Synthesis method of 2-hydroxy-6-methyl benzoate

Abstract

The invention discloses a synthetic method of 2-hydroxy-6-methyl benzoate. The synthetic method comprises the following steps: step 1, preparing an intermediate: carrying out Michael addition reaction on crotonaldehyde and 2-halogenated acetoacetate to obtain an intermediate 2-acetyl-2-halo-3-methyl-5-oxovalerate; step 2, preparation of a product: an intermediate 2-acetyl-2-halo-3-methyl-5-oxovalerate is subjected to intramolecular Adol condensation elimination aromatization reaction, 2-hydroxy-6-methyl benzoate is prepared with higher yield from economical and easily available raw materials and reagents under milder conditions, and the method is suitable for industrial production. The initial raw materials, the solvent and the catalyst are industrially cheap and easily available raw materials, so that the cost is low, and the method is more suitable for industrial production; the adopted reaction conditions are mild, byproducts are few, the yield is high, and a target product can be prepared more efficiently; the adopted synthesis route is high in atom economy, adopted solvents and reagents are easy to recycle, generated industrial three wastes are few, and the method is more environmentally friendly.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical production, in particular to a method for synthesizing 2-hydroxy-6-methylbenzoate. Background Art

[0002] 2-Hydroxy-6-methylbenzoate is an important synthetic raw material for natural products, medicines and pesticides. Its synthesis methods have been widely reported in recent decades. The currently reported synthesis methods of 2-hydroxy-6-methylbenzoate mainly include the following four:

[0003] Method 1: Frank M. Hauser et al. reported in SYNTHESIS.1980.p814-815 a method suitable for preparing ethyl 2-hydroxy-6-methylbenzoate in large quantities. The method uses crotonaldehyde and ethyl acetoacetate as starting materials, ethanol as solvent, and performs Michael addition reaction under the catalysis of sodium methoxide. The product does not need to be treated, and hydrogen chloride gas is directly introduced into the reaction solution to perform Adol condensation dehydration reaction. Finally, ethyl 2-hydroxy-6-methylbenzoate is obtained through bromination and elimination reaction. The total yield of the whole route is 40%. This method has many steps and low total yield. George A.Kraus et al. in J.Org.Chem.1983.p3439-3444, based on this method, used NBS and BPO to replace bromine for bromination reaction and then eliminated, and the yield was not significantly improved compared with the previous method. Yasumasa Hamada et al. in Tetrahedron.1991.p8635-8652 further improved the bromination reaction of this route, using copper chloride and lithium chloride, and the total yield of the whole route was increased to 53%;

[0004] Method 2: US6441219 reported a method for preparing ethyl 2-hydroxy-6-methylbenzoate in one step using crotonaldehyde and ethyl 2-chloroacetoacetate as starting materials. The method used acetic acid as solvent and refluxed under the catalysis of sodium acetate to obtain the product ethyl 2-hydroxy-6-methylbenzoate with a yield of 65%.

[0005] Method 3: Yiqing Yang et al. reported in Organic Letters, 2012, p2874-2877 that ethyl o-methylbenzoate was used as a raw material to perform ruthenium-catalyzed hydroxylation of the benzene ring to prepare ethyl 2-hydroxy-6-methylbenzoate with a yield of 66%. This method has harsh conditions and requires the use of precious metal catalysts, making it difficult to apply industrially. Currently, it is only suitable for laboratory-scale preparation.

[0006] Method 4: CN117069555 reported the preparation of ethyl 2-hydroxy-6-methylbenzoate using ethyl 3-methyl-1-oxo-2-cyclohexene-2-carboxylate as raw material and tetrabutylammonium iodide as catalyst, with a yield of 69%. However, the raw materials used in this method are less available, the cost is high, and the total yield is not significantly improved compared with the previously described method.

[0007] The four synthetic methods of ethyl 2-hydroxy-6-methylbenzoate reported above have the following disadvantages:

[0008] Method 1 has a longer route, a lower total yield, and requires the use of halogenated reagents and oxidants, producing more industrial wastes; Method 2 uses a one-step method to directly obtain the target product, which has a high reaction temperature and produces a large amount of black tar-like impurities, and has a low total yield; Compared with Method 2, Methods 3 and 4 have no significant improvement in reaction yield, and the reagents used are relatively expensive, which are not suitable for industrial production. Summary of the invention

[0009] The purpose of the present invention is to provide a method for synthesizing 2-hydroxy-6-methylbenzoate to solve the problems that the method 1 proposed in the above background technology has a long route, a low total yield, and requires the use of a halogenating agent and an oxidant, thereby generating more industrial waste; the method 2 adopts a one-step method to directly obtain the target product, the reaction temperature of the method is high, a large amount of black tar-like impurities are generated in the reaction, and the total yield is low; compared with the method 2, the reaction yield of the method 3 and the method 4 is not significantly improved, and the reagents used are expensive and are not suitable for industrial production.

[0010] To achieve the above object, the present invention provides the following technical solution: a method for synthesizing 2-hydroxy-6-methylbenzoate, comprising the following steps:

[0011] Step 1, preparation of intermediate: crotonaldehyde and 2-haloacetoacetate are subjected to Michael addition reaction to obtain the intermediate 2-acetyl-2-halo-3-methyl-5-oxopentanoate;

[0012] Step 2, preparation of the product: the intermediate 2-acetyl-2-halogeno-3-methyl-5-oxopentanoate is subjected to intramolecular Adol condensation elimination aromatization reaction to obtain 2-hydroxy-6-methylbenzoate.

[0013] As a preferred technical solution of the present invention, the Michael addition reaction in step 1 specifically comprises: mixing a solvent, crotonaldehyde, 2-haloacetoacetate and a catalyst, and performing a Michael addition reaction at a certain temperature.

[0014] As a preferred technical solution of the present invention, in the step 1, R in the 2-haloacetoacetate is selected from C1-C 20 Straight or branched alkyl, C3-C 20 Cycloalkyl, C5-C20 One of the aromatic groups; or, R is selected from C1-C 10 Straight or branched alkyl, C3-C 10 Cycloalkyl, C5-C 10 In the step 1, X in the 2-haloacetoacetate is selected from one of Cl, Br, and I, and in the step 1, R in the 2-acetyl-2-halo-3-methyl-5-oxopentanoate is selected from one of C1-C 20 Straight or branched alkyl, C3-C 20 Cycloalkyl, C5-C 20 One of the aromatic groups; or, R is selected from C1-C 10 Straight or branched alkyl, C3-C 10 Cycloalkyl, C5-C 10 One of the aromatic groups, wherein X in the 2-acetyl-2-halogenated-3-methyl-5-oxopentanoate in step 1 is selected from one of Cl, Br and I.

[0015] As a preferred technical solution of the present invention, the solvent in step 1 is a polar solvent and a non-polar solvent, and the polar solvent is one or more of methanol, ethanol, isopropanol, water, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, ethyl acetate, tetrahydrofuran, and 1,4-dioxane; the non-polar solvent is one or more of dichloromethane, chloroform, toluene, n-hexane, and cyclohexane; the solvent is preferably a polar solvent, and the catalyst in step 1 is an acid catalyst, a base catalyst, a bifunctional catalyst, or an acid-base mixed catalyst, and the acid catalyst is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, and p-toluenesulfonic acid; the base catalyst is sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium phosphate, pyridine, imidazole, One or more of tetrahydropyrrole, piperidine, morpholine, methylamine, ethylamine, triethylamine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene; the bifunctional catalyst is a natural amino acid and a non-natural amino acid; the acid-base mixed catalyst is a mixture of two or more acids and bases, the acid includes one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, and p-toluenesulfonic acid, and the base includes one or more of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium phosphate, pyridine, imidazole, tetrahydropyrrole, piperidine, morpholine, methylamine, ethylamine, triethylamine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene, and the catalyst is preferably an acid-base mixed catalyst.

[0016] As a preferred technical solution of the present invention, in the step one, the molar ratio of 2-haloacetoacetate to crotonaldehyde is 1:1, 20:1, and the molar ratio is preferably 1:1-1.5:1. In the step one, the molar ratio of the catalyst to crotonaldehyde is 0.01:1-20:1, and the molar ratio is preferably 0.1:1-1:1. In the step one, the reaction temperature is -20°C-50°C, and the reaction temperature is preferably 0°C-25°C; in the step one, the reaction time is 5h-48h, and the reaction time is preferably 10h-24h.

[0017] As a preferred technical solution of the present invention, the intramolecular Adol condensation elimination aromatization reaction in step 2 specifically includes: mixing a solvent, an intermediate 2-acetyl-2-halo-3-methyl-5-oxopentanoate and a catalyst, and performing an intramolecular Adol condensation elimination aromatization reaction at a certain temperature.

[0018] As a preferred technical solution of the present invention, in the step 2, 2-acetyl-2-halogenated-3-methyl-5-oxopentanoate, R is selected from C1-C 20 Straight or branched alkyl, C3-C 20 Cycloalkyl, C5-C 20 One of the aromatic groups; or, R is selected from C1-C 10 Straight or branched alkyl, C3-C 10 Cycloalkyl, C5-C 10 In the step 2, X in 2-acetyl-2-halogenated-3-methyl-5-oxopentanoate is selected from one of Cl, Br, and I; in the step 2, R in 2-hydroxy-6-methylbenzoate is selected from one of C1-C 20 Straight or branched alkyl, C3-C 20 Cycloalkyl, C5-C 20 One of the aromatic groups; or, R is selected from C1-C 10 Straight or branched alkyl, C3-C 10 Cycloalkyl, C5-C 10 One of the aromatic groups.

[0019] As a preferred technical solution of the present invention, in the step 2, the solvent is a polar solvent and a non-polar solvent, the polar solvent is one or more of methanol, ethanol, isopropanol, water, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, ethyl acetate, tetrahydrofuran, 1,4-dioxane; the non-polar solvent is one or more of dichloromethane, chloroform, toluene, n-hexane, cyclohexane; or, the solvent is preferably a non-polar solvent, in the step 2, the catalyst is an acid catalyst, a base catalyst, a bifunctional catalyst or an acid-base mixed catalyst, the acid catalyst is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, p-toluenesulfonic acid; the base catalyst is sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium phosphate, pyrrolidone, chlorinated bicarbonate ... The bifunctional catalyst is a natural amino acid and a non-natural amino acid; the acid-base mixed catalyst is a mixture of two or more acids and bases, the acid includes one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, and p-toluenesulfonic acid, the base includes sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium phosphate, pyridine, imidazole, tetrahydropyrrole, piperidine, morpholine, methylamine, ethylamine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and the catalyst is preferably a base catalyst.

[0020] As a preferred technical solution of the present invention, in the step 2, the molar ratio of the catalyst to the intermediate is 0.01:1-50:1, and the molar ratio is preferably 0.1:1-1:1; in the step 2, the reaction temperature is -20°C-100°C, and the reaction temperature is preferably 25°C-80°C; in the step 2, the reaction time is 5h-48h, and the reaction time is preferably 10h-24h.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] 1. The starting materials, solvents and catalysts used in the present invention are all cheap and readily available industrial raw materials, with low cost and more suitable for industrial production;

[0023] 2. The reaction conditions used in the present invention are mild, with few by-products and high yield, and the target product can be prepared more efficiently;

[0024] 3. The synthetic route adopted in the present invention has high atom economy, the solvents and reagents used are easy to recycle, less industrial waste is generated, and it is more environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is a flow chart of the present invention;

[0026] Figure 2 It is the synthesis principle diagram of the present invention;

[0027] Figure 3 is the Michael addition reaction diagram of the present invention;

[0028] Figure 4 It is the Adol condensation elimination aromatization reaction diagram of the present invention;

[0029] Figure 5 is the molecular formula diagram of 2-hydroxy-6-methylbenzoate of the present invention;

[0030] Figure 6 The molecular formula diagram of 2-acetyl-2-halo-3-methyl-5-oxopentanoate of the present invention;

[0031] Figure 7 This is one of the preparation diagrams of the intermediate 2-acetyl-2-chloro-3-methyl-5-oxopentanoic acid ethyl ester of the present invention;

[0032] Figure 8 This is the second preparation diagram of the intermediate 2-acetyl-2-chloro-3-methyl-5-oxopentanoic acid ethyl ester of the present invention;

[0033] Fig. 9 The third diagram is the preparation diagram of the intermediate 2-acetyl-2-chloro-3-methyl-5-oxopentanoic acid ethyl ester of the present invention;

[0034] Fig.10 This is the fourth diagram of the preparation of the intermediate 2-acetyl-2-chloro-3-methyl-5-oxopentanoic acid ethyl ester of the present invention. 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 making creative work are within the scope of protection of the present invention.

[0036] See also Figure 1-10 The present invention provides a method for synthesizing 2-hydroxy-6-methylbenzoate, comprising the following steps:

[0037] Step 1, preparation of intermediate: crotonaldehyde and 2-haloacetoacetate are subjected to Michael addition reaction to obtain the intermediate 2-acetyl-2-halo-3-methyl-5-oxopentanoate;

[0038] Step 2, preparation of the product: the intermediate 2-acetyl-2-halogeno-3-methyl-5-oxopentanoate is subjected to intramolecular Adol condensation elimination aromatization reaction to obtain 2-hydroxy-6-methylbenzoate.

[0039] The Michael addition reaction in step 1 specifically includes: mixing a solvent, crotonaldehyde, 2-haloacetoacetate and a catalyst, and performing a Michael addition reaction at a certain temperature.

[0040] In step 1, R in the 2-haloacetoacetate is selected from C1-C 20 Straight or branched alkyl, C3-C 20 Cycloalkyl, C5-C 20 One of the aromatic groups; or, R is selected from C1-C 10 Straight or branched alkyl, C3-C 10 Cycloalkyl, C5-C 10 one of the aromatic groups, in step 1, X in the 2-haloacetoacetate is selected from one of Cl, Br, and I, and in step 1, R in the 2-acetyl-2-halo-3-methyl-5-oxopentanoate is selected from one of C1-C 20 Straight or branched alkyl, C3-C 20 Cycloalkyl, C5-C 20 One of the aromatic groups; or, R is selected from C1-C 10 Straight or branched alkyl, C3-C 10 Cycloalkyl, C5-C 10 One of the aromatic groups, in step 1, X in 2-acetyl-2-halo-3-methyl-5-oxopentanoate is selected from one of Cl, Br and I.

[0041] The solvent in step 1 is a polar solvent and a non-polar solvent, the polar solvent is one or more of methanol, ethanol, isopropanol, water, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, ethyl acetate, tetrahydrofuran, and 1,4-dioxane; the non-polar solvent is one or more of dichloromethane, chloroform, toluene, n-hexane, and cyclohexane; the solvent is preferably a polar solvent, the catalyst in step 1 is an acid catalyst, a base catalyst, a bifunctional catalyst, or an acid-base mixed catalyst, the acid catalyst is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, and p-toluenesulfonic acid; the base catalyst is sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium phosphate, pyridine, imidazole, tetrahydropyrrole, piperidine, morpholine The catalyst is preferably a mixture of two or more acids and bases, wherein the acid comprises one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, and p-toluenesulfonic acid, and the base comprises one or more of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium phosphate, pyridine, imidazole, tetrahydropyrrole, piperidine, morpholine, methylamine, ethylamine, triethylamine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene. The catalyst is preferably an acid-base mixed catalyst.

[0042] In step one, the molar ratio of 2-haloacetoacetate and crotonaldehyde is 1:1, 20:1, and the molar ratio of is preferably 1:1-1.5:1. In step one, the molar ratio of the catalyst and crotonaldehyde is 0.01:1-20:1, and the molar ratio of is preferably 0.1:1-1:1. In step one, the reaction temperature is -20°C-50°C, and the reaction temperature is preferably 0°C-25°C; in step one, the reaction time is 5h-48h, and the reaction time is preferably 10h-24h.

[0043] The intramolecular Adol condensation elimination aromatization reaction in step 2 specifically comprises: mixing a solvent, an intermediate 2-acetyl-2-halogenated-3-methyl-5-oxopentanoate and a catalyst, and performing an intramolecular Adol condensation elimination aromatization reaction at a certain temperature.

[0044] In step 2, 2-acetyl-2-halogenated-3-methyl-5-oxopentanoate, wherein R is selected from C1-C 20 Straight or branched alkyl, C3-C 20 Cycloalkyl, C5-C 20 One of the aromatic groups; or, R is selected from C1-C 10 Straight or branched alkyl, C3-C 10 Cycloalkyl, C5-C 10one of the aromatic groups; in step 2, X in 2-acetyl-2-halogenated-3-methyl-5-oxopentanoate is selected from one of Cl, Br, and I; in step 2, R in 2-hydroxy-6-methylbenzoate is selected from one of C1-C 20 Straight or branched alkyl, C3-C 20 Cycloalkyl, C5-C 20 One of the aromatic groups; or, R is selected from C1-C 10 Straight or branched alkyl, C3-C 10 Cycloalkyl, C5-C 10 One of the aromatic groups.

[0045] In step 2, the solvent is a polar solvent and a non-polar solvent, the polar solvent is one or more of methanol, ethanol, isopropanol, water, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, ethyl acetate, tetrahydrofuran, 1,4-dioxane; the non-polar solvent is one or more of dichloromethane, chloroform, toluene, n-hexane, cyclohexane; or, the solvent is preferably a non-polar solvent, in step 2, the catalyst is an acid catalyst, a base catalyst, a bifunctional catalyst or an acid-base mixed catalyst, the acid catalyst is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, p-toluenesulfonic acid; the base catalyst is sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium phosphate, pyridine, imidazole, tetrahydropyrrole , piperidine, morpholine, methylamine, ethylamine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene or more; the bifunctional catalyst is a natural amino acid and a non-natural amino acid; the acid-base mixed catalyst is a mixture of two or more acids and bases, the acid includes one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, and p-toluenesulfonic acid, the base includes sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium phosphate, pyridine, imidazole, tetrahydropyrrole, piperidine, morpholine, methylamine, ethylamine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene or more, and the catalyst is preferably a base catalyst.

[0046] In step 2, the molar ratio of the catalyst to the intermediate is 0.01:1-50:1, preferably 0.1:1-1:1. In step 2, the reaction temperature is -20°C-100°C, preferably 25°C-80°C. In step 2, the reaction time is 5h-48h, preferably 10h-24h.

[0047] Embodiment 1:

[0048] In the present invention, in conjunction with the specification Figure 7, under nitrogen atmosphere, crotonaldehyde (5.0 g, 1.0 eq) and ethyl 2-chloroacetoacetate (12.3 g, 1.05 eq) were added to dichloromethane (15 mL) and water (5 mL), and stirred continuously at room temperature. During the stirring process, a catalyst tetrahydropyrrole (0.51 g, 0.1 eq) was added. After reacting at room temperature for 16 hours, dichloromethane and saturated brine were added to the reaction solution for extraction, and the organic phase was separated. The aqueous phase was extracted with dichloromethane for several times, and the organic phases were combined and concentrated to dryness in vacuo to obtain the intermediate 2-acetyl-2-chloro-3-methyl-5-oxopentanoic acid ethyl ester as a yellow oil (16.2 g, purity: 94.5%, yield: 91.5%), 1H NMR (400MHz, Chloroform-d) δ9.75 (s, 1H), 4.30 (q, J=7.1Hz, 2H), 3.35-3.16 (m, 1H), 2.71 (d, J=17.8Hz, 1H), 2.37 (dd, J=18. 1, 10.8Hz, 1H), 2.32 (s, 3H), 1.31 (t, J=7.1Hz, 3H), 1.02 (d, J=6.6Hz, 3H). CalcdforC10H15ClO4: 234.07, GCMSFound: 234.0.

[0049] Embodiment 2:

[0050] In the present invention, in conjunction with the specification Figure 8 Under a nitrogen atmosphere, crotonaldehyde (10.0 g, 1.0 eq) and ethyl 2-chloroacetoacetate (25.8 g, 1.1 eq) were added to toluene (240 ml), and the mixture was cooled to -20 ° C and stirred continuously. Pyrrolidine (1.04 g, 0.1 eq) and benzoic acid (1.76 g, 0.1 eq) were added during the stirring process. After reacting at -20 ° C for 16 hours, saturated brine was added to the reaction solution for washing, and the organic phase was concentrated to dryness in vacuo to obtain the intermediate 2-acetyl-2-chloro-3-methyl-5-oxopentanoic acid ethyl ester as a yellow oil (34.0 g, purity 92.78%, yield 94.3%).

[0051] Embodiment 3:

[0052] In the present invention, in conjunction with the specification Fig. 9Under a nitrogen atmosphere, crotonaldehyde (3.0 g, 1.0 eq) and ethyl 2-chloroacetoacetate (7.74 g, 1.1 eq) were added to toluene (72 ml), and the mixture was cooled to -20 °C and stirred continuously. During the stirring process, a catalyst (2R)-2-[diphenyl[(trimethylsilyl)oxy]methyl]-pyrrolidine (0.3 g, 0.02 eq) was added. After reacting at -20 °C for 16 hours, saturated brine was added to the reaction solution for washing. The organic phase was concentrated to dryness in vacuo to obtain the intermediate ethyl 2-acetyl-2-chloro-3-methyl-5-oxopentanoate as a yellow oil (8.46 g, purity 88.9%, yield 74.9%).

[0053] Embodiment 4:

[0054] In the present invention, in conjunction with the specification Fig.10 , under nitrogen atmosphere, 2-acetyl-2-chloro-3-methyl-5-oxopentanoic acid ethyl ester (6.0 g, 1.0 eq) was dissolved in toluene (30 ml) and stirred continuously at room temperature. N, N-diisopropylethylamine (0.33 g, 0.1 eq) was added during stirring. After heating to 80°C for 16 hours, 1 M hydrochloric acid was added to the reaction solution to adjust the pH to 2-3, and saturated brine was added for washing. The organic layer was concentrated to dryness in vacuo to obtain 2-hydroxy-6-methylbenzoic acid ethyl ester. White solid (4.5 g, purity 92.3%, yield 90.9%), 1HNMR (400 MHz, Chloroform-d) δ 11.38 (s, 1H), 7.31-7.27 (m, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 7.4 Hz, 1H), 4.43 (q, J = 7.0 Hz, 2H), 2.55 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H).

[0055] Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments, or to make equivalent substitutions for some of the technical features therein. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 2-hydroxy-6-methylbenzoate, characterized in that: The following steps are involved: Step 1, preparation of intermediate: crotonaldehyde and 2-haloacetoacetate are subjected to Michael addition reaction to obtain the intermediate 2-acetyl-2-halo-3-methyl-5-oxopentanoate; Step 2, preparing the product: the intermediate 2-acetyl-2-halogeno-3-methyl-5-oxopentanoate is subjected to intramolecular Adol condensation elimination aromatization reaction to obtain 2-hydroxy-6-methylbenzoate.

2. The method for synthesizing 2-hydroxy-6-methylbenzoate according to claim 1, wherein: The Michael addition reaction in step 1 specifically includes: mixing a solvent, crotonaldehyde, 2-haloacetoacetate and a catalyst, and performing a Michael addition reaction at a certain temperature.

3. The method for synthesizing 2-hydroxy-6-methylbenzoate according to claim 2, characterized in that: In the step 1, R in the 2-haloacetoacetate is selected from C1-C 20 Straight or branched alkyl, C3-C 20 Cycloalkyl, C5-C 20 One of the aromatic groups; or, R is selected from C1-C 10 Straight or branched alkyl, C3-C 10 Cycloalkyl, C5-C 10 In the step 1, X in the 2-haloacetoacetate is selected from one of Cl, Br, and I, and in the step 1, R in the 2-acetyl-2-halo-3-methyl-5-oxopentanoate is selected from one of C1-C 20 Straight or branched alkyl, C3-C 20 Cycloalkyl, C5-C 20 One of the aromatic groups; or, R is selected from C1-C 10 Straight or branched alkyl, C3-C 10 Cycloalkyl, C5-C 10 One of the aromatic groups, wherein X in the 2-acetyl-2-halogenated-3-methyl-5-oxopentanoate in step 1 is selected from one of Cl, Br and I.

4. The method for synthesizing 2-hydroxy-6-methylbenzoate according to claim 2, characterized in that: The solvent in step 1 is a polar solvent and a non-polar solvent, and the polar solvent is one or more of methanol, ethanol, isopropanol, water, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, ethyl acetate, tetrahydrofuran, and 1,4-dioxane; the non-polar solvent is one or more of dichloromethane, chloroform, toluene, n-hexane, and cyclohexane; the solvent is preferably a polar solvent, and the catalyst in step 1 is an acid catalyst, a base catalyst, a bifunctional catalyst, or an acid-base mixed catalyst, and the acid catalyst is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, and p-toluenesulfonic acid; the base catalyst is sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium phosphate, pyridine, imidazole, tetrahydropyrrole, piperidine , morpholine, methylamine, ethylamine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene or more; the bifunctional catalyst is a natural amino acid and a non-natural amino acid; the acid-base mixed catalyst is a mixture of two or more acids and bases, the acid includes one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, and p-toluenesulfonic acid, the base includes sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium phosphate, pyridine, imidazole, tetrahydropyrrole, piperidine, morpholine, methylamine, ethylamine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene or more, and the catalyst is preferably an acid-base mixed catalyst.

5. The method for synthesizing 2-hydroxy-6-methylbenzoate according to claim 2, characterized in that: In the step one, the molar ratio of 2-haloacetoacetate to crotonaldehyde is 1:1, 20:1, and the molar ratio is preferably 1:1-1.5:

1. In the step one, the molar ratio of the catalyst to crotonaldehyde is 0.01:1-20:1, and the molar ratio is preferably 0.1:1-1:

1. In the step one, the reaction temperature is -20°C-50°C, and the reaction temperature is preferably 0°C-25°C; in the step one, the reaction time is 5h-48h, and the reaction time is preferably 10h-24h.

6. The method for synthesizing 2-hydroxy-6-methylbenzoate according to claim 1, characterized in that: The intramolecular Adol condensation elimination aromatization reaction in step 2 specifically comprises: mixing a solvent, an intermediate 2-acetyl-2-halogenated-3-methyl-5-oxopentanoate and a catalyst, and performing an intramolecular Adol condensation elimination aromatization reaction at a certain temperature.

7. The method for synthesizing 2-hydroxy-6-methylbenzoate according to claim 6, characterized in that: In the step 2, 2-acetyl-2-halogenated-3-methyl-5-oxopentanoate, R is selected from C1-C 20 Straight or branched alkyl, C3-C 20 Cycloalkyl, C5-C 20 One of the aromatic groups; or, R is selected from C1-C 10 Straight or branched alkyl, C3-C 10 Cycloalkyl, C5-C 10 In the step 2, X in 2-acetyl-2-halogenated-3-methyl-5-oxopentanoate is selected from one of Cl, Br, and I; in the step 2, R in 2-hydroxy-6-methylbenzoate is selected from one of C1-C 20 Straight or branched alkyl, C3-C 20 Cycloalkyl, C5-C 20 One of the aromatic groups; or, R is selected from C1-C 10 Straight or branched alkyl, C3-C 10 Cycloalkyl, C5-C 10 One of the aromatic groups.

8. The method for synthesizing 2-hydroxy-6-methylbenzoate according to claim 6, characterized in that: In the step 2, the solvent is a polar solvent and a non-polar solvent, the polar solvent is one or more of methanol, ethanol, isopropanol, water, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, ethyl acetate, tetrahydrofuran, 1,4-dioxane; the non-polar solvent is one or more of dichloromethane, chloroform, toluene, n-hexane, and cyclohexane; or, the solvent is preferably a non-polar solvent, in the step 2, the catalyst is an acid catalyst, a base catalyst, a bifunctional catalyst or an acid-base mixed catalyst, the acid catalyst is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, and p-toluenesulfonic acid; the base catalyst is sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium phosphate, pyridine, imidazole, tetrahydropyridine The bifunctional catalyst is a natural amino acid and a non-natural amino acid; the acid-base mixed catalyst is a mixture of two or more acids and bases, the acid includes one or more of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, benzoic acid, and p-toluenesulfonic acid, the base includes sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, potassium phosphate, pyridine, imidazole, tetrahydropyrrole, piperidine, morpholine, methylamine, ethylamine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and the catalyst is preferably a base catalyst.

9. The method for synthesizing 2-hydroxy-6-methylbenzoate according to claim 6, characterized in that: In the step 2, the molar ratio of the catalyst to the intermediate is 0.01:1-50:1, and the molar ratio is preferably 0.1:1-1:

1. In the step 2, the reaction temperature is -20°C-100°C, and the reaction temperature is preferably 25°C-80°C. In the step 2, the reaction time is 5h-48h, and the reaction time is preferably 10h-24h.

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