Preparation method of 3-hydroxy-4-fluorobenzoate

Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a preparation method of 3-hydroxy-4-fluorobenzoate. According to the preparation method disclosed by the invention, 3-bromo-4-fluorobenzaldehyde is taken as an initial raw material, and the compound 3-hydroxy-4-fluorobenzoate is prepared through four steps of reactions including aldolization, boronation, oxidation and esterification. The 3-hydroxy-4-fluorobenzoate can be used for preparing the acomidid or an intermediate 3-(3-(3, 5-dimethyl-1H-pyrazol-4-yl) propoxy)-4-fluorobenzoate of the acomidid, and the 3-(3, 5-dimethyl-1H-pyrazol-4-yl) propoxy)-4-fluorobenzoate can be used for preparing the acomidid. The preparation method has the advantages of easily available raw materials, mild reaction conditions, simple operation, high yield and purity, and suitableness for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a method for preparing the acomedi intermediate 3-hydroxy-4-fluorobenzoate. Background Technology

[0002] Methyl 4-fluoro-3-hydroxybenzoate is an important intermediate in pharmaceuticals, pesticides, and chemical raw materials. There are few reports on its preparation methods, but its domestic and international demand is constantly increasing. Moreover, the process of this product is complex and technically challenging.

[0003] In the prior art, for example, patent WO2022 / 058733A1 discloses the method of obtaining 4-fluoro-3-hydroxybenzoic acid by methylation with trimethyl orthoformate in a sulfuric acid / methanol system; or WO2018 / 128720A1 by methylation with methanol; however, 4-fluoro-3-hydroxybenzoic acid is expensive and its cost remains high.

[0004] Some traditional processes use precious metals as catalysts. For example, J. Am. Chem. Soc., 2021, 143, 6915-6921 reported using 4-fluorobenzoate as the starting material, with an iridium catalyst [Ir(COD)OMe]2 directing the pinacol ester, which is then converted to a phenolic hydroxyl group. The catalyst used is expensive and not suitable for industrial production. The synthetic route is as follows: .

[0005] Another patent, US6020368A, reports a synthetic route for constructing carboxylic acids by hydrolyzing trifluoromethylphenol using 2-fluoro-5-trifluoromethylphenol as the starting material and concentrated sulfuric acid as the reaction medium. The route is as follows: The starting materials for this method are expensive, and it generates a large amount of waste acid and highly toxic hydrogen fluoride. Conventional equipment cannot meet the production requirements, making it unsuitable for industrial production.

[0006] Therefore, existing methods need to be improved to obtain methyl 4-fluoro-3-hydroxybenzoate using cheaper and more readily available raw materials and milder conditions. Summary of the Invention

[0007] This invention provides a method for preparing 3-hydroxy-4-fluorobenzoic acid ester. The method uses 3-bromo-4-fluorobenzaldehyde as the starting material, has mild reaction conditions, readily available raw materials, high yield and purity, and is suitable for industrial production.

[0008] The technical solution of this invention is a method for preparing 3-hydroxy-4-fluorobenzoic acid ester, the route of which is shown below: In the compound of formula II, R1 is a C1-C6 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 1-pentyl, isopentyl, 1-hexyl, etc.; R2 is a C1-C6 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 1-pentyl, isopentyl, 1-hexyl, etc.; or R1 and R2 are alkylene groups, such as 1,2-ethylene, 1,3-propylene, propane-1,2-diyl, butane-2,3-diyl, 1,4-butylene, 2,2-dimethylpropane-1,3-diyl, 1,5-pentylene, 1,6-hexylene, etc., preferably 1,2-ethylene; In compound V, R is a C1-C6 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 1-pentyl, isopentyl, 1-hexyl, etc., preferably methyl; The steps include: (1) Under acidic conditions, the compound of formula I reacts with an alcohol in an organic solvent under reflux to remove water. Specifically, the compound of formula I reacts with an alcohol under reflux to remove water and undergoes an acetal reaction to obtain the compound of formula II. (2) Compound II is reacted with orthoboronic ester in an inert solvent after dehalogenation by organolithium, followed by acid hydrolysis to obtain compound III; (3) Compound III is oxidized in an organic acid solvent by an oxidizing agent to obtain compound IV; (4) Compound IV was prepared by Lewis acid catalysis in an alcohol solvent to obtain compound V.

[0009] In step (1), the mass ratio of the compound of formula I, alcohol and acid is 1:1-2:0.05-0.8, preferably 1:1.3-1.6:0.1-0.4, and more preferably 1:1.4:0.2; the molar volume concentration of the compound of formula I in the organic solvent is 1-2 mol / L, preferably 1.4-1.5 mol / L.

[0010] In step (1), the organic solvent includes, but is not limited to, dichloromethane, THF, cyclohexane, etc., and is preferably cyclohexane.

[0011] In step (1), the acid used is an inorganic acid or an organic acid. The inorganic acid is a protic acid, including but not limited to hydrochloric acid or phosphoric acid, preferably hydrochloric acid. The organic acid is an organic sulfonic acid, including but not limited to methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-methylbenzenesulfonic acid, etc., preferably p-methylbenzenesulfonic acid.

[0012] In step (1), the alcohol is a C1-C6 alkyl alcohol, further a C1-C6 alkyl monohydric alcohol or a C1-C6 alkyl dihydric alcohol, specifically such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, 1-pentanol, isoamyl alcohol, 1-hexanol, ethylene glycol, propylene glycol, 1,4-butanediol, neopentanediol, 1,5-pentanediol, 1,6-hexanediol, etc., and is further preferably a C2-C3 alkyl dihydric alcohol, such as ethylene glycol or propylene glycol, and even more preferably ethylene glycol.

[0013] In step (1), the reaction solution is cooled to room temperature, an alkaline solution is added, the mixture is separated, the organic phase is dried with anhydrous sodium sulfate, filtered, and the solvent is removed by vacuum distillation of the filtrate to obtain compound II. The alkaline solution is a carbonate solution, such as sodium carbonate solution, potassium carbonate solution, etc., preferably a 10% potassium carbonate solution.

[0014] In step (2), the molar ratio of compound II, organolithium and orthoboronic ester is 1:1-1.5:1-2, preferably 1:1:1.2-1.3; the molar volume ratio of compound II to inert solvent is 0.5-1.5 mol:1 L, preferably 0.7-0.8 mol:1 L.

[0015] In step (2), the organic lithium includes, but is not limited to, n-butyllithium, tert-butyllithium, diisopropylaminolithium, ditrimethylsilylaminolithium, etc., with n-butyllithium being preferred.

[0016] In step (2), the inert solvent is a solvent that is stable under strong alkali, including but not limited to tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, ethylene glycol dimethyl ether, n-hexane, toluene, etc., preferably tetrahydrofuran.

[0017] In step (2), the orthoboronic ester includes, but is not limited to, alkylboronic esters, arylboronic esters, allylboronic esters, etc., preferably alkylboronic esters. Alkylboronic esters include, but are not limited to, trimethyl borate, triethyl borate, triisopropyl borate, etc., preferably trimethyl borate or triisopropyl borate.

[0018] In step (2), under temperature control conditions of -75 to -80℃, compound II is dehalogenated in an inert solvent with an organolithium ester, then orthoboronic ester is added, and after being heated to room temperature, it reacts with orthoboronic ester and is then acid-hydrolyzed to obtain compound III.

[0019] In step (2), the reaction solution that reacts with the orthoboronic ester is added to an acid solution for acid hydrolysis to obtain compound III. The acid solution is dilute hydrochloric acid or dilute sulfuric acid, preferably 3V 18% hydrochloric acid.

[0020] The acid used in the acid hydrolysis is an inorganic acid. Sulfate or hydrochloric acid is preferred. The molar ratio of the acid to the compound of formula II is 1 to 1.5:1, preferably 1.2:1.

[0021] In step (2), the solvent in the reaction solution obtained after acid hydrolysis is removed by vacuum distillation, filtered, and the filter cake is taken to obtain compound III.

[0022] In step (3), the molar ratio of compound III to oxidant is 1:45, preferably 1:4-4.5, more preferably 1:4.2-4.3; the molar volume ratio of compound III to organic acid solvent is 1.5-3 mol:1L, preferably 1.5-2 mol:1L, more preferably 1.6-1.7 mol:1L.

[0023] In step (3), the organic acid is a C1-C6 organic acid, including but not limited to formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, succinic acid, valeric acid, isovaleric acid, glutaric acid, hexanoic acid, adipic acid, benzoic acid, etc., preferably acetic acid.

[0024] In step (3), the oxidant is a perborate or its hydrate, including but not limited to sodium perborate, potassium perborate, lithium perborate, calcium perborate, or their hydrates, preferably sodium perborate or its hydrate.

[0025] In step (3), under temperature control of 80-90℃, compound III is oxidized in an organic acid solvent by an oxidant to obtain compound IV.

[0026] In step (3), the reaction solution obtained from the reaction is poured into ice water, a solid is precipitated, the solid is mixed with water and pulped, the solid is collected by centrifugation and dried to obtain compound IV.

[0027] In step (4), the molar ratio of compound IV to Lewis acid catalyst is 1:1-2, preferably 1:1.1-1.2; the molar volume ratio of compound IV to alcohol solvent is 0.8-2 mol:1L, preferably 1-1.5 mol:1L, and more preferably 1 mol:1L.

[0028] In step (4), the alcohol solvent is a C1-C6 alkyl alcohol, further a C1-C6 alkyl monohydric alcohol or a C1-C6 alkyl dihydric alcohol, including but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, 1-pentanol, isopentanol, 1-hexanol, ethylene glycol, propylene glycol, 1,4-butanediol, 2,3-butanediol, neopentanediol, 1,5-pentanediol, 1,6-hexanediol, etc., and is further preferably a C1-C3 alkyl monohydric alcohol, such as methanol, ethanol or n-propanol, and even more preferably methanol.

[0029] In step (4), the Lewis acid catalyst is an inorganic acid or an acid-producing reagent, including but not limited to hydrochloric acid, sulfuric acid, nitric acid, titanium tetrachloride, tin tetrachloride, thionyl chloride, silicon tetrafluoride, phosphorus pentachloride, sulfur tetrafluoride, boron trifluoride, boron trichloride, aluminum trichloride, zinc chloride, ferric bromide, aldehydes, ketones, etc., preferably thionyl chloride. The acid-producing reagent refers to reagents such as thionyl chloride and chlorosulfonic acid that react with alcohols to produce inorganic acidic substances.

[0030] In step (4), under heating conditions, compound IV is catalyzed by Lewis acid in an alcohol solvent to obtain compound V; further, under heating and reflux conditions, compound IV is catalyzed by Lewis acid in an alcohol solvent to obtain compound V.

[0031] In step (4), the reaction solution obtained from the reaction is subjected to vacuum distillation to remove the solvent, water is added to make a slurry, the solid is collected by centrifugation and dried to obtain compound V.

[0032] The 3-hydroxy-4-fluorobenzoate prepared by this invention can be used to prepare accommodative or its intermediate 3-(3-(3,5-dimethyl-1H-pyrazol-4-yl)propoxy)-4-fluorobenzoate.

[0033] This invention synthesizes 3-hydroxy-4-fluorobenzoic acid esters from 3-bromo-4-fluorobenzaldehyde using only four reaction steps under mild conditions and simple operation. The overall yield can reach over 76%, and the purity can reach 99.4%. The product has been verified through kilogram-scale process testing and can be stably prepared using only a simple process, making it suitable for industrial production. Attached Figure Description

[0034] Figure 1 This is the gas phase spectrum of compound II.

[0035] Figure 2 This is the liquid phase spectrum of compound III.

[0036] Figure 3 This is the liquid phase spectrum of compound IV.

[0037] Figure 4 This is the mass spectrum of compound IV.

[0038] Figure 5 This is the liquid phase spectrum of compound V.

[0039] Figure 6 This is the mass spectrum of compound V. Detailed Implementation

[0040] This invention provides a novel synthetic method for the intermediate 3-hydroxy-4-fluorobenzoate, the route of which is shown below: Step 1: Synthesis of compound II with R1R2 = (CH2)2 and L = Br At room temperature, compound I (33 kg) was added to cyclohexane (86 kg), and stirring was started. Ethylene glycol (14.5 kg) and p-toluenesulfonic acid (6.2 kg) were added, and the mixture was heated under reflux to separate the water. Samples were taken for analysis until the starting material was completely converted. The mixture was cooled to room temperature, and the reaction solution was added dropwise to a 10% potassium carbonate solution (33 kg). The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate. The solution was filtered, and the solvent was removed by vacuum distillation to obtain crude compound II, which was a light yellow oily substance, in a molar yield of 99% and a GC purity of 98.2%.

[0041] The structural formula of compound II obtained in step 1 is as follows: .

[0042] Step 2: Synthesis of Compound III At room temperature, compound II (39.8 kg) was added to tetrahydrofuran (200 kg), and stirring was started. The mixture was then cooled to -75 to -80°C, and a 2.5 M n-butyllithium solution (45 kg, density 0.68 g / cm³) was added dropwise. 3 Stir at 25℃ for 15 minutes; add triisopropyl borate (36.4 kg), allow to naturally warm to room temperature, and then react. Sample and analyze until the starting material is completely converted to the intermediate borate ester. Add the reaction solution dropwise to 3 V 18% hydrochloric acid and maintain the temperature until the intermediate is completely converted. Remove n-hexane and THF by vacuum distillation, cool to room temperature, filter, wash the filter cake with water, and dry to obtain 24.3 kg of the bright yellow product of formula III, molar yield: 90%, HPLC purity: 98.2%.

[0043] Step 3: Synthesis of Compound IV At room temperature, compound III (24.3 kg) was added to glacial acetic acid (93 kg), and the temperature was raised to 80-90°C. Sodium perborate (50 kg) was added in portions, and the reaction was maintained at this temperature for 30 minutes. Samples were taken for analysis until the starting material was completely converted. The reaction solution was poured into ice water (300 L), and stirred until a large amount of solid precipitated. The solid was collected by centrifugation, and water (50 L) was added to the solid to make a slurry. The product was collected by centrifugation and dried in a forced-air oven at 60°C to obtain 20.4 kg of white solid of formula IV. Molar yield: 90%, MS (m / z): 155 [M-1]. - HPLC purity 99.6%.

[0044] Step 4: Synthesis of R=Me type V compound Compound of formula III (20.4 kg) was added to methanol (100 kg), and thionyl chloride (17.8 kg) was added dropwise. The mixture was refluxed for 1 hour, and samples were taken for analysis until the starting material was completely converted. The solvent was removed by vacuum distillation, and water (200 L) was added to form a slurry. The solid was collected by centrifugation and dried in a forced-air oven at 60 °C to give 21.1 kg of the product, molar yield: 95%, MS (m / z): 169 [M-1]. - HPLC purity 99.4%.

Claims

1. A method for preparing a 3-hydroxy-4-fluorobenzoic acid ester, characterized in that the step... include: (1) Under acidic conditions, the compound of formula I reacts with an alcohol in an organic solvent under reflux to remove water. Specifically, the compound of formula I reacts with an alcohol under reflux to remove water and undergoes an acetal reaction to obtain the compound of formula II. (2) Compound II is reacted with orthoboronic ester in an inert solvent after dehalogenation by organolithium, followed by acid hydrolysis to obtain compound III; (3) Compound III is oxidized in an organic acid solvent by an oxidizing agent to obtain compound IV; (4) Compound IV was prepared by Lewis acid catalysis in an alcohol solvent to obtain compound V; In compounds of formula II, R1 is a C1-C6 alkyl group; R2 is a C1-C6 alkyl group; or R1R2 is an alkylene group; In compound V, R is a C1-C6 alkyl group.

2. The preparation method according to claim 1, characterized in that, In step (1), the mass ratio of compound I, alcohol and acid is 1:1-2:0.05-0.8, and the molar volume concentration of compound I in organic solvent is 1-2 mol / L.

3. The preparation method according to claim 1, characterized in that, In step (1), the organic solvent is any one or any combination of dichloromethane, THF, and cyclohexane, the acid used is an inorganic acid or an organic acid, and the alcohol is a C1-C6 alkyl alcohol.

4. The preparation method according to claim 1, characterized in that, In step (2), the molar ratio of compound II, organolithium and orthoboronic ester is 1:1-1.5:1-2, and the molar volume ratio of compound II to inert solvent is 0.5-1.5 mol:1 L.

5. The preparation method according to claim 1, characterized in that, In step (2), the organolithium is any one or any combination of n-butyllithium, tert-butyllithium, diisopropylaminolithium, and bistrimethylsilylaminolithium, the inert solvent is a solvent stable under strong alkali, and the orthoboronic ester is any one or any combination of alkylboronic ester, arylboronic ester, and allylboronic ester.

6. The preparation method according to claim 1, characterized in that, In step (3), the molar ratio of compound III to oxidant is 1:45, and the molar volume ratio of compound III to organic acid solvent is 1.5-3 mol:1L.

7. The preparation method according to claim 1, characterized in that, In step (3), the organic acid is a C1-C6 organic acid, and the oxidant is a perborate or its hydrate.

8. The preparation method according to claim 1, characterized in that, In step (4), the molar ratio of compound IV to Lewis acid catalyst is 1:1-2, and the molar volume ratio of compound IV to alcohol solvent is 0.8-2 mol:1 L.

9. The preparation method according to claim 1, characterized in that, In step (4), the alcohol solvent is a C1-C6 alkyl alcohol, and the Lewis acid catalyst is an inorganic acid or an acid-producing reagent.

10. The 3-hydroxy-4-fluorobenzoate prepared by any one of claims 1-9 is used to prepare accommodative or its intermediate 3-(3-(3,5-dimethyl-1H-pyrazol-4-yl)propoxy)-4-fluorobenzoate.

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