Method for preparing 4-n-butylresorcinol

Abstract

The invention belongs to the technical field of organic synthesis, and relates to a method for preparing 4-n-butylresorcinol. Comprising the following steps: carrying out alkylation reaction on triphenylphosphine and 1-iodopropane to obtain an intermediate 1; mixing the intermediate 1 with 2, 4-dihydroxybenzaldehyde, dropwise adding a potassium tert-butoxide solution at the temperature of 20-50 DEG C, and carrying out coupling reaction for 4-12 hours to obtain an intermediate 2; and carrying out hydrogenation reduction reaction on the intermediate 2 to obtain the 4-n-butylresorcinol. The method provided by the invention is easy to amplify, simple to operate, relatively low in cost and beneficial to industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a method for preparing 4-n-butylresorcinol. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] 4-n-Butylresorcinol is a derivative of resorcinol. It is a strong inhibitor of tyrosinase and peroxidase, which is beneficial to cut off pigment formation. It is also a powerful skin whitening agent, which effectively fights against chloasma and age spots caused by ultraviolet rays. It is often used as a whitening additive for skin care products, can be used to synthesize FXR agonist intermediates, and can also be used to treat diseases such as heart disease, high cholesterol and cholestasis. It is mainly used in the fields of spices, medicine and dyes.

[0004] At present, there are few records on the synthesis method of 4-n-butylresorcinol, and even fewer methods that can be applied to industrial production. At present, the synthesis method of 4-n-butylresorcinol mainly comprises: taking resorcinol as a raw material, sequentially performing Friedel-Crafts acylation to obtain the intermediate 4-butyrylresorcinol, and then performing a reduction reaction. The reaction route is as follows:

[0005] The main problem in this route is the reduction reaction stage. Catalytic hydrogenation requires high temperature and high pressure, and the system uses hydrogen, which is flammable and explosive. In addition, the use of palladium carbon has high material costs. Or when zinc amalgam is used, the use of highly toxic mercury reagents pollutes the environment and reduces production safety. Summary of the invention

[0006] In order to solve the deficiencies of the prior art, the purpose of the present invention is to provide a method for preparing 4-n-butylresorcinol. The method provided by the present invention is easy to scale up, simple to operate, low in cost, and is conducive to industrial production.

[0007] In order to achieve the above object, the technical solution of the present invention is: A method for preparing 4-n-butylresorcinol comprises the following steps: Alkylation reaction of triphenylphosphine with 1-iodopropane gave intermediate 1; After the intermediate 1 is mixed with 2,4-dihydroxybenzaldehyde, a potassium tert-butoxide solution is added dropwise at a temperature of 20 to 50 °C to carry out a coupling reaction for 4 to 12 hours to obtain an intermediate 2; The intermediate 2 is subjected to a hydrogenation reduction reaction to obtain 4-n-butylresorcinol; The chemical structure of intermediate 1 is: , X - is iodide ion; The chemical structure of intermediate 2 is: .

[0008] The reaction route is as follows:

[0009] In some embodiments, the molar ratio of triphenylphosphine to 1-iodopropane is 1:1.05-2.00.

[0010] In some embodiments, the temperature for the alkylation reaction of triphenylphosphine with 1-iodopropane is 40-80°C. The reaction time is 4-12 hours. Studies have shown that temperature affects the yield of intermediate 1. When the temperature for the alkylation reaction of triphenylphosphine with 1-iodopropane is 75-80°C, the yield of intermediate 1 is higher.

[0011] In some embodiments, 1-iodopropane is added dropwise to a triphenylphosphine solution, and then an alkylation reaction is performed. Specifically, the time for adding 1-iodopropane dropwise is 10 to 30 minutes. Studies have shown that the time for adding 1-iodopropane dropwise also affects the yield of intermediate 1. When the time for adding 1-iodopropane dropwise is 15 to 30 minutes, especially 25 to 35 minutes, the yield of intermediate 1 is higher, the reaction rate is faster, and the reaction time can be shortened by more than 2 hours.

[0012] In some embodiments, the purification method of intermediate 1 is: concentrating the material after the alkylation reaction, adding methyl tert-butyl ether for crystallization, filtering, washing and drying.

[0013] In some embodiments, the molar ratio of intermediate 1 to 2,4-dihydroxybenzaldehyde is 1.03-1.5:1.

[0014] In some embodiments, the coupling reaction temperature is 40-50°C. Studies have shown that when the coupling reaction temperature is 40-50°C, the yield of intermediate 2 is higher and the reaction rate is faster. The reaction time is 4-5 hours.

[0015] In some embodiments, the molar ratio of 2,4-dihydroxybenzaldehyde to potassium tert-butoxide is 1:1.10-1.20.

[0016] In some embodiments, the purification method of intermediate 2 is as follows: filtering the material after the coupling reaction, adding ethyl acetate and water to the filtrate after concentrating it for the first extraction and separation, adding citric acid aqueous solution to the upper organic phase after the first extraction and separation for the second extraction and separation, dehydrating the upper organic phase after the second extraction and separation, concentrating it, adding n-heptane for pulping or crystallization, filtering, washing, and drying. Specifically, the mass concentration of the citric acid aqueous solution is 3-7%. Specifically, the upper organic phase after the second extraction and separation is dehydrated, and can be dried with anhydrous sodium sulfate, or can be separated with saline solution with a mass concentration of 5% or more.

[0017] In some embodiments, intermediate 2 is subjected to a hydrogenation reduction reaction with sodium borohydride.

[0018] Specifically, the molar ratio of intermediate 2 to sodium borohydride is 1:1.8~2.2.

[0019] Specifically, the temperature of the hydrogen reduction reaction is 20-50°C. The reaction time is 5-12 hours. When the temperature of the hydrogen reduction reaction is 40-50°C, the yield of 4-n-butylresorcinol is higher and the reaction rate is faster. The reaction time is 5-6 hours.

[0020] In some embodiments, the purification method of 4-n-butylresorcinol is as follows: water and isopropyl acetate are added to the material after the hydrogenation reduction reaction to perform a first extraction and separation, the organic phase of the first extraction and separation is dehydrated and concentrated, n-heptane is added to heat and dissolve, the temperature is lowered for crystallization, and the phase is filtered, washed, and dried. Specifically, the organic phase of the first extraction and separation is dehydrated by adding a desiccant (e.g., anhydrous sodium sulfate) to dry, or by adding a salt solution with a mass concentration of 5% or more to separate.

[0021] In some embodiments, the purification method of 4-n-butylresorcinol is as follows: water and isopropyl acetate are added to the material after the hydrogenation reduction reaction for the first extraction and separation, citric acid aqueous solution is added to the upper organic phase after the first extraction and separation for the second extraction and separation, the organic phase of the second extraction and separation is dehydrated and concentrated, n-heptane is added for crystallization, filtered, isopropyl ether is added to the filtered solid, heated to dissolve, cooled for crystallization, filtered, washed, and dried.

[0022] The beneficial effects of the present invention are: The synthesis method provided by the invention uses triphenylphosphine, 1-iodopropane and 2,4-dihydroxybenzaldehyde as raw materials, the raw materials are easy to obtain, the preparation process is simple to operate, the cost is low, the yield of the product obtained in each step is high, the purification is simple, the use of silica gel column chromatography purification can be avoided, the scale-up is easy, and the industrial production is conducive. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0024] Figure 1 The hydrogen nuclear magnetic resonance spectrum of 4-n-butylresorcinol prepared by the present invention; Figure 2 This is the chromatogram of 4-n-butylresorcinol prepared in Example 12 of the present invention. DETAILED DESCRIPTION

[0025] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0026] Example 1 Synthesis of iodide intermediate 1:

[0027] At room temperature, 160 mL of acetonitrile and triphenylphosphine (10 g, 0.0381 mol) were added to a three-necked reaction flask. After stirring for 15 minutes to dissolve, 1-iodopropane (6.81 g, 0.0400 mol) was added dropwise for 10 minutes. The temperature was raised to 40°C and stirred for 12 hours. TLC showed that some of the raw materials of triphenylphosphine remained. The reaction system was cooled to room temperature and directly concentrated to dryness under reduced pressure. 150 mL of methyl tert-butyl ether was added and stirred for 0.5 hours. The precipitate was filtered and the solid was washed with 25 mL of cold methyl tert-butyl ether. The solid was dried at 45°C for 2 hours to obtain 7.6 g of off-white solid iodine salt intermediate 1 (crude yield was 46.1%). TLC showed that some triphenylphosphine remained in the product.

[0028] Example 2 Synthesis of iodide intermediate 1: At room temperature, 160 mL of acetonitrile and triphenylphosphine (10 g, 0.0381 mol) were added to a three-necked reaction flask. After stirring for 15 minutes to dissolve, 1-iodopropane (12.95 g, 0.0762 mol) was added dropwise for 15 minutes. The temperature was raised to 40°C and stirred for 12 hours. TLC showed that a small amount of triphenylphosphine raw material remained. The reaction system was cooled to room temperature and directly concentrated to dryness under reduced pressure. 150 mL of methyl tert-butyl ether was added and stirred for 0.5 hours. The precipitate was filtered, and the solid was washed with 25 mL of cold methyl tert-butyl ether. The solid was dried at 45°C for 2 hours to obtain 9.8 g of off-white solid iodine salt intermediate 1 (yield 59.5%).

[0029] Example 3 Synthesis of iodide intermediate 1: At room temperature, add 200 mL of acetonitrile and triphenylphosphine (10 g, 0.0381 mol) to a three-necked reaction flask, stir for 15 minutes to dissolve, then add 1-iodopropane (6.81 g, 0.040 mol) dropwise for 10 minutes. Heat to 80°C and stir for 6 hours. TLC shows that triphenylphosphine disappears, the reaction system is cooled to room temperature, and it is directly concentrated to dryness under reduced pressure. 150 mL of methyl tert-butyl ether is added and stirred for 0.5 hours. The precipitate is filtered, and the solid is washed with 25 mL of cold methyl tert-butyl ether. The solid is dried at 45°C for 2 hours to obtain 14.6 g of off-white solid iodine salt intermediate 1 (yield is 88.6%).

[0030] Example 4 Synthesis of iodide intermediate 1: At room temperature, 3 L of acetonitrile and triphenylphosphine (100 g, 0.381 mol) were added to a 1 L three-necked reaction bottle. After stirring for 15 minutes to dissolve, 1-iodopropane (68.1 g, 0.400 mol) was added dropwise for 30 minutes. The temperature was raised to 80°C and stirred for 4 hours. TLC showed that the triphenylphosphine raw material disappeared, and the reaction system was cooled to room temperature and concentrated under reduced pressure to about 500 mL. The concentrated system was added dropwise to 1.5 L of methyl tert-butyl ether at 5-10°C. After crystallization and stirring at 5-10°C for 1 hour, the precipitate was filtered, and the solid was washed with 100 mL of cold methyl tert-butyl ether. The solid was dried at 45°C for 3 hours to obtain 154.6 g of off-white solid iodine salt intermediate 1 (yield 93.8%).

[0031] Example 5 Synthesis of intermediate 2:

[0032] At room temperature, 100 mL of tetrahydrofuran, 2,4-dihydroxybenzaldehyde (10 g, 0.072 mol) and iodine salt intermediate 1 (34.2 g, 0.079 mol) were added to a three-necked reaction flask, and a tetrahydrofuran solution (50 mL) of potassium tert-butoxide (8.86 g, 0.079 mol) was added dropwise to the above system, and the reaction was carried out at 25°C for 12 hours. TLC showed that a small amount of 2,4-dihydroxybenzaldehyde remained, the reaction system was filtered, the filtrate was concentrated, and purified by silica gel column chromatography (n-heptane: ethyl acetate = 2:1, V / V), and concentrated to obtain 9.3 g of off-white solid intermediate 2 (yield 78.8%).

[0033] Example 6 Synthesis of intermediate 2: At room temperature, 100 mL of tetrahydrofuran, 2,4-dihydroxybenzaldehyde (10 g, 0.072 mol) and iodine salt intermediate 1 (46.68 g, 0.108 mol) were added to a three-necked reaction flask, and a tetrahydrofuran solution (50 mL) of potassium tert-butoxide (12.11 g, 0.108 mol) was added dropwise to the above system, and the reaction was carried out at 25°C for 6 hours. TLC showed that the 2,4-dihydroxybenzaldehyde raw material disappeared, the reaction system was filtered, the filtrate was concentrated, and purified by silica gel column chromatography (n-heptane: ethyl acetate = 2:1, V / V), and concentrated to obtain 10.4 g of off-white solid intermediate 2 (yield 88.1%).

[0034] Example 7 Synthesis of intermediate 2: At room temperature, 50 mL of tetrahydrofuran, 2,4-dihydroxybenzaldehyde (10 g, 0.072 mol) and iodine salt intermediate 1 (32.8 g, 0.076 mol) were added to a three-necked reaction flask, and the temperature was raised to 45°C. Then, a tetrahydrofuran solution (50 mL) of potassium tert-butoxide (9.37 g, 0.084 mol) was added dropwise to the system, and the reaction was carried out at 45°C for 5 hours. TLC showed that the 2,4-dihydroxybenzaldehyde raw material disappeared, the reaction system was filtered, the filtrate was concentrated to dryness, ethyl acetate (150 mL) and purified water (70 mL) were added, and the mixture was separated after stirring for 15 minutes. A 5% citric acid aqueous solution (50 mL) was added to the upper organic phase and stirred for 15 minutes before separation. The upper organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and n-heptane (150 mL) was added and stirred evenly. After slurrying for 1 hour, the mixture was filtered, and the solid was rinsed with 15 mL of cold n-heptane. The solid was dried at 45°C for 2 hours to obtain 10.7 g of off-white solid intermediate 2 (yield: 90.6%).

[0035] Example 8 Synthesis of intermediate 2: At room temperature, 300 mL of tetrahydrofuran, 2,4-dihydroxybenzaldehyde (45 g, 0.326 mol) and iodine salt intermediate 1 (147.8 g, 0.342 mol) were added to a 1 L three-necked reaction flask. The temperature was raised to 45°C and stirred for 1 hour to dissolve. A tetrahydrofuran solution (150 mL) of potassium tert-butoxide (42.2 g, 0.376 mol) was added dropwise to the above system for half an hour and reacted at 45°C for 4 hours. TLC showed that the 2,4-dihydroxybenzaldehyde raw material disappeared. After the reaction system was cooled to room temperature, the system was concentrated to about 150 mL. 500 mL of purified water and 300 mL of isopropyl acetate were added to the turbid liquid. After stirring for 15 minutes, the liquids were separated. 300 mL of isopropyl acetate was added to the lower aqueous phase. After stirring for 15 minutes, the liquids were separated. TLC detection of the lower aqueous phase showed that there was no intermediate 2, and the aqueous phase was discarded. The two organic phases were combined, 100 mL of 5% citric acid aqueous solution was added, and the mixture was stirred for 15 minutes for separation. 100 mL of 5% saline was added to the organic phase, and the mixture was stirred for 15 minutes for separation. The organic phase was concentrated to about 70 mL, and the concentrated system was added dropwise to 300 mL of n-heptane. The crystallization was stirred for half an hour, and the solid was filtered. The solid was rinsed with 50 mL of cold n-heptane and dried at 45°C for 2 hours to obtain 45.1 g of off-white solid intermediate 2 (yield: 84.2%).

[0036] Example 9 Synthesis of 4-n-butylresorcinol:

[0037] At room temperature, 40 mL of ethanol and intermediate 2 (5 g, 0.0305 mol) were added to a three-necked reaction bottle, and sodium borohydride solid (2.30 g, 0.061 mol) was added. The reaction was carried out at 25°C for 12 hours. LCMS showed that a small amount of raw materials remained. Purified water (50 mL) and ethyl acetate (80 mL) were added to the system, and the mixture was stirred for 15 minutes and then separated. The aqueous phase was extracted with ethyl acetate (80 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by silica gel column chromatography (n-heptane: ethyl acetate = 1:1, V / V) to obtain 3.3 g of white solid (yield 65.1%).

[0038] Example 10 Synthesis of 4-n-butylresorcinol: At room temperature, 50 mL of methanol and intermediate 2 (6 g, 0.0365 mol) were added to a three-necked reaction bottle, and sodium borohydride solid (2.76 g, 0.073 mol) was added. The reaction was carried out at 25°C for 12 hours. LCMS showed that a small amount of raw materials remained. Purified water (65 mL) and ethyl acetate (90 mL) were added to the system, and the mixture was stirred for 15 minutes before separation. The aqueous phase was extracted with ethyl acetate (90 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by silica gel column chromatography (n-heptane: ethyl acetate = 1:1, V / V) to obtain 4.2 g of a white solid (yield: 69.2%).

[0039] Embodiment 11 Synthesis of 4-n-butylresorcinol: At room temperature, 100 mL of ethanol and intermediate 2 (10 g, 0.0609 mol) were added to a three-necked reaction flask, and solid sodium borohydride (4.61 g, 0.122 mol) was added, and the reaction was carried out at 40°C for 6 hours. HPCL showed that the raw material disappeared, and purified water (150 mL) and isopropyl acetate (200 mL) were added to the system. After stirring for 15 minutes, the liquid was separated, and the aqueous phase was extracted with isopropyl acetate (150 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and 60 mL of n-heptane was added and stirred at 40°C for 2 hours. After cooling to room temperature, the solid was washed with 10 mL of n-heptane and dried at 40°C for 1 hour to obtain 9.5 g of white solid (yield 93.8%).

[0040] Example 12 Synthesis of 4-n-butylresorcinol: At room temperature, add 400 mL of ethanol and intermediate 2 (45 g, 0.274 mol) to a 1 L three-necked reaction bottle, heat to 40 ° C and stir for half an hour to dissolve, then add sodium coborohydride solid (20.7 g, 0.548 mol) to the above system in four batches, pay attention to degassing, and react at 40 ° C for 5 hours. HPLC shows that the intermediate 2 raw material disappears. After the system is cooled to room temperature, the system is concentrated to about 150 mL. The concentrated system is added dropwise to 500 mL of 5-10 ° C purified water, pay attention to degassing, add 300 mL of isopropyl acetate, stir for 15 minutes to separate, add 300 mL of isopropyl acetate to the lower aqueous phase, stir for 15 minutes and separate, TLC detection of the lower aqueous phase shows no product, and the aqueous phase is discarded. Combine the organic phases, add 100 mL of 5% citric acid aqueous solution, stir for 15 minutes to separate, add 150 mL of 5% saline to the organic phase, stir for 15 minutes to separate. The organic phase was concentrated to about 100 mL, added dropwise to 500 mL of n-heptane, stirred for 1 hour, filtered, and the solid was rinsed with 50 mL of cold n-heptane and dried. The solid was added to 160 mL of isopropyl ether, heated and stirred for 2 hours, cooled to room temperature, stirred for 2 hours, filtered, and the solid was rinsed with 30 mL of cold isopropyl ether. The solid was dried at 35°C for 3 hours to obtain 41.5 g of white solid 4-n-butylresorcinol (yield 91.2%, purity 99.935%).

[0041] The structural characterization of 4-n-butylresorcinol is as follows Figure 1 As shown in the chromatogram Figure 2 As shown, the chromatographic peak table is shown in Table 1 below.

[0042] Table 1 Chromatographic peak related data

[0043] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing 4-n-butylresorcinol, characterized in that: The steps include: Alkylation reaction of triphenylphosphine with 1-iodopropane gave intermediate 1; After the intermediate 1 is mixed with 2,4-dihydroxybenzaldehyde, a potassium tert-butoxide solution is added dropwise at a temperature of 20 to 50 °C to carry out a coupling reaction for 4 to 12 hours to obtain an intermediate 2; The intermediate 2 is subjected to a hydrogenation reduction reaction to obtain 4-n-butylresorcinol; The chemical structure of intermediate 1 is: , X - is a halogen ion; The chemical structure of intermediate 2 is: .

2. The method for preparing 4-n-butylresorcinol as claimed in claim 1, characterized in that: The temperature for the alkylation reaction of triphenylphosphine with 1-iodopropane is 75~80 ℃.

3. The method for preparing 4-n-butylresorcinol as claimed in claim 1, characterized in that: 1-Iodopropane is added dropwise to the triphenylphosphine solution, and then an alkylation reaction is performed.

4. The method for preparing 4-n-butylresorcinol as claimed in claim 3, characterized in that: The time for adding 1-iodopropane dropwise is 25 to 35 minutes.

5. The method for preparing 4-n-butylresorcinol as claimed in claim 1, characterized in that: The purification method of intermediate 1 is as follows: concentrating the material after the alkylation reaction, adding methyl tert-butyl ether for crystallization, filtering, washing and drying.

6. The method for preparing 4-n-butylresorcinol as claimed in claim 1, characterized in that: The temperature of the coupling reaction is 40~50 ℃.

7. The method for preparing 4-n-butylresorcinol as claimed in claim 1, characterized in that: The purification method of intermediate 2 is as follows: filtering the material after the coupling reaction, adding ethyl acetate and water to the filtrate after concentration for the first extraction and separation, adding citric acid aqueous solution to the upper organic phase after the first extraction and separation for the second extraction and separation, removing water from the upper organic phase after the second extraction and separation and concentrating, adding n-heptane for pulping or crystallization, filtering, washing and drying.

8. The method for preparing 4-n-butylresorcinol as claimed in claim 1, characterized in that: Intermediate 2 is subjected to hydrogenation reduction reaction with sodium borohydride.

9. The method for preparing 4-n-butylresorcinol as claimed in claim 1, characterized in that: The temperature of the hydrogen reduction reaction is 40~50 ℃.

10. The method for preparing 4-n-butylresorcinol according to claim 1, characterized in that: The purification method of 4-n-butylresorcinol is as follows: water and isopropyl acetate are added to the material after the hydrogenation reduction reaction to perform a first extraction and separation, the organic phase of the first extraction and separation is dehydrated and concentrated, n-heptane is added to heat and dissolve, the temperature is lowered for crystallization, filtering, washing, and drying; Alternatively, the purification method of 4-n-butylresorcinol is as follows: water and isopropyl acetate are added to the material after the hydrogenation reduction reaction for a first extraction and separation, a citric acid aqueous solution is added to the upper organic phase after the first extraction and separation for a second extraction and separation, the organic phase of the second extraction and separation is dehydrated and concentrated, n-heptane is added for crystallization, filtered, isopropyl ether is added to the filtered solid, heated to dissolve, cooled for crystallization, filtered, washed, and dried.

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