Safe preparation process of 2-cyclopropyl-6-methylphenol

Abstract

The invention discloses a safe preparation process of 2-cyclopropyl-6-methylphenol, and belongs to the technical field of organic pesticide intermediates. The preparation method comprises the following steps: taking 1-bromo-2-chloro-3-methyl benzene as a raw material, reacting with magnesium to generate a Grignard reagent, and reacting with cyclopropyl ketone to generate an intermediate 1; reacting the intermediate 1 with tetrahydroxy diboron under the action of a nickel catalyst and organic alkali to generate an intermediate 2; performing catalytic hydrogenation on the intermediate 2 in the presence of triphenyl boron and palladium / carbon to generate an intermediate 3; the intermediate 3 is oxidized into phenolic hydroxyl groups in the presence of hydrogen peroxide, and 2-cyclopropyl-6-methylphenol is obtained. The method is mild in reaction condition, high in conversion rate and suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a safe preparation process of 2-cyclopropyl-6-methylphenol, belonging to the technical field of organic pesticide intermediates. Background Art

[0002] 2-Cyclopropyl-6-methylphenol is primarily used as a pesticide raw material or intermediate, particularly as a main raw material for the synthesis of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-hydroxypyridazine, codenamed SW-065. This herbicide is one of the most cost-effective herbicides for controlling barnyardgrass and various broadleaf weeds in farmland. Its chemical structure is as follows:

[0003]

[0004] The currently reported methods for synthesizing 2-cyclopropyl-6-methylphenol are mainly the following: using 2-allyloxy-1-bromo-3-methylbenzene as a raw material, butyl lithium and TMEDA are used to synthesize 2-cyclopropyl-6-methylphenol [US2010125081A; WO20112409A; JP20182627A]; using 3-bromo(chloro)methyl-7-methyl-2,3-dihydrobenzofuran as a raw material, reacting with magnesium metal to form a Grignard reagent, self-reacting, and acidifying to produce 2-cyclopropyl-6-methylphenol [JP20182627A]; using 2-bromo-6-methylphenol as a raw material, reacting with cyclopropylboric acid in the presence of palladium catalyst to produce 2-cyclopropyl-6-methylphenol [CN110041253A]. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a simple, practical, economical and efficient safe preparation process for 2-cyclopropyl-6-methylphenol.

[0006] To solve the above technical problems, the present invention adopts the following technical solution: 1-bromo-2-chloro-3-methylbenzene is used as a raw material, reacted with magnesium to form a Grignard reagent, and then reacted with cyclopropyl ketone to produce intermediate 1; intermediate 1 reacts with tetrahydroxydiboron in the presence of a nickel catalyst and an organic base to produce intermediate 2; intermediate 2 is catalytically hydrogenated in the presence of triphenylboron and palladium / carbon to produce intermediate 3; intermediate 3 is oxidized to a phenolic hydroxyl group in the presence of hydrogen peroxide to obtain 2-cyclopropyl-6-methylphenol. The present invention has mild reaction conditions, high conversion rate, and is suitable for industrial production.

[0007] In order to achieve the above object, the technical solution of the present invention is expressed as follows using the reaction equation:

[0008]

[0009] The preparation method of 2-cyclopropyl-6-methylphenol of the present invention comprises the following steps:

[0010] A. 1-Bromo-2-chloro-3-methylbenzene reacts with magnesium metal to generate a Grignard reagent. Under low temperature conditions, the generated Grignard reagent is added to cyclopropyl ketone to obtain intermediate 1;

[0011] B. Intermediate 1, tetrahydroxydiboron, nickel catalyst and organic base are mixed in an alcohol solvent and heated to obtain intermediate 2;

[0012] C. Intermediate 2 is subjected to catalytic hydrogenation in the presence of triphenylboron and palladium on carbon to obtain intermediate 3;

[0013] D. Intermediate 3 reacts in the presence of hydrogen peroxide and acetic acid to obtain 2-cyclopropyl-6-methylphenol.

[0014] Preferably, in step A of the above technical solution, the molar ratio of 1-bromo-2-chloro-3-methylbenzene, metallic magnesium and cyclopropyl ketone is 1:1.1-1.3:1-1.4.

[0015] Preferably, in step A of the above technical solution, the low temperature condition is -20°C to +20°C.

[0016] Preferably, in step B of the above technical solution, the nickel catalyst is NiCl2(dppp); the organic base is selected from triethylamine or diisopropylamine; and the solvent is selected from methanol, ethanol or isopropanol.

[0017] Preferably, in step B of the above technical solution, the temperature is raised to 40-90°C.

[0018] Preferably, in step B of the above technical solution, the molar ratio of the intermediate 1, tetrahydroxydiboron, nickel catalyst and organic base is 1:1-1.5:0.02-0.05:2-3.

[0019] Preferably, in step C of the above technical solution, the molar ratio of the intermediate 2 to triphenylboron is 1:0.01-0.05.

[0020] Preferably, in step D of the above technical solution, the reaction is carried out in acetonitrile, DMSO or dioxane.

[0021] Preferably, in step D of the above technical solution, the reaction conditions are 20-60°C.

[0022] Preferably, in step D of the above technical solution, the molar ratio of the intermediate 3 to hydrogen peroxide is 1:1.2-2.5.

[0023] Beneficial effects of the present invention:

[0024] A. The starting material 1-bromo-2-chloro-3-methylbenzene used in the present invention is cheap, the overall route design is relatively reasonable, and the operation continuity is strong.

[0025] B. The present invention uses intermediate 1 to undergo borylation and cyclization reaction under the joint action of tetrahydroxydiboron, palladium catalyst and base, with high conversion rate, suitable for industrial production, and provides a reference for the synthesis of such compounds.

[0026] C. The present invention adopts hydrogen peroxide to phenolize boric acid, which has high yield, simple operation and high product purity. Specific embodiments

[0027] Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and such modifications or substitutions shall be within the scope of the present invention. Any person skilled in the art who can easily conceive of changes or substitutions within the technical scope disclosed in the present invention shall be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be based on the scope of protection described in the claims.

[0028] Example 1

[0029]

[0030] Under nitrogen, magnesium metal (2.9 g, 0.12 mol) and a few iodine particles were added to 20 mL of anhydrous tetrahydrofuran. The temperature was raised to 40-45°C, and a solution of 1-bromo-2-chloro-3-methylbenzene (20.5 g, 0.1 mol) and anhydrous tetrahydrofuran (200 mL) was added dropwise to initiate the reaction. The remaining portion was then added dropwise. The reaction was then heated to reflux for 1.5 hours. After cooling to room temperature, the mixture was slowly added dropwise to a solution of cyclopropyl ketone (6.73 g, 0.12 mol) in 70 mL of tetrahydrofuran, which had been previously cooled to below -10°C. The addition was complete, and the mixture was kept at no more than 0°C for 2 hours. 0.5 M hydrochloric acid was then added to adjust the pH to 6-7. The organic layer was separated and concentrated. The crude product was purified by column chromatography using petroleum ether / ethyl acetate (v / v = 40 / 1) as eluent to obtain 16.4 g of intermediate 1 with a yield of 90% and an HPLC purity of 99.5%. 1 H-NMR (400MHz, CDCl3): 7.22(t,1H),7.06(d,1H),7.02(d,1H),2.37(s,1H),2.33(s,3H),1.26-1.22(m,2H),1.05-1.02(m,2H).

[0031] Example 2

[0032]

[0033] Under nitrogen protection, intermediate 1 (18.3 g, 0.1 mol), tetrahydroxydiboron 10.8 g (0.12 mol), NiCl2dppp catalyst 1.6 g (0.003 mmol) and triethylamine 22.3 g (0.22 mol) were mixed in 300 mL of ethanol, heated to 60 ° C, reacted for 5 hours, cooled to room temperature, filtered, and concentrated. The crude product was purified by column chromatography with dichloromethane / methanol (v / v = 300 / 1) as eluent to obtain 13.9 g of intermediate 2 with a yield of 80% and a GC value of 99.3%. 1 H-NMR (400MHz, CDCl3): 8.05 (s, 1H), 7.58 (d, 1H), 7.21 (d, 1H), 7.04 (s, 1H), 1.32 (s, 4H).

[0034] Example 3

[0035]

[0036] Under nitrogen protection, intermediate 1 (18.3 g, 0.1 mol), tetrahydroxydiboron 10.8 g (0.12 mol), NiCl2dppp catalyst 1.6 g (0.003 mmol) and diisopropylamine 22.3 g (0.22 mol) were mixed in 300 mL of isopropanol, heated to 70 ° C, reacted for 4 hours, cooled to room temperature, filtered, and concentrated. The crude product was purified by column chromatography with dichloromethane / methanol (v / v = 300 / 1) as eluent to obtain 13.2 g of intermediate 2 with a yield of 76% and a GC value of 98.9%.

[0037] Example 4

[0038]

[0039] Under nitrogen, intermediate 2 (17.4 g, 0.1 mol), triphenylborane (0.73 g, 0.003 mol), and 5% Pd / C (0.87 g) were mixed in 220 mL of ethyl acetate. The mixture was initially purged with nitrogen three times, followed by hydrogen replacement three times. The mixture was then filled with 3.5 kg of hydrogen and heated to 35-40° C. for 4 hours. After the reaction was complete, the temperature was lowered, the catalyst was filtered, and the mixture was concentrated. The crude product was purified by column chromatography using petroleum ether / ethyl acetate (v / v = 1 / 1) as eluent to obtain 14.3 g of intermediate 3, with a yield of 81% and an HPLC purity of 99.2%. 1H-NMR(DMSO-d6,400MHz): 8.11(s,2H),7.32(m,1H),7.25(m,1H),7.10(m, 1H),2.40(s,3H),1.94-1.86(m,1H),0.96-0.89(m,2H),0.71-0.65(m,2H).

[0040] Example 5

[0041]

[0042] Under nitrogen, intermediate 2 (17.4 g, 0.1 mol), triphenylborane (0.73 g, 0.003 mol), and 5% Pd / C (0.87 g) were mixed in 220 mL of tetrahydrofuran. The mixture was initially purged with nitrogen three times, followed by hydrogen three times. The mixture was then filled with 3.5 kg of hydrogen and heated to 35-40° C. for 6 hours. After completion of the reaction, the mixture was cooled, filtered, and concentrated. The crude product was purified by column chromatography using petroleum ether / ethyl acetate (v / v = 1 / 1) as eluent to obtain 13.7 g of intermediate 3 in a yield of 78% with an HPLC purity of 99%.

[0043] Example 6

[0044]

[0045] Under nitrogen protection, intermediate 3 (17.6 g, 0.1 mol) and 25% hydrogen peroxide (19 g) were mixed in 150 mL of acetonitrile and 15 mL of acetic acid solvent, heated to 40° C. for 3 hours, cooled to room temperature, and then added to 60 mL of saturated sodium thiosulfate aqueous solution. The mixture was extracted twice with 200 mL of ethyl acetate. The organic layers were combined and concentrated. The crude product was purified by column chromatography with petroleum ether / ethyl acetate (v / v=9 / 1) as eluent to obtain 13.6 g of 2-cyclopropyl-6-methylphenol in a yield of 92% and an HPLC purity of 99.1%. 1 H-NMR (400MHz, DMSO-d6): 7.03(d,1H),6.98(d,1H),6.77(d,1H),5.56(s, 1H),2.26(s,3H),1.78-1.72(m,1H),0.98-0.93(m,2H),0.66-0.62(m,2H).

[0046] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.

Claims

1. A method for preparing 2-cyclopropyl-6-methylphenol, characterized in that: The steps include: A. 1-Bromo-2-chloro-3-methylbenzene reacts with magnesium metal to generate a Grignard reagent. Under low temperature conditions, the generated Grignard reagent is added to cyclopropyl ketone to obtain intermediate 1; B. Intermediate 1, tetrahydroxydiboron, nickel catalyst and organic base are mixed in an alcohol solvent and heated to obtain intermediate 2; C. Intermediate 2 is subjected to catalytic hydrogenation in the presence of triphenylboron and palladium on carbon to obtain intermediate 3; D. Intermediate 3 reacts in the presence of hydrogen peroxide and acetic acid to obtain 2-cyclopropyl-6-methylphenol.

2. The method for preparing 2-cyclopropyl-6-methylphenol according to claim 1, wherein: In step A, the molar ratio of 1-bromo-2-chloro-3-methylbenzene, metallic magnesium and cyclopropyl ketone is 1:1.1-1.3:1-1.

4.

3. The preparation method of 2-cyclopropyl-6-methylphenol according to claim 1, wherein: In step A, the low temperature condition is -20°C to +20°C.

4. The method for preparing 2-cyclopropyl-6-methylphenol according to claim 1, wherein: In step B, the nickel catalyst is NiCl2(dppp); the organic base is selected from triethylamine or diisopropylamine; and the solvent is selected from methanol, ethanol or isopropanol.

5. The method for preparing 2-cyclopropyl-6-methylphenol according to claim 1, wherein: In step B, the temperature is raised to 40-90°C.

6. The method for preparing 2-cyclopropyl-6-methylphenol according to claim 1, wherein: In step B, the molar ratio of the intermediate 1, tetrahydroxydiboron, nickel catalyst and organic base is 1:1-1.5:0.02-0.05:2-3.

7. The method for preparing 2-cyclopropyl-6-methylphenol according to claim 1, wherein: In step C, the molar ratio of the intermediate 2 to triphenylboron is 1:0.01-0.

05.

8. The method for preparing 2-cyclopropyl-6-methylphenol according to claim 1, wherein: In step D, the solvent is selected from acetonitrile, DMSO or dioxane.

9. The method for preparing 2-cyclopropyl-6-methylphenol according to claim 1, wherein: In step D, the reaction temperature is 20-60°C.

10. The method for preparing 2-cyclopropyl-6-methylphenol according to claim 1, wherein: In step D, the molar ratio of the intermediate 3 to hydrogen peroxide is 1:1.2-2.5.

Images