Preparation method of 2, 6-dialkoxy or sulfenyl benzoic acid

Abstract

The invention discloses a preparation method of 2, 6-dialkoxy or sulfenyl benzoic acid, and the synthesis route of the method is as follows: X1, X2, Y, R1 and R2 are defined in the specification. Compared with the existing process route, the preparation method disclosed by the invention has the characteristics of mild reaction conditions, simplicity in operation, low production cost, easiness in industrialization and the like.

Description

Technical Field

[0001] This invention relates to a method for preparing intermediates, and more particularly to a method for preparing 2,6-dialkoxy or thiobenzoic acid. Background Technology

[0002] 2,6-Dimethoxybenzoic acid is an important organic synthesis intermediate, commonly used as a basic building block in pharmaceutical and pesticide molecules, and can also be used in the preparation of photosensitive elements.

[0003]

[0004] An analysis of the reported preparation methods for this compound reveals that there are currently three main technical approaches:

[0005] Option 1:

[0006]

[0007] 2,6-Dimethoxytoluene or 2,6-dimethoxybenzaldehyde were used as raw materials and oxidized to obtain 2,6-dimethoxybenzoic acid. Literature (Journal of the Chemical Society (1952), 3499-502; ACS Sustainable Chemistry & Engineering (2018), 6(4), 4916-4921; ACS Sustainable Chemistry & Engineering (2022), 10(43), 14119-14125) reported that this route had a high yield of 80-95%. However, the reaction required the use of oxidants such as oxygen and potassium permanganate, posing significant safety risks. Furthermore, the high price of the raw materials presented difficulties for industrial production.

[0008] Option 2:

[0009]

[0010] Using resorcinol as a raw material, a carboxyl group is introduced through reaction with carbon dioxide, followed by methylation and hydrolysis to obtain 2,6-dimethoxybenzoic acid. This method is simple to operate, but the yield reported in the literature (GB 916548) is low at 48%, and it uses the carcinogenic compound dimethyl sulfate, posing a safety risk to operators.

[0011] Option 3:

[0012]

[0013] Using resorcinol as a raw material, dimethyl resorcinol is obtained through methylation, followed by reaction with an alkali metal to introduce a carboxyl group, yielding 2,6-dimethoxybenzoic acid. This method not only uses the highly toxic compound dimethyl sulfate but also flammable and explosive metallic sodium, requiring high operational standards and posing significant safety risks. Furthermore, the yields reported in the literature are low (WO9959941, CN101284778, WO9959941, Science of Synthesis (2006), 8b, 1197-1203; Angewandte Chemie, International Edition (2002), 41(2), 340343; US4845276, US4845277, CN104058956), which is not conducive to industrialization.

[0014] Therefore, seeking synthetic routes for 2,6-dimethoxybenzoic acid suitable for industrial production, especially those with stable, environmentally friendly, and simple operation, is of great significance for achieving green processization and improving market competitiveness. Summary of the Invention

[0015] The purpose of this invention is to overcome the problems existing in the preparation of 2,6-dimethoxybenzoic acid in the prior art, and to provide a low-cost, simple, and easily industrialized synthetic route for 2,6-dimethoxybenzoic acid.

[0016] To achieve the above objectives, the present invention provides a method for preparing 2,6-dimethoxybenzoic acid, the preparation scheme of which is as follows:

[0017]

[0018] Among them, X1 and X2 are each independently selected from halogens;

[0019] R1 and R2 are each independently selected from C1 to C6 alkyl groups;

[0020] Y is selected from either O or S.

[0021] Beneficial effects

[0022] The preparation method provided by this invention yields 2,6-dimethoxybenzoic acid with high purity and high yield. Furthermore, the raw materials used in the method provided by this invention are low-cost, and compared with existing processes and preparation methods, the reaction conditions are mild, the cost is low, the operation is simple, and the yield is high, giving it a high degree of market competitiveness. Detailed Implementation

[0023] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprising of," etc., will be understood to include the stated components or steps, without excluding other substances or steps.

[0024] Furthermore, to better illustrate the present invention, numerous specific details are provided in the following detailed embodiments.

[0025] Those skilled in the art will understand that the present invention can be practiced even without certain specific details. In some embodiments, materials, methods, and means well known to those skilled in the art are not described in detail in order to highlight the spirit of the invention.

[0026] As used herein, the term "alkyl" (and in other groups containing alkyl, such as the alkyl moiety of alkoxy, the alkyl moiety of alkylthio) in each case means a straight-chain or branched alkyl group generally having 1-20 carbon atoms, often 1-6 carbon atoms, preferably 1-4 carbon atoms, and especially 1-3 carbon atoms. Examples of C1-C4 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), and 1,1-dimethylethyl (tert-butyl). Examples of C1-C6 alkyl groups, in addition to those mentioned for C1-C4 alkyl groups, include n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl.

[0027] In this invention, "alkali metal" has the conventional meaning in the art.

[0028] In the invention, "halogen" is usually fluorine, chlorine, bromine or iodine, preferably fluorine, bromine or chlorine.

[0029] In this invention, "inorganic acid" has the common meaning in the art, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., but is not limited thereto;

[0030] The term "organic acid" in this invention has the common meaning in the art, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucoconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trichloroacetic acid, trifluoroacetic acid, etc., but is not limited thereto.

[0031] The bases suitable for the purposes of this invention include inorganic bases and organic bases. The inorganic bases include, for example, alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide; alkali metal carbonates, such as sodium carbonate and potassium carbonate; alkali metal bicarbonates, such as sodium bicarbonate and potassium bicarbonate; alkali metal phosphates, such as sodium phosphate and potassium phosphate; alkali metal hydrogen phosphates, such as sodium hydrogen phosphate and potassium hydrogen phosphate; alkali metal dihydrogen phosphates, such as sodium dihydrogen phosphate and potassium dihydrogen phosphate; and nitrogen bases, such as ammonia. Alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide, are particularly preferred.

[0032] The inorganic base of the present invention can be used in solid form or in the form of its industrial aqueous solution. A 1-80% by weight aqueous solution is preferred.

[0033] Examples of organic bases in this invention include nitrogen-containing organic bases, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, DMAP, or DBU, but are not limited thereto.

[0034] The C1 to C6 alkyl alcohols of this invention refer to alcohols containing 1 to 6 carbon atoms. Examples of C1 to C6 alkyl alcohols include methanol, ethanol, butanol, etc., but are not limited thereto.

[0035] The C2 to C6 ethers of this invention refer to ethers containing 2 to 6 carbon atoms, such as diethyl ether, methyl ethyl ether, etc., but not limited thereto.

[0036] The C2 to C7 esters of this invention refer to esters containing 2 to 7 carbon atoms, such as ethyl acetate, methyl acetate, etc., but are not limited thereto.

[0037] In this invention, percentage content refers to mass / weight percentage content unless otherwise specified.

[0038] Specifically, the present invention first provides a method for preparing a compound of formula I, which includes the following steps:

[0039] Step 1): Compound III undergoes an etherification reaction with an etherifying agent in an organic solvent to give compound II;

[0040] Step 2): Compound II undergoes a hydrolysis reaction to obtain compound I in one step.

[0041]

[0042] Among them, X1 and X2 are each independently selected from halogens;

[0043] R1 and R2 are each independently selected from C1 to C6 alkyl groups;

[0044] Y is selected from O or S.

[0045] Preferably, in the above preparation method, the organic solvent in step 1) is selected from one or more combinations of acetonitrile, DMF, DMAc, NMP, toluene, 1,2-dichloroethane, dichloromethane, chlorobenzene, chloroform, carbon tetrachloride, C1-C6 alkyl alcohols, C2-C6 ethers, C2-C7 esters, cyclohexane, carbon disulfide, and acetone, preferably DMF; the etherifying agent is selected from C1-C6 alkyl alcohols or their alkali metal salts, C1-C6 alkyl thiols or their alkali metal salts, preferably sodium salts of C1-C6 alkyl alcohols or sodium salts of C1-C6 alkyl thiols; the molar ratio of compound III to the etherifying agent is 1:2.0-3.5, preferably 1:2.0-2.8; the reaction temperature of the etherification reaction is 30-150℃, preferably 70-140℃; the etherification reaction time is 2-12 h, preferably 3-10 h.

[0046] Preferably, in the above preparation method, in step 2), compound II undergoes a hydrolysis reaction in the presence of an acid or a base. The acid is an organic or inorganic acid, preferably one of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, or trichloroacetic acid. The base is an inorganic or organic base. The inorganic base is preferably one of potassium hydroxide, sodium hydroxide, alkali metal carbonate, or alkali metal bicarbonate, particularly preferably an aqueous solution of sodium hydroxide or potassium hydroxide. The organic base is preferably one of DMAP or DBU. The concentration of the aqueous solution of sodium hydroxide or potassium hydroxide is 5%–50%, preferably 10%–35%. The molar ratio of compound II to the base is 1:2.0–5.0, preferably 1:2.0–3.5. The reaction pressure is 0.1–2.0 MPa, preferably 0.3–1.5 MPa. The reaction temperature is 50–200°C, preferably 80–180°C. The reaction time is 5–24 h, preferably 8–15 h.

[0047] The present invention will be further described in detail below through embodiments. The following embodiments include:

[0048] The amounts of reactants and products were determined by liquid chromatography (Agilent HPLC1260).

[0049] The conversion rate and selectivity of the reaction are calculated using the following formulas:

[0050] Conversion rate = (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input × 100%.

[0051] Selectivity = (Actual molar amount of target product / Theoretical molar amount of target product) × 100%

[0052] Unless otherwise specified, all raw materials used are commercially available products.

[0053] Example 12: Preparation of 6-dimethoxybenzoic acid

[0054] 87.8 g of 2,6-dichlorophenylcyanuron and 351.0 g of DMF were added sequentially to a 1000 mL four-necked flask. The temperature was then raised to 85–100 °C, and 225.0 g of 30% sodium methoxide methanol solution was slowly added dropwise while maintaining the reaction temperature. After the reaction was completed, 79.9 g of 2,6-dimethoxyphenylcyanuron was obtained, with a yield of 91.2%.

[0055] 87.6 g of 2,6-dimethoxybenzoic acid and 600 g of 10% sodium hydroxide aqueous solution were added sequentially to a 1000 mL high-pressure reactor. The reactor was sealed, and stirring was started. The temperature was raised to 120–125 °C, and the pressure was maintained at 0.7 MPa for 5 h by supplementing with nitrogen. After the reaction, 86.6 g of 2,6-dimethoxybenzoic acid was obtained, with a yield of 92.2%.

[0056] Examples 2-5: 2,6-Dimethoxyphenylcyanury was prepared using reaction conditions similar to step 1) of Example 1, with only one condition changed. The experimental results are shown in Table 1 below:

[0057] Table 1

[0058] Serial Number solvent Temperature / °C yield Example 2 DMAc 85～100 89.1％ Example 3 Acetonitrile 70～75 79.8％ Example 4 NMP 85～100 85.1％ Example 5 DMSO 85～100 82.7％

[0059] Examples 6-8: Examples 6-8 prepared 2,6-dimethoxybenzoic acid under similar reaction conditions as Example 1, only the reaction pressure was changed (by depressurization or nitrogen pressurization). The experimental results are shown in the table below:

[0060] Table 2

[0061] Serial Number Reaction pressure yield Example 6 0.1MPa 53.4％ Example 7 0.3MPa 83.2％ Example 8 1.0MPa 88.7％

[0062] Example 92: Preparation of 6-dimethoxybenzoic acid

[0063] Unlike Example 2, 80% sulfuric acid was used instead of sodium hydroxide solution to prepare 71.3g of 2,6-dimethoxybenzoic acid, with a yield of 40.1%.

[0064] Example 10: Preparation of 2,6-dimethoxybenzoic acid

[0065] 87.6 g of 2,6-dimethoxybenzyl cyanide and 133.3 g of 45% sodium hydroxide aqueous solution were added sequentially to a 500 mL four-necked flask. The temperature was then raised to 95–105 °C and maintained for reaction. After the reaction was completed, 89.7 g of 2,6-dimethoxybenzamide was obtained, with a yield of 88.3%.

[0066] 101.6 g of 2,6-dimethoxybenzamide, 183.8 g of 80% sulfuric acid, and 304 g of acetonitrile were added sequentially to a 1000 mL four-necked flask. The temperature was then raised to 35–40 °C, and 1.5 eq of 30% sodium nitrite aqueous solution was slowly added dropwise. After the addition was complete, the reaction was maintained at the specified temperature. After the reaction was completed, 87.3 g of 2,6-dimethoxybenzoic acid was obtained, with a yield of 84.6%.

[0067] Examples 11-17: 2,6-Dimethoxybenzoic acid was prepared using reaction conditions similar to those in Example 1, with only one condition changed. The experimental results are shown in Table 3 below.

[0068] Table 3

[0069] Serial Number Inorganic base aqueous solution Temperature / °C yield Example 11 20% NaOH 120～125 85.2％ Example 12 30% NaOH 120～125 73.9％ Example 13 40% NaOH 120～125 66.4％ Example 14 50% NaOH 120～125 57.6％ Example 15 10% KOH 120～125 90.4％ Example 16 10% NaOH 110～115 80.6％ Example 17 10% NaOH 130～135 86.3％

[0070] Examples 18-20 and 16-18 used similar reaction conditions as Example 1 to prepare 2,6-dimethoxybenzoic acid, only changing the amount of sodium hydroxide. The experimental results are shown in Table 4 below:

[0071] Table 4

[0072] Serial Number 10% NaOH solution yield Example 18 3.5eq 82.61％ Example 19 2.5eq 90.1％ Example 20 2eq 86.3％

[0073] Example 21: Preparation of 2,6-dimethyl sulfide benzoic acid

[0074] 87.8 g of 2,6-dichlorophenylcyanuron and 351.0 g of DMF were added sequentially to a 1000 mL four-necked flask. The temperature was then raised to 85–100 °C, and 437.0 g of a 20% sodium methanethiol aqueous solution was slowly added dropwise while maintaining the temperature for the reaction. After the reaction was completed, 96.7 g of 2,6-dimethyl sulfide phenylcyanuron was obtained, with a yield of 93.3%.

[0075] 103.6 g of 2,6-dimethyl sulfide benzoic acid and 250 g of 20% sodium hydroxide aqueous solution were added sequentially to a 500 mL high-pressure reactor. The reactor lid was tightened, and the temperature was raised to 110–115 °C. The pressure was maintained at 1.0 MPa by supplementing with nitrogen gas, and the reaction was carried out for 4 hours. After the reaction was completed, 100.5 g of 2,6-dimethyl sulfide benzoic acid was obtained, with a yield of 90.4%.

[0076] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A method for preparing a compound of formula I, characterized in that, Includes the following steps: Step 1): Compound III undergoes an etherification reaction with an etherifying agent in an organic solvent to give compound II; Step 2): Compound II undergoes a hydrolysis reaction to obtain compound I in one step; Among them, X1 and X2 are each independently selected from halogens; R1 and R2 are each independently selected from C1 to C6 alkyl groups; Y is selected from either O or S.

2. The preparation method according to claim 1, characterized in that, The organic solvent in step 1) is selected from one or more combinations of acetonitrile, DMF, DMAc, NMP, toluene, 1,2-dichloroethane, dichloromethane, chlorobenzene, chloroform, carbon tetrachloride, C1-C6 alkyl alcohols, C2-C6 ethers, C2-C7 esters, cyclohexane, carbon disulfide, and acetone, preferably DMF; Preferably, the etherifying agent is selected from C1-C6 alkyl alcohols or their alkali metal salts, C1-C6 alkyl thiols or their alkali metal salts, and more preferably sodium salts of C1-C6 alkyl alcohols or sodium salts of C1-C6 alkyl thiols; Preferably, the molar ratio of compound III to the etherifying agent is 1:2.0 to 3.5, more preferably 1:2.0 to 2.8; Preferably, the reaction temperature of the etherification reaction is 30–150°C, more preferably 70–140°C; Preferably, the etherification reaction time is 2 to 12 hours, more preferably 3 to 10 hours.

3. The preparation method according to claim 1, characterized in that, In step 2), compound II undergoes a hydrolysis reaction in the presence of an acid or a base. The acid is preferably one of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, or trichloroacetic acid. The base is an inorganic or organic base. The inorganic base is preferably one of potassium hydroxide, sodium hydroxide, an alkali metal carbonate, or an alkali metal bicarbonate, and particularly preferably an aqueous solution of sodium hydroxide or potassium hydroxide. The organic base is preferably one of DMAP or DBU. Preferably, the concentration of the aqueous solution of sodium hydroxide or potassium hydroxide is 5% to 50%, more preferably 10% to 35%; Preferably, the molar ratio of compound II to the base is 1:2.0 to 5.0, more preferably 1:2.0 to 3.5; Preferably, the reaction pressure is 0.1–2.0 MPa, more preferably 0.3–1.5 MPa; Preferably, the hydrolysis reaction temperature is 50–200°C, more preferably 80–180°C; Preferably, the hydrolysis reaction takes 5 to 24 hours, and more preferably 8 to 15 hours.

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