Synthesis method of 4-(4-phenylbutoxy) methyl benzoate

Abstract

The invention is suitable for the technical field of organic synthesis, and provides a 4-(4-phenylbutoxy) methyl benzoate synthesis method, which comprises the following steps: S1, adding methyl parahydroxybenzoate and 1-bromo-3-chloropropane into a solvent, adding inorganic alkali in batches, then carrying out a heat preservation reaction, and after the reaction is finished, carrying out reduced pressure distillation to obtain 4-(4-phenylbutoxy) methyl benzoate; recovering the solvent, adding water for quenching, extracting with methylbenzene, washing with water to obtain a 4-(3-chloropropoxy) methyl benzoate methylbenzene solution, and then directly entering the next procedure; and S2, under the protection of nitrogen, mixing the 4-(3-chloropropoxy) methyl benzoate toluene solution, phenethyl boric acid, a catalyst, alkali and a solvent for reaction, and performing coupling to obtain the 4-(4-phenylbutoxy) methyl benzoate. According to the method, palladium is used for catalyzing coupling, Grignard reaction and Friedel-Crafts reaction are avoided, blue-green copper ion waste water is avoided, a large amount of acid waste water generated by using aluminum trichloride is also avoided, the method is environmentally friendly, the synthesis route is simple, the yield of each step is high, and the preparation cost of the p-phenylbutoxybenzoic acid is reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly to a method for synthesizing methyl 4-(4-phenylbutoxy)benzoate. Background Art

[0002] Methyl 4-(4-phenylbutoxy)benzoate is a precursor of 4-(phenylbutoxy)benzoic acid and an important intermediate for synthesizing pranlukast, which is a drug ingredient for treating asthma and plays an important role in asthma treatment; it is a leukotriene receptor antagonist that can competitively occupy the leukotriene receptor on the mast cell membrane, prevent leukotriene from binding to the receptor, and thus inhibit the inflammatory response; pranlukast can be used to relieve symptoms such as wheezing, coughing, and chest tightness caused by bronchial asthma; for patients with chronic bronchitis, it can relieve discomfort such as coughing and expectoration. The structural formula is as follows:

[0003]

[0004] The following are the main synthesis methods reported in the existing literature:

[0005] 1. In Chinese Patent CN101450943A, using furan as the starting material, reacting with hydrogen chloride at high temperature to synthesize 4-chloro-butanol, then reacting with benzene and aluminum trichloride in a Friedel-Crafts reaction to synthesize phenylbutanol, then brominating with potassium bromide under the action of sulfuric acid to produce phenylbutyl bromide, and finally etherifying with methyl p-hydroxybenzoate to obtain methyl 4-(4-phenylbutoxy)benzoate. This route has a long process, uses a large amount of highly toxic chemicals, and a large amount of wastewater will be generated after the Friedel-Crafts reaction, and the overall route cost is relatively high.

[0006] 2. Japanese Patent JP2001131099 reports that using bromobenzene as the raw material, after Grignard reaction and then coupling with 1,4-dibromobutane under the action of catalysts cuprous chloride and lithium chloride to obtain phenylbutyl bromide, and finally etherifying with methyl p-hydroxybenzoate to obtain methyl 4-(4-phenylbutoxy)benzoate. The cuprous chloride used in this route will produce a large amount of green copper ion wastewater and a large amount of magnesium salt solid waste, and since 1,4-dibromobutane is relatively reactive, the purity of the obtained phenylbutyl bromide is not high, and a double-coupling product of the Grignard reagent and 1,4-dibromobutane will be generated.

[0007] 3. In Chinese Patent CN201910660523.1, using chlorobenzene and 4-chloro-1-butene under the action of a catalyst, first coupling to obtain 4-chloro-1-phenylbutene, then hydrogenating with palladium-carbon to obtain 1-chloro-phenylbutane, and then etherifying with methyl p-hydroxybenzoate to obtain methyl 4-(4-phenylbutoxy)benzoate. This route needs to use noble metal catalysts twice, and there are a small amount of by-product phenylbutane products during the palladium-carbon hydrogenation process, which will affect the quality of the final product.

[0008] 4. "Synthesis Study of 4-(4-Phenylbutoxy) Benzoic Acid" in the 3rd issue of "Fine and Specialty Chemicals" in 2010 reported that in the preparation route using 4-chloro-1-butanol, benzene, methylsulfonyl chloride and methyl p-hydroxybenzoate as raw materials, the highly toxic intermediate phenylbutyl bromide was avoided. However, highly toxic benzene and a large amount of wastewater containing aluminum trichloride still need to be treated. At the same time, this method uses methylsulfonic acid, which is a strongly corrosive and irritating liquid. It decomposes into toxic formaldehyde and sulfur dioxide when heated, causing great environmental pollution. This method also has disadvantages such as low product purity and little industrial significance.

[0009] All of the above four methods have defects to varying degrees. In this regard, the present invention aims to provide a new synthetic process that is green, environmentally friendly, safe, efficient, and low-cost. Summary of the Invention

[0010] The purpose of the present invention is to provide a method for synthesizing methyl 4-(4-phenylbutoxy) benzoate to solve the problems in the above background technology.

[0011] To achieve the above purpose, the present invention provides the following technical solution: A method for synthesizing methyl 4-(4-phenylbutoxy) benzoate, wherein the methyl 4-(4-phenylbutoxy) benzoate uses methyl p-hydroxybenzoate as a raw material, undergoes substitution with 1-bromo-3-chloropropane, and then undergoes coupling with phenylethylboronic acid to obtain the target product. The specific steps are as follows:

[0012] S1. Add methyl p-hydroxybenzoate and 1-bromo-3-chloropropane to a solvent, and add inorganic base in batches, then keep the temperature for reaction. After the reaction is completed, recover the solvent, quench with water, extract with toluene, and wash with water to obtain a toluene solution of methyl 4-(3-chloropropoxy) benzoate, and then directly enter the next process;

[0013] S2. Under nitrogen protection, mix and react the toluene solution of methyl 4-(3-chloropropoxy) benzoate, phenylethylboronic acid, a catalyst, a base and a solvent to perform coupling to obtain methyl 4-(4-phenylbutoxy) benzoate.

[0014] Preferably, the solvent in S1 is one or more of acetone, methyl ethyl ketone, and tetrahydrofuran, and the dosage of the solvent is 3 to 5 times the weight ratio of methyl p-hydroxybenzoate.

[0015] Preferably, the inorganic base in S1 is sodium carbonate or potassium carbonate, and the molar ratio of the inorganic base to methyl p-hydroxybenzoate is 1:1.05 to 1.3.

[0016] Preferably, the reaction temperature in S1 is 40 to 80 °C, and the reaction time is 8 to 12 hours.

[0017] Preferably, the catalyst for S2 is one or more of palladium chloride, palladium acetate, and tetrakis(triphenylphosphine)palladium, and the amount of the catalyst used is 2‰-5‰ of methyl 4-(3-chloropropoxy)benzoate.

[0018] Preferably, the base for S2 is sodium bicarbonate or sodium acetate.

[0019] Preferably, the solvent for S2 is one or more of tetrahydrofuran, toluene, water, and dimethylformamide.

[0020] Preferably, the reaction temperature for S2 is 60-120°C, and the reaction time is 2-6 h.

[0021] The present invention has at least the following beneficial effects:

[0022] (1) A synthetic method of methyl 4-(4-phenylbutoxy)benzoate provided by the present invention uses palladium-catalyzed coupling, avoiding Grignard reaction and Friedel-Crafts reaction, thus avoiding the generation of blue-green copper ion wastewater and a large amount of acidic wastewater generated by using aluminum trichloride. It is environmentally friendly, and the synthetic route is simple, with a relatively high yield in each step, reducing the preparation cost of 4-(4-phenylbutoxy)benzoic acid.

[0023] (2) A synthetic method of methyl 4-(4-phenylbutoxy)benzoate provided by the present invention, after detection, the obtained methyl 4-(4-phenylbutoxy)benzoate has high purity, good solubility, the total yield reaches 70%, and the HPLC purity is greater than 99%. It avoids the problems of safety and environmental pollution caused by the use of a large amount of DMF and DMSO in the traditional method. Description of the Drawings

[0024] Figure 1 is the reaction route diagram of the present invention;

[0025] Figure 2 is the HPLC detection spectrum of methyl 4-(3-chloropropoxy)benzoate in Example 4 of the present invention;

[0026] Figure 3 is the HPLC detection spectrum of methyl 4-(4-phenylbutoxy)benzoate in Example 4 of the present invention. Detailed Embodiments

[0027] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0028] The present invention provides a method for synthesizing methyl 4-(4-phenylbutoxy)benzoate, and the synthetic route diagram is as Figure 1 shown. Its synthetic process is carried out in the following steps in sequence:

[0029] Step 1: Add methyl p-hydroxybenzoate, 1-chloro-3-bromopropane and acetone into a reaction flask, add sodium carbonate in batches. After the reaction is completed, heat up to 60 °C, react for 10 h, stop the reaction, filter, recover acetone under reduced pressure, and extract with toluene to obtain a toluene solution of methyl 4-(3-chloropropoxy)benzoate;

[0030] Step 2: Add the toluene solution of methyl 4-(3-chloropropoxy)benzoate and phenylethylboronic acid into a reaction flask. After purging with nitrogen, add sodium acetate and palladium acetate in sequence, then heat up to 110 °C, react for 4 h, filter to recover the catalyst, wash with water, concentrate to dryness, and recrystallize with ethanol to obtain methyl 4-(4-phenylbutoxy)benzoate.

[0031] Based on the above synthetic method of using the pharmaceutical intermediate methyl 4-(4-phenylbutoxy)benzoate, the present invention provides the following partial examples:

[0032] Example 1

[0033] 1. Synthesis of methyl 4-(3-chloropropoxy)benzoate:

[0034] Add methyl p-hydroxybenzoate and 1-bromo-3-chloropropane into acetone according to the molar ratio in the synthetic route. The weight ratio of acetone to methyl p-hydroxybenzoate is 3 times. Add sodium carbonate in batches. The molar ratio of sodium carbonate to methyl p-hydroxybenzoate is 1:1.05. Then keep the reaction at 40 °C for 12 hours. Recover the solvent, quench with water, extract with toluene, and wash with water to obtain a toluene solution of methyl 4-(3-chloropropoxy)benzoate;

[0035] 2. Synthesis of methyl 4-(4-phenylbutoxy)benzoate:

[0036] Under nitrogen protection, mix and react the toluene solution of methyl 4-(3-chloropropoxy)benzoate, phenylethylboronic acid, catalyst, base and solvent, and react at 60 °C for 6 h to carry out coupling to obtain methyl 4-(4-phenylbutoxy)benzoate;

[0037] Among them, the catalyst is palladium chloride, and the dosage of the catalyst is 2‰ of methyl 4-(3-chloropropoxy)benzoate; the base is sodium bicarbonate; the solvent is tetrahydrofuran.

[0038] Example 2

[0039] 1. Synthesis of methyl 4-(3-chloropropoxy)benzoate:

[0040] Methyl 4-(3-chloropropoxy)benzoate was prepared by adding methyl p-hydroxybenzoate and 1-bromo-3-chloropropane in the molar ratio in the synthetic route to methyl ethyl ketone. The weight ratio of methyl ethyl ketone to methyl p-hydroxybenzoate was 4:1. Potassium carbonate was added in batches, and the molar ratio of potassium carbonate to methyl p-hydroxybenzoate was 1:1.2. Then the reaction was carried out with heat preservation at 60 °C for 11 hours. The solvent was recovered, and the reaction was quenched with water, extracted with toluene, and washed with water to obtain a toluene solution of methyl 4-(3-chloropropoxy)benzoate;

[0041] 2. Synthesis of methyl 4-(4-phenylbutoxy)benzoate:

[0042] Under nitrogen protection, a toluene solution of methyl 4-(3-chloropropoxy)benzoate, phenethylboronic acid, a catalyst, a base, and a solvent were mixed and reacted at 100 °C for 4 h for coupling to obtain methyl 4-(4-phenylbutoxy)benzoate;

[0043] Among them, the catalyst was palladium acetate, and the dosage of the catalyst was 3‰ of methyl 4-(3-chloropropoxy)benzoate; the base was sodium acetate; the solvent was water.

[0044] Example 3

[0045] 1. Synthesis of methyl 4-(3-chloropropoxy)benzoate:

[0046] Methyl p-hydroxybenzoate and 1-bromo-3-chloropropane were added in the molar ratio in the synthetic route to tetrahydrofuran. The weight ratio of tetrahydrofuran to methyl p-hydroxybenzoate was 5:1. Sodium carbonate was added in batches, and the molar ratio of sodium carbonate to methyl p-hydroxybenzoate was 1:1.3. Then the reaction was carried out with heat preservation at 80 °C for 8 hours. The solvent was recovered, and the reaction was quenched with water, extracted with toluene, and washed with water to obtain a toluene solution of methyl 4-(3-chloropropoxy)benzoate;

[0047] 2. Synthesis of methyl 4-(4-phenylbutoxy)benzoate:

[0048] Under nitrogen protection, a toluene solution of methyl 4-(3-chloropropoxy)benzoate, phenethylboronic acid, a catalyst, a base, and a solvent were mixed and reacted at 120 °C for 2 h for coupling to obtain methyl 4-(4-phenylbutoxy)benzoate;

[0049] Among them, the catalyst was tetrakis(triphenylphosphine)palladium, and the dosage of the catalyst was 5‰ of methyl 4-(3-chloropropoxy)benzoate; the base was sodium acetate; the solvent was dimethylformamide.

[0050] Example 4

[0051] 1. Synthesis of methyl 4-(3-chloropropoxy)benzoate:

[0052] A 1000 ml three-necked flask was equipped with an oil bath, a thermometer, a stirrer, and a reflux condenser. Then, 100 g of methyl 4-hydroxybenzoate, 113 g of 1-chloro-3-bromopropane, and 500 g of acetone were added. Stirring was started, and 76.6 g of sodium carbonate was added in 3 batches. The temperature was slowly raised to 60 °C, and the reaction was maintained for 10 h with timing. After filtration, acetone was recovered by vacuum distillation. 400 g of toluene was added, and then the mixture was washed with 100 ml of water three times to obtain a toluene solution of methyl 4-(3-chloropropoxy)benzoate. The purity was detected by liquid phase to be 97%, and the molar yield was 90%.

[0053] 2. Synthesis of methyl 4-(4-phenylbutoxy)benzoate:

[0054] A 1000 ml three-necked flask was equipped with an electric heating mantle, a thermometer, a stirrer, a reflux condenser, and a nitrogen protection device. The toluene solution of methyl 4-(3-chloropropoxy)benzoate and 105.8 g of phenethylboronic acid were added in sequence. After purging with nitrogen, stirring was started, and then 72.8 g of sodium acetate was added. The temperature was raised to 60 °C, 0.27 g of palladium acetate was added, and the temperature was further raised to 110 °C for reaction for 4 h. After cooling to 60 °C, filtration was carried out. The organic phase was washed with 200 ml of water three times and then concentrated. The crude product was frozen with 1-fold ethanol at -10 °C for 24 h to obtain white solid methyl 4-(4-phenylbutoxy)benzoate. The purity was detected by liquid phase to be greater than 99%, and the molar yield was 85%.

[0055] HPLC detection was carried out on methyl 4-(3-chloropropoxy)benzoate and methyl 4-(4-phenylbutoxy)benzoate in Example 4, as Figures 2 - 3 shown.

[0056] In addition, the identification of methyl 4-(4-phenylbutoxy)benzoate was also carried out, and the results are as follows:

[0057] Identification method: Agilent 1220 high performance liquid chromatograph, Bruker Avance III 400 MHz superconducting nuclear magnetic resonance spectrometer

[0058] Analysis method: LC (liquid chromatographic purity); Agilent 1220 high performance liquid chromatograph, Agilent C-18 chromatographic column YMC Pack ODS-AM 6.0*150 mm, mobile phase A: 0.02 mol / L sodium dihydrogen phosphate solution, mobile phase B: acetonitrile; detection wavelength 254 nm.

[0059] LC-MS: (m / z) 284 [M-H];

[0060] 1H NMR (400 MHz, DMSO-d6) δ: 1.82 (m, 4H); 2.69 (t, 2H); 3.87 (s, 3H); 4.00 (t, 2H); 6.88 (d, 2H); 7.18 - 7.31 (sc, 5H); 7.98 (d, 2H).

[0061] The foregoing has shown and described the basic principles, main features and advantages of the present invention. For those skilled in the art, it is obvious that the present invention is not limited to the details of the above-described exemplary embodiments, and without departing from the spirit or basic features of the present invention, the present invention can be implemented in other specific forms. Therefore, from any point of view, the embodiments should be regarded as exemplary and non-limiting. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be embraced within the present invention.

[0062] Although the embodiments of the present invention have been shown and described, for those of ordinary skill in the art, it can be understood that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing methyl 4-(4-phenylbutoxy)benzoate, characterized in that, The methyl 4-(4-phenylbutoxy)benzoate is prepared from methyl 4-hydroxybenzoate through substitution with 1-bromo-3-chloropropane and then coupling with phenylethylboronic acid to obtain the target product. The specific steps are as follows: S1. Methyl 4-hydroxybenzoate and 1-bromo-3-chloropropane are added to a solvent, and an inorganic base is added in batches. Then, the mixture is kept at a certain temperature for reaction. After the reaction is completed, the solvent is recovered, water is added for quenching, toluene is used for extraction, and washing with water gives a toluene solution of methyl 4-(3-chloropropoxy)benzoate, which then directly enters the next process step; S2. Under nitrogen protection, the toluene solution of methyl 4-(3-chloropropoxy)benzoate, phenylethylboronic acid, a catalyst, a base, and a solvent are mixed for reaction to carry out coupling to obtain methyl 4-(4-phenylbutoxy)benzoate.

2. The synthetic method of methyl 4-(4-phenylbutoxy)benzoate according to claim 1, characterized in that: In S1, the solvent is one or more of acetone, methyl ethyl ketone, and tetrahydrofuran, and the amount of the solvent used is 3 to 5 times the weight ratio of methyl 4-hydroxybenzoate.

3. A method for synthesizing methyl 4-(4-phenylbutoxy)benzoate according to claim 1, characterized in that: In S1, the inorganic base is sodium carbonate or potassium carbonate, and the molar ratio of the inorganic base to methyl 4-hydroxybenzoate is 1:1.05 to 1.

3.

4. A method for synthesizing methyl 4-(4-phenylbutoxy)benzoate according to claim 1, characterized in that: In S1, the reaction temperature is 40 to 80 °C, and the reaction time is 8 to 12 hours.

5. A method for synthesizing methyl 4-(4-phenylbutoxy)benzoate according to claim 1, characterized in that: In S2, the catalyst is one or more of palladium chloride, palladium acetate, and tetrakis(triphenylphosphine)palladium, and the amount of the catalyst used is 2‰ - 5‰ of methyl 4-(3-chloropropoxy)benzoate.

6. The synthetic method of methyl 4-(4-phenylbutoxy)benzoate according to claim 1, wherein: In S2, the base is sodium bicarbonate or sodium acetate.

7. A method for synthesizing methyl 4-(4-phenylbutoxy)benzoate according to claim 1, characterized in that: In S2, the solvent is one or more of tetrahydrofuran, toluene, water, and dimethylformamide.

8. A method for synthesizing methyl 4-(4-phenylbutoxy)benzoate according to claim 1, characterized in that: In S2, the reaction temperature is 60 to 120 °C, and the reaction time is 2 to 6 h.

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