is completely dissolved, slowly add 50mL of sodium chlorite (12.2g, 134mmol) aqueous solution at 0°C. After the dropwise addition was completed, stirring was continued at 0°C for 1 hour, and then sodium sulfite (16.9g, 134mmol) was added at 0°C. The resulting mixture was stirred at 0°C for 30 minutes, and TLC (PE:EtOAC=3:1, _Rf product=0.3) indicated that the reaction was complete. The reaction mixture was acidified with 6M HCl to pH=1-2, the reaction mixture was diluted with 100 mL of water, and extracted with ethyl acetate (300 mL*2). The combined organic layers were washed with 800 mL of water, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The crude product was titrated with 50 mL of n-hexane at 20°C for 1 hour, and filtered to obtain 2-hydroxy-5-isopropylbenzoic acid (16.4 g, yield 88.1%, purity 95.53%) as a yellow solid, which was compound 3.

1H NMR: EB7512-188-P1B (400MHz, CDCl3) δ10.2 (s, 1H), 7.78 (d, J = 2.4Hz, 1H), 7.43 (dd, J = 2.4, 8.4Hz, 1H), 6.97 ( d,J＝8.4Hz,1H),2.85-2.99(m,1H),1.26(d,J＝6.8Hz,6H)

Comparative Example 1: Effect of existing reaction conditions on the yield of compound 3

Add compound 2 (20g, 121mmol), 30% H ₂ O ₂ (16ml, 208.1mmol in water) and SeO ₂ (0.4g, 3.6mmol) in Example 1 to the reaction bottle in sequence. The reaction time requires 15 hours, and The reaction yield is not high and HPLC preparation is required to remove the produced impurities. The reaction conditions of Comparative Example 1 are the conditions currently reported, the yield is only 11%, and a highly toxic reagent (SeO _{2 )} is used. There is a risk of explosion of H ₂ O ₂ during post-processing, and the reaction risk is very high.

Comparative Example 2: Synthesis of Compound 2

4-Isopropylphenol (20g, 146mmol), TEA (54.9g, 543mmol, 75.6mL), MgCl ₂ (20.9g, 220mmol, 9.04mL) and (CH ₂ O)n ( 27.5g, 538mmol), nitrogen replacement 3 times, reaction at 50°C for 2 hours, TLC (PE: EtOAC = 10:1, R _f product = 0.8) showed that the product was generated, and the fluorescent spots of the raw materials other than the product also appeared on TLC. , indicating that this reaction has raw materials that are not completely reacted. The reaction mixture was acidified with 1M HCl to pH=2-3, the reaction mixture was diluted with 100mL water, and extracted with ethyl acetate (300mL*2); the combined organic layer was washed twice with 500mL water, dried with Na ₂ SO ₄ , and filtered , concentrated under reduced pressure to obtain 2-hydroxy-5-isopropylbenzaldehyde (18g, crude) as yellow oil, which was compound 2. When the reaction temperature is 50°C, the temperature is too low and the reaction is incomplete. The yield of compound 2 is 10.32%.

Comparative Example 3: Synthesis of Compound 2

4-Isopropylphenol (20g, 146mmol), TEA (54.9g, 543mmol, 75.6mL), MgCl ₂ (20.9g, 220mmol, 9.04mL) and (CH ₂ O)n ( 27.5g, 538mmol), nitrogen replacement 3 times, reaction at 90°C for 2 hours, TLC (PE: EtOAC = 10:1, R _f product = 0.8) showed that a product was generated, and TLC also showed two products besides the product and raw materials. Fluorescent spots, almost no major products are produced, indicating that the raw materials react completely and impurities are produced. The reaction mixture was acidified with 1M HCl to pH=2-3, the reaction mixture was diluted with 100mL water, and extracted with ethyl acetate (300mL*2); the combined organic layer was washed twice with 500mL water, dried with Na ₂ SO ₄ , and filtered , concentrated under reduced pressure to obtain 2-hydroxy-5-isopropylbenzaldehyde (20g, crude) as yellow oil, which is compound 2. When the reaction temperature is 90°C, the temperature is too high and more impurities are produced by the reaction. The yield of compound 2 is 13.76%. Conclusion: Comparing the results of Comparative Example 2 and Comparative Example 3 with those of Example 1, it can be seen that the optimal reaction temperature in the synthesis reaction of the first step to synthesize compound 2 is 70°C, and the yield of compound 2 is the highest at 86%.

Comparative Example 4: Synthesis of Compound 3

Compound 2 (17.0g, 103mmol) obtained in Example 1 was dissolved in a solution of 1,4-dioxane (600mL) and water (200mL), and sulfamic acid (15.1g, 155mmol, 7.01mL) was added successively. ), sodium dihydrogen phosphate (49.7g, 414mmol), after it is completely dissolved, slowly add 50mL of sodium chlorite (12.2g, 134mmol) aqueous solution at -5°C. After the dropwise addition was completed, stirring was continued at -5°C for 1 hour, and then sodium sulfite (16.9g, 134mmol) was added at -5°C. The resulting mixture was stirred at -5°C for 30 minutes. TLC (PE: EtOAC = 3:1, R _f product = 0.3) showed that a product was formed. Fluorescent spots of the raw materials other than the product also appeared on the TLC, indicating that there were no raw materials in this reaction. Complete reaction. The reaction mixture was acidified with 6M HCl to pH=1-2, the reaction mixture was diluted with 100 mL of water, and extracted with ethyl acetate (300 mL*2). The combined organic layers were washed with 800 mL of water, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The crude product was titrated with 50 mL n-hexane at 20°C for 1 hour, and filtered to obtain 2-hydroxy-5-isopropylbenzoic acid (3.5 g, yield 18.8%, purity 96%) as a yellow solid, which was compound 3. When the reaction temperature was -5°C, the temperature was too low and the reaction was incomplete. The yield of compound 3 was 18.8%.

Comparative Example 5: Synthesis of Compound 3

Compound 2 (17.0g, 103mmol) obtained in Example 1 was dissolved in a solution of 1,4-dioxane (600mL) and water (200mL), and sulfamic acid (15.1g, 155mmol, 7.01mL) was added successively. ), sodium dihydrogen phosphate (49.7g, 414mmol), after it is completely dissolved, slowly add 50mL of sodium chlorite (12.2g, 134mmol) aqueous solution at 5°C. After the dropwise addition was completed, stirring was continued at 5°C for 1 hour, and then sodium sulfite (16.9g, 134mmol) was added at 5°C. The resulting mixture was stirred at 5°C for 30 minutes. TLC (PE: EtOAC = 3:1, R _f product = 0.3) showed that a product was formed. TLC also showed a fluorescent point in addition to the product and the raw material, indicating that the raw material reaction was complete and Impurities are generated. The reaction mixture was acidified with 6M HCl to pH=1-2, the reaction mixture was diluted with 100 mL of water, and extracted with ethyl acetate (300 mL*2). The combined organic layers were washed with 800 mL of water, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The crude product was titrated with 50 mL of n-hexane at 20°C for 1 hour, and filtered to obtain 2-hydroxy-5-isopropylbenzoic acid (6.7 g, yield 36%, purity 92.13%) as a yellow solid, which was compound 3. When the reaction temperature is 5°C, the temperature is too high and impurities are generated in the reaction. The yield of compound 3 is 36%.

Conclusion: Comparing the results of Comparative Example 4 and Comparative Example 5 with those of Example 2, it can be seen that the optimal reaction temperature in the synthesis reaction of compound 3 in the second step is 0°C. At this time, the highest yield of compound 3 is 88.1%.

Comparative Example 6: Synthesis of Compound 2

4-Isopropylphenol (20g, 146mmol), pyridine (54.9g, 543mmol, 75.6mL), MgCl ₂ (20.9g, 220mmol, 9.04mL) and (CH ₂ O)n ( 27.5g, 538mmol), nitrogen replacement 3 times, reaction at 70°C for 2 hours, TLC (PE: EtOAC=10:1, R _f product=0.8) showed that the product was formed, and the fluorescence spots of the raw materials other than the product also appeared on TLC. , indicating that this reaction has raw materials that are not completely reacted. The reaction mixture was acidified with 1M HCl to pH=2-3, the reaction mixture was diluted with 100mL water, and extracted with ethyl acetate (300mL*2); the combined organic layer was washed twice with 500mL water, dried with Na ₂ SO ₄ , and filtered , concentrated under reduced pressure to obtain 2-hydroxy-5-isopropylbenzaldehyde (15g, crude) as yellow oil, which was compound 2. In Comparative Example 6, pyridine is used as an alkaline substance. Since pyridine is weakly alkaline, the reaction is incomplete, and the yield of compound 2 is 46.4%.

Comparative Example 7: Synthesis of Compound 2

4-Isopropylphenol (20g, 146mmol), DIPEA (54.9g, 543mmol, 75.6mL), MgCl ₂ (20.9g, 220mmol, 9.04mL) and (CH ₂ O)n ( 27.5g, 538mmol), nitrogen replacement 3 times, reaction at 70°C for 2 hours, TLC (PE: EtOAC = 10:1, R _f product = 0.8) showed that a product was generated, and TLC also showed two other components besides the product and raw materials. Fluorescent spots indicate that the raw materials have reacted completely and impurities have been produced. The reaction mixture was acidified with 1M HCl to pH=2-3, the reaction mixture was diluted with 100mL water, and extracted with ethyl acetate (300mL*2); the combined organic layer was washed twice with 500mL water, dried with Na ₂ SO ₄ , and filtered , concentrated under reduced pressure to obtain 2-hydroxy-5-isopropylbenzaldehyde (21g, crude) as yellow oil, which was compound 2. In Comparative Example 7, the basic substance used is ethyldiisopropylamine. Since ethyldiisopropylamine is highly alkaline, impurities are generated during the reaction. The yield of compound 2 is 42.7%.

Conclusion: Comparing the results of Comparative Examples 6 and 7 with those of Example 1, it can be seen that in the first step of the synthesis reaction of compound 2, the best reaction occurs when triethylamine is used as an alkaline substance. At this time, the yield of compound 2 is The highest is 86%.

Comparative Example 8: Synthesis of Compound 3

Compound 2 (17.0g, 103mmol) obtained in Example 1 was dissolved in a solution of 1,4-dioxane (600mL) and water (200mL), and sulfamic acid (15.1g, 155mmol, 7.01mL) was added successively. ), sodium dihydrogen phosphate (49.7g, 414mmol), after it is completely dissolved, slowly add 50mL of sodium bicarbonate (12.2g, 134mmol) aqueous solution at 0°C. After the dropwise addition was completed, stirring was continued at 0°C for 1 hour, and then sodium sulfite (16.9g, 134mmol) was added at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. TLC (PE: EtOAC = 3:1, R _f product = 0.3) showed that product was formed. In addition, fluorescent spots of the raw materials other than the product also appeared on TLC, indicating that the raw materials did not react. completely. The reaction mixture was acidified with 6M HCl to pH=1-2, the reaction mixture was diluted with 100 mL of water, and extracted with ethyl acetate (300 mL*2). The combined organic layers were washed with 800 mL of water, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The crude product was titrated with 50 mL of n-hexane at 20°C for 1 hour, and filtered to obtain 2-hydroxy-5-isopropylbenzoic acid (7.5 g, yield 40.3%, purity 96%) as a yellow solid, which was compound 3. The alkaline substance used in Comparative Example 8 is sodium bicarbonate. Since sodium bicarbonate is weakly alkaline, the reaction is incomplete, and the yield of compound 3 is 40.3%.

Comparative Example 9: Synthesis of Compound 3

Compound 2 (17.0g, 103mmol) in Example 1 was dissolved in a solution of 1,4-dioxane (600mL) and water (200mL), and sulfamic acid (15.1g, 155mmol, 7.01mL) was added sequentially. After sodium dihydrogen phosphate (49.7g, 414mmol) is completely dissolved, slowly add 50mL of sodium hydroxide (12.2g, 134mmol) aqueous solution at 0°C. After the dropwise addition was completed, stirring was continued at 0°C for 1 hour, and then sodium sulfite (16.9g, 134mmol) was added at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. TLC (PE: EtOAC = 3:1, R _f product = 0.3) showed that the product was generated. Four fluorescent spots besides the product and the raw material also appeared on the TLC, indicating the reaction of the raw material. Complete and impurities generated. The reaction mixture was acidified with 6M HCl to pH=1-2, the reaction mixture was diluted with 100 mL of water, and extracted with ethyl acetate (300 mL*2). The combined organic layers were washed with 800 mL of water, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The crude product was titrated with 50 mL n-hexane at 20°C for 1 hour, and filtered to obtain 2-hydroxy-5-isopropylbenzoic acid (2.8 g, yield 15%, purity 90%) as a yellow solid, which was compound 3. The alkaline substance used in Comparative Example 9 is sodium hydroxide. Since sodium hydroxide N is highly alkaline, impurities are generated during the reaction. The yield of compound 3 is 15%.

Conclusion: Comparing the results of Comparative Example 8 and Comparative Example 9 with those of Example 2, it can be seen that in the second step of the synthesis reaction of compound 3, the best reaction is when sodium chlorite is used. At this time, the highest yield of compound 3 is 88.1 %.

Claims (10)

1. A synthesis method of 2-hydroxy-5-isopropylbenzoic acid, which is characterized in that: using 4-isopropylphenol as raw material, undergoing a two-step reaction, compound 3, i.e., 2-hydroxy-5-isopropylbenzoic acid is obtained. Propylbenzoic acid; the synthesis method includes the following steps: S1. Synthesis of compound 2: 4-Isopropylphenol, TEA, MgCl ₂ and (CH ₂ O)n were mixed and reacted in MeCN. The reaction temperature was 60-80°C. After post-treatment, compound 2 was obtained; S2. Synthesis of compound 3: Compound 2 is dissolved in dioxane and water, and then sulfamic acid, sodium dihydrogen phosphate, sodium chlorite and sodium sulfite are added to react. The reaction temperature is -5 to 5°C. After post-treatment, compound 3 is obtained. 2. The synthesis method according to claim 1, characterized in that: the reaction temperature in step S1 is 65-75°C, preferably 70°C; the reaction time is 2-5 hours. 3. The synthesis method according to claim 1, characterized in that: in step S2, compound 2 is added to 1,4-dioxane and water, and after the sulfamic acid and sodium dihydrogen phosphate are completely dissolved, the compound 2 is added in sequence. At 0-5℃, add the aqueous solution of sodium chlorite, stir for 0.5-1h, then add sodium sulfite and stir for 0.5-1h to react. 4. The synthesis method according to claim 1, characterized in that: the post-processing in steps S1 and S2 includes: using a mixture of petroleum ether and ethyl acetate for chromatographic detection, HCl acidification, and mixing ethyl acetate with water. Solvent extraction, washing the organic layer, drying and concentrating, wherein the ratio of ethyl acetate to water is 2:1-6:1, preferably 3:1, and the mixture is extracted twice. 5. The synthesis method according to claim 4, characterized in that: after concentration in the post-processing of step S2, titration with n-hexane is used, and compound 3 is obtained by filtration; wherein, the temperature of the titration is 15-25°C, Preferably 20°C; the titration time is 1-3h, preferably 2h. 6. The synthesis method according to claim 4, characterized in that: in step S1, the ratio of the petroleum ether and ethyl acetate is 9:1-11:1, preferably 10:1; the concentration of the HCl It is 1-3M, preferably 1M; the acidification is to pH=1-4, preferably pH=2-3. 7. The synthesis method according to claim 4, characterized in that: in step S2, the ratio of the petroleum ether and ethyl acetate is 2:1-4:1, preferably 3:1; the concentration of the HCl It is 5-7M, preferably 6M; the acidification is to pH=1-4, preferably pH=1-2. 8. The synthesis method according to claim 1, characterized in that: the molar concentration of 4-isopropylphenol in the reaction solution in step S1 is 0.4-0.6mol/L, preferably 0.55mol/L; The molar concentration of TEA in the reaction solution is 1.0-3.0mol/L, preferably 2.05mol/L; the molar concentration of _MgCl2 in the reaction solution is 0.6-1.0mol/L, preferably 0.83mol/L; The molar concentration of (CH ₂ O)n in the reaction solution is 1.0-3.0 mol/L, preferably 2.03 mol/L; the volume ratio of MeCN to the reaction solution is 0.5:1-0.8:1, preferably 0.68 :1; In step S2, the molar concentration of compound 2 in the reaction solution is 0.1-0.3mol/L, preferably 0.12mol/L; the volume ratio of 1,4-dioxane to the reaction solution is 0.6:1- 0.8:1, preferably 0.7:1; the molar concentration of the sulfamic acid in the reaction solution is 0.1-0.3mol/L, preferably 0.18mol/L; the molar concentration of the disodium hydrogen phosphate in the reaction solution It is 0.3-0.6mol/L, preferably 0.48mol/L; the molar concentration of sodium chlorite in the reaction solution is 0.1-0.2mol/L, preferably 0.16mol/L; the sodium sulfite is in the reaction solution The molar concentration is 0.1-0.2mol/L, preferably 0.16mol/L. 9. A method for synthesizing drug intermediates, characterized in that: using 4-isopropylphenol as raw material, the drug intermediate compound 2 is synthesized; the structural formula of compound 2 is as follows: 4-Isopropylphenol, TEA, MgCl ₂ and (CH ₂ O)n were mixed and reacted in MeCN at a reaction temperature of 60-80°C, and compound 2 was obtained after post-treatment. 10. A method for synthesizing pharmaceutical intermediates, characterized in that compound 3 is synthesized from compound 2. The structural formula of compound 3 is as follows: Compound 2,1,4-dioxane, water, sulfamic acid, sodium dihydrogen phosphate, sodium chlorite and sodium sulfite are reacted at a reaction temperature of -5 to 5°C, and compound 3 is obtained after post-treatment.