A preparation method of o-hydroxyphenylacetic acid

Abstract

The present invention relates to the technical field of azoxystrobin intermediate synthesis, in particular to the field of IPC C07C59, and more specifically to a method for preparing o-hydroxyphenylacetic acid. The preparation method comprises the following steps: S1, adding o-chlorophenylacetic acid, a base, a palladium catalyst, and a ligand to a solvent for reaction to obtain a reaction solution 1; S2, neutralizing the reaction solution in sequence, filtering, and adding acid for acidification to obtain a reaction solution 2; S3, cooling and filtering the reaction solution 2. When the molar ratio of the o-chlorophenylacetic acid, the base, the catalyst, and the ligand is 1:(3-7):(0.002-0.025):(0.015-0.1), the purity and yield of the o-hydroxyphenylacetic acid can be improved.

Description

Technical Field

[0001] The present invention relates to the technical field of azoxystrobin intermediate synthesis, in particular to the field of IPC C07C59, and more specifically to a method for preparing o-hydroxyphenylacetic acid. Background Art

[0002] The structure of o-hydroxyphenylacetic acid contains hydroxyl, carbonyl, and methylene groups, all of which are reactive and capable of undergoing condensation and cyclization reactions, exhibiting strong biological activity. Therefore, o-hydroxyphenylacetic acid is widely used in the synthesis of pesticides and pharmaceuticals. As an important intermediate for azoxystrobin, o-hydroxyphenylacetic acid holds significant research value in new synthetic technologies. Currently, o-hydroxyphenylacetic acid is primarily synthesized using copper sulfate as a catalyst and sodium hydroxide to hydrolyze o-chlorophenylacetic acid.

[0003] US4390723 discloses a method of using o-chlorophenylacetic acid and sodium hydroxide as raw materials, and reacting them at 170°C and 0.65-0.7 MPa under the catalysis of 8-hydroxyquinoline copper. The reaction conditions require high temperature and high pressure, which poses certain safety risks.

[0004] US5221772 discloses a method of using o-chlorophenylacetic acid, an alkali metal hydroxide and an inert hydrocarbon organic solvent as raw materials, reacting at 130-300°C in the presence of a copper catalyst, and obtaining a product through post-treatment. This method has a relatively complex post-treatment and a high reaction temperature.

[0005] CN111269109 A discloses a method for producing o-hydroxyphenylacetic acid using o-chlorophenylacetic acid and sodium hydroxide as raw materials. The reaction is carried out in the presence of water at 210°C under normal pressure and catalyzed by a copper catalyst. After a 4-hour reaction, post-treatment is performed to obtain o-hydroxyphenylacetic acid. Although this method avoids high-pressure reaction, the reaction still requires high temperature, which poses certain risks. Summary of the Invention

[0006] To overcome the deficiencies in the background art, the present invention provides a method for preparing o-hydroxyphenylacetic acid with high yield, safety and environmental protection.

[0007] To achieve the object of the present invention, the present invention provides a method for preparing o-hydroxyphenylacetic acid, comprising the following steps:

[0008] S1, adding o-chlorophenylacetic acid, a base, a palladium catalyst, and a ligand to a solvent for reaction to obtain a reaction solution;

[0009] S2, neutralizing the reaction solution, filtering it, and adding an acidifying agent to acidify it to obtain reaction solution 2;

[0010] S3, cooling the reaction solution 2 and filtering it.

[0011] The base includes one of K2CO3, KOAc, NaOAc, Na2CO3, K2CO3, NaOH, KOH, K3PO4, Na3PO4 or LiOH.

[0012] Preferably, the base comprises one of KOH, NaOH and LiOH.

[0013] More preferably, the base comprises NaOH.

[0014] The solvent includes water and an organic solvent, and the weight ratio of the water to the organic solvent is 1:(0.3-4).

[0015] Preferably, the solvent includes water and an organic solvent, and the weight ratio of water to the organic solvent is 1:(0.5-2).

[0016] Further preferably, the solvent includes water and an organic solvent, and the weight ratio of the water to the organic solvent is 1:1.5.

[0017] Preferably, the organic solvent includes at least one of 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, and dimethyl ether.

[0018] More preferably, the organic solvent includes at least one of 1,4-dioxane and tetrahydrofuran.

[0019] More preferably, the organic solvent comprises tetrahydrofuran.

[0020] Preferably, the palladium catalyst comprises one of PdCl2 (CAS: 7647-10-1), Pd(OAc)2 (CAS: 3375-31-3), Pd2(dba)3 (CAS: 51364-51-3), Pd(PPh3)4 (CAS: 14221-01-3), Pd(dppf)Cl2 (CAS: 72287-26-4), Pd(PPh3)2Cl2 (CAS: 13965-03-2), Pd(dppp)Cl2 (CAS: 59831-02-6), and Pd(acac)2 (CAS: 14024-61-4).

[0021] Further preferably, the palladium catalyst comprises Pd2(dba)3.

[0022] The ligand includes one of PPh3 (CAS: 603-35-0), XPhos (CAS: 1028206-56-5), Sphos (CAS: 1445085-82-4), RuPhos (CAS: 1445085-77-7), XantPhos (CAS: 161265-03-8), Dppf (CAS: 12150-46-8), BINOL (CAS: 128544-05-8), BINAP (CAS: 76189-56-5), and PCy3 (CAS: 58656-04-5).

[0023] Preferably, the ligand comprises one of XPhos, Sphos, RuPhos, and XantPhos.

[0024] Further preferably, the ligand comprises XPhos.

[0025] Preferably, the acidifying agent includes one of hydrochloric acid and sulfuric acid.

[0026] Further preferably, the acidifying agent includes hydrochloric acid, and preferably, the concentration of hydrochloric acid is 30 wt %.

[0027] The applicants have discovered that a molar ratio of o-chlorophenylacetic acid, base, catalyst, and ligand of 1:(3-7):(0.002-0.025):(0.015-0.1) can improve the purity and yield of o-hydroxyphenylacetic acid. Increasing the amount of base added increases the forward reaction rate, but excessive base addition reduces the catalytic effect to a certain extent. This is because under excessively strong alkalinity, palladium easily reacts with the base to precipitate, resulting in significant surface agglomeration of the palladium catalyst, causing some palladium particles to agglomerate and affecting reaction efficiency. Further research has revealed that one of the ligands XPhos, Sphos, RuPhos, or XantPhos can improve catalytic efficiency. This is likely due to the combined effects of the steric hindrance between the ligand and the palladium catalyst and the electronic properties of the phosphine under alkaline conditions.

[0028] Preferably, the molar ratio of o-chlorophenylacetic acid, base, palladium catalyst and ligand is 1:(3-7):(0.002-0.025):(0.015-0.1).

[0029] More preferably, the molar ratio of o-chlorophenylacetic acid, base, palladium catalyst and ligand is 1:(2.5-6):(0.008-0.016):(0.03-0.06).

[0030] More preferably, the molar ratio of o-chlorophenylacetic acid, base, palladium catalyst and ligand is 1:2.5:0.01:0.04.

[0031] Preferably, the reaction temperature is 50-100°C.

[0032] More preferably, the reaction temperature is 80-100°C.

[0033] More preferably, the reaction temperature is 80°C.

[0034] Preferably, the reaction time is 6-12 hours.

[0035] More preferably, the reaction time is 9 hours.

[0036] Preferably, the pH value of the reaction solution 2 is 1-3.

[0037] More preferably, the pH value of the reaction solution 2 is 1-2.

[0038] More preferably, the pH value of the reaction solution 2 is 1.

[0039] Beneficial effects

[0040] 1. The molar ratio of o-chlorophenylacetic acid, base, catalyst and ligand is 1:(3-7):(0.002-0.025):

[0041] (0.015-0.1), the purity and yield of o-hydroxyphenylacetic acid can be improved.

[0042] 2. Select specific palladium catalysts and acceptors to reduce the reaction activation energy and improve the green safety of the reaction.

[0043] 3. The reaction temperature is 50-100°C and the reaction time is 6-12h, which can further improve the reaction yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 This is the reaction process for preparing o-hydroxyphenylacetic acid in Example 1.

[0045] Figure 2 The HPLC spectrum of the reference substance o-hydroxyphenylacetic acid.

[0046] Figure 3 This is the HPLC spectrum of o-hydroxyphenylacetic acid prepared in Example 1. DETAILED DESCRIPTION

[0047] Example 1

[0048] A preparation method of o-hydroxyphenylacetic acid comprises the following steps:

[0049] S1, o-chlorophenylacetic acid (85.00 g, 0.5 mol), NaOH (80.00 g, 2.0 mol), Pd2(dba)3 (6.87 g, 8 mmol), and RuPhos (13.99 g, 30 mmol) were placed in a reaction flask containing 200 g of water and 200 g of 1,4-dioxane, the temperature was raised to 90°C, and the reaction was kept at this temperature for 6 h;

[0050] S2, after the reaction is completed, the catalyst is removed by filtration, and the filtrate is acidified with 30 wt% hydrochloric acid (182.50 g, 1.5 mol) to pH = 1;

[0051] S3, cool to -5°C, keep warm and stir for 1 hour, then filter to obtain.

[0052] Example 2

[0053] A preparation method of o-hydroxyphenylacetic acid comprises the following steps:

[0054] S1, o-chlorophenylacetic acid (85.00 g, 0.5 mol), KOH (106.40 g, 1.90 mol), PdCl2 (1.06 g, 6 mmol), and RuPhos (4.29 g, 15 mmol) were placed in a reaction flask containing 200 g of water and 200 g of 1,4-dioxane, heated to 100°C, and kept for 8 h;

[0055] S2, after the reaction is completed, the catalyst is removed by filtration, and the filtrate is acidified with 30% hydrochloric acid (170.33 g, 1.40 mol) to pH = 1;

[0056] S3, cool to -5°C, keep warm and stir for 1 hour, then filter to obtain.

[0057] Example 3

[0058] A preparation method of o-hydroxyphenylacetic acid comprises the following steps:

[0059] S1, o-chlorophenylacetic acid (85.00 g, 0.5 mol), K2CO3 (345.50 g, 2.50 mol), Pd(PPh3)2Cl2 (2.81 g, 4 mmol), and XantPhos (14.47 g, 25 mmol) were placed in a reaction flask containing 200 g of water and 400 g of tetrahydrofuran, heated to 100°C, and kept for 8 h;

[0060] S2, after the reaction is completed, the catalyst is removed by filtration, and the filtrate is acidified with 30 wt% hydrochloric acid (547.50 g, 4.5 mol) to pH = 1;

[0061] S3, cool to -5°C, keep warm and stir for 1 hour, then filter to obtain.

[0062] Example 4

[0063] A preparation method of o-hydroxyphenylacetic acid comprises the following steps:

[0064] S1, o-chlorophenylacetic acid (85.00 g, 0.5 mol), K3PO4 (636.78 g, 3.00 mol), Pd(dppf)Cl2 (2.93 g, 4 mmol), and SPhos (10.26 g, 25 mmol) were placed in a reaction flask containing 490 g of water and 260 g of tetrahydrofuran, heated to 100°C, and kept for 12 h;

[0065] S2, after the reaction is completed, the catalyst is removed by filtration, and the filtrate is acidified with 30 wt% hydrochloric acid (1034.17 g, 8.50 mol) to pH = 1;

[0066] S3, cool to -5°C, keep warm and stir for 1 hour, then filter to obtain.

[0067] Example 5

[0068] A preparation method of o-hydroxyphenylacetic acid comprises the following steps:

[0069] S1, o-chlorophenylacetic acid (85.00 g, 0.5 mol), NaOH (70.00 g, 1.75 mol), Pd2(dba)3 (4.58 g, 5 mmol), and XPhos (9.53 g, 20 mmol) were placed in a reaction flask containing 200 g of water and 300 g of tetrahydrofuran, heated to 80°C, and kept for 9 h;

[0070] S2, after the reaction is completed, the catalyst is removed by filtration, and the filtrate is acidified with 30 wt% hydrochloric acid (152.08 g, 1.25 mol) to pH = 1;

[0071] S3, cool to -5°C, keep warm and stir for 1 hour, then filter to obtain.

[0072] Comparative Example 1

[0073] A preparation method of o-hydroxyphenylacetic acid comprises the following steps:

[0074] S1, o-chlorophenylacetic acid (85.00 g, 0.5 mol), NaOH (70.00 g, 1.75 mol), Pd2(dba)3 (4.58 g, 5 mmol), and XPhos (9.53 g, 20 mmol) were placed in a reaction flask containing 200 g of water and 20 g of tetrahydrofuran, heated to 80°C, and kept warm for 24 h;

[0075] S2, after the reaction is completed, the catalyst is removed by filtration, and the filtrate is acidified with 30 wt% hydrochloric acid (152.08 g, 1.25 mol) to pH = 1;

[0076] S3, cool to -5°C, keep warm and stir for 1 hour, then filter to obtain.

[0077] Comparative Example 2

[0078] A preparation method of o-hydroxyphenylacetic acid comprises the following steps:

[0079] S1, o-chlorophenylacetic acid (85.00 g, 0.5 mol), KOH (42.00 g, 0.75 mol), PdCl2 (0.09 g, 0.5 mmol), and BINOL (0.14 g, 0.5 mmol) were placed in a reaction flask containing 200 g of water and 200 g of 1,4-dioxane, heated to 100°C, and kept for 36 h;

[0080] S2, after the reaction is completed, the catalyst is removed by filtration, and the filtrate is acidified with 30% hydrochloric acid (24.33 g, 0.2 mol) to pH = 1;

[0081] S3, cool to -5°C, keep warm and stir for 1 hour, then filter to obtain.

[0082] Performance testing methods

[0083] The purity of o-hydroxyphenylacetic acid obtained in Example 1-5 was tested by HPLC using the external standard method and calculated using the following formula:

[0084] W=(A2×m1×p) / (A1×m2)

[0085] W: mass fraction of o-hydroxyphenylacetic acid in the sample, expressed in %;

[0086] A2: peak area of ​​o-hydroxyphenylacetic acid in the sample;

[0087] m1: mass of o-hydroxyphenylacetic acid reference substance, in milligrams (mg);

[0088] p: mass fraction of o-hydroxyphenylacetic acid in the reference substance, expressed in %;

[0089] A1: average value of the peak area of ​​o-hydroxyphenylacetic acid in the reference substance;

[0090] m2: The mass of the sample, in milligrams (mg).

[0091] Taking Example 1 as an example, Figure 1 and Figure 2 As shown, A2: 19556.5; m1: 81.24 mg; p: 99.22%; A1: 18494.63; m2: 92.1 mg; calculated W = 92.5%.

[0092] The data are listed in Table 1.

[0093] Typical:

[0094] Performance test data

[0095] Table 1

[0096] purity(%) Yield (%) Example 1 92.55 94.60 Example 2 91.80 92.60 Example 3 94.30 93.90 Example 4 90.28 91.70 Example 5 93.20 95.40 Comparative Example 1 73.20 63.80 Comparative Example 2 66.80 52.60

Claims

1. A method for preparing o-hydroxyphenylacetic acid, characterized in that, The following steps are involved: S1, adding o-chlorophenylacetic acid, a base, a palladium catalyst, and a ligand to a solvent for reaction to obtain a reaction solution 1; S2, neutralizing the reaction solution, filtering it, and adding an acidifying agent to acidify it to obtain reaction solution 2; S3, cooling the reaction solution 2 and filtering it; The palladium catalyst includes one of PdCl2, Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, Pd(dppf)Cl2, Pd(PPh3)2Cl2, Pd(dppp)Cl2, and Pd(acac)2; the ligand includes one of PPh3, XPhos, Sphos, RuPhos, XantPhos, Dppf, BINOL, BINAP, and PCy3; The molar ratio of o-chlorophenylacetic acid, base, palladium catalyst and ligand is 1:(3-7):(0.002-0.025):(0.015-0.1); The reaction temperature is 50-100° C., and the reaction time is 6-12 hours.

2. The method for preparing o-hydroxyphenylacetic acid according to claim 1, wherein The solvent includes water and an organic solvent, and the weight ratio of the water to the organic solvent is 1:(0.3-4).

3. The method for preparing o-hydroxyphenylacetic acid according to claim 2, wherein The solvent includes water and an organic solvent, and the weight ratio of the water to the organic solvent is 1:(0.5-2).

4. The method for preparing o-hydroxyphenylacetic acid according to claim 3, wherein The organic solvent includes at least one of 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide and dimethyl ether.

5. The method for preparing o-hydroxyphenylacetic acid according to claim 1 or 4, wherein: The base includes one of K2CO3, KOAc, NaOAc, Na2CO3, K2CO3, NaOH, KOH, K3PO4, Na3PO4, and LiOH.

6. The method for preparing o-hydroxyphenylacetic acid according to claim 5, wherein The reaction temperature is 80-100°C.

7. The method for preparing o-hydroxyphenylacetic acid according to claim 6, wherein The pH value of the reaction solution 2 is 1-3.

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