Additive and synthetic process of p-hydroxyanisole / o-hydroxyanisole

Abstract

The invention relates to a synthesis process for co-production of p-hydroxyanisole and o-hydroxyanisole, anisole and hydrogen peroxide are used as raw materials, and under the action of a catalyst and an auxiliary agent, the content of p-hydroxyanisole and o-hydroxyanisole can be adjusted. The additive is prepared by taking benzothiophene as a raw material through alkyl ether, ethynylation and ring closing reaction, has certain solvent effect and limiting effect, and can change the proportion of p-hydroxyanisole to o-hydroxyanisole in a product.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a continuous synthesis process for the co-production of p-hydroxyanisole and o-hydroxyanisole. Background Technology

[0002] p-Hydroxyanisole, a white, flaky crystal, also known as 4-methoxyphenol (MEHQ), is readily soluble in common organic solvents. It is mainly used as a polymerization inhibitor for acrylic acid monomers, a UV suppressant, a dye intermediate, and in the synthesis of the antioxidant BHA. o-Hydroxyanisole, also known as guaiacol, is a colorless or pale yellow liquid at room temperature with a strong guaiacol aroma. It is a permitted food flavoring in Chinese national standard 2760. Guaicol is often used as an intermediate in the synthesis of vanillin and guaiacol glycerol ethers, as well as in the pharmaceutical industry. Both p-hydroxyanisole and o-hydroxyanisole are high-value-added fine chemicals. Currently, the mainstream synthesis process for both is alkylation. p-Hydroxyanisole uses hydroquinone and methanol as raw materials, while o-hydroxyanisole uses catechol and methanol. Because hydroquinone and catechol are relatively expensive, and alkylation is a high-temperature, high-pressure reaction requiring significant equipment investment, the economic viability of this synthesis process needs improvement.

[0003] To obtain p- / o-hydroxyanisole at low cost, patent CN101250092A uses inexpensive alkyl aromatic ethers as raw materials. Through a hydroxylation reaction with hydrogen peroxide, both p- and o-hydroxy aromatic ethers can be generated simultaneously, significantly improving product economics. However, this process uses catalysts with low activity, requires large quantities of catalyst, and necessitates multiple solvents and oxidants, making the process complex. Patent CN101250092A modifies the catalyst by first modifying microsphere titanium silicate molecular sieves with alkali, and then preparing a copper- and cadmium-loaded microsphere titanium silicate molecular sieve catalyst via an equal-volume impregnation method. The hydroxyanisole of this invention exhibits excellent yield and selectivity, and the catalyst of this application has a long lifetime. Patent CN119409559A discloses a method for the oxidative synthesis of p-hydroxyanisole using titanium-silicon molecular sieve catalysis. The method includes steps such as reaction, catalyst separation, and vacuum distillation. The modified TS-1 titanium-silicon molecular sieve catalyst is used as the core, resulting in the absence of black oil in the p-hydroxyanisole production reaction. Acetonitrile and tert-butanol solvents increase the p-hydroxyanisole yield to 93% and the selectivity to 97%, which greatly improves the selectivity and conversion rate of the reaction and reduces the impact of black oil on the reaction system and the recovery and utilization of the catalyst.

[0004] Although the aforementioned patents can efficiently obtain p-hydroxyanisole and o-hydroxyanisole, the content of p-hydroxyanisole and o-hydroxyanisole produced is relatively fixed and cannot be adjusted according to market demand. Summary of the Invention

[0005] To improve process flexibility and address the limitation of existing processes in adjusting the ratio of p-hydroxyanisole to o-hydroxyanisole in the product, this invention proposes a synthesis process for hydroxyanisole with an adjustable o-hydroxyanisole ratio (p-hydroxyanisole / o-hydroxyanisole). Using anisole and hydrogen peroxide as raw materials, the adjustable o-hydroxyanisole ratio is achieved with the aid of catalysts and auxiliaries.

[0006] The technical solution of the present invention is as follows:

[0007] First, this invention provides a novel auxiliary agent and applies it to the hydroxylation reaction of anisole. The molecular structure of this auxiliary agent is as follows:

[0008]

[0009] The present invention also provides a method for preparing the aforementioned adjuvant, comprising the following steps:

[0010] (1) Compound 1 was obtained by reacting hydroxybenzothiophene, allyl chloride and alkaline solution with catalyst 1.

[0011] (2) Compound 1 prepared in step (1) is reacted with bromopropyne to obtain compound 2;

[0012] (3) Compound 2 is reacted with hydrogen peroxide under the action of catalyst 2 to generate compound 3.

[0013] The synthetic route of the preparation method is shown below:

[0014]

[0015] Step (1) of the present invention can be carried out in solvent A, which includes one or more of toluene, ethylbenzene, tetrahydrofuran, water, DMF and diethyl ether, preferably water or DMF.

[0016] In step (1) of the present invention, the weight ratio of hydroxybenzothiophene to solvent A is 1:(1-10), preferably 1:(5-8).

[0017] In step (1) of the present invention, the mass ratio of hydroxybenzothiophene to allyl chloride is 1:(0.5-3), preferably 1:(1-1.5).

[0018] The alkaline solution used in step (1) of the present invention is one of sodium hydroxide solution, potassium hydroxide solution, or ammonia water, preferably sodium hydroxide.

[0019] In step (1) of this invention, the mass concentration of the alkali solution is 1%-20%, preferably 5%-10%.

[0020] In step (1) of the present invention, the mass ratio of hydroxybenzothiophene to alkaline solution is 1:(2-10), preferably 1:(4-8).

[0021] In step (1) of the present invention, catalyst 1 is at least one of ferric sulfate, manganese sulfate, cobalt sulfate and copper sulfate.

[0022] In step (1) of the present invention, the mass ratio of catalyst 1 to hydroxybenzothiophene is 1:(100-1000), preferably 1:(200-600).

[0023] In step (1) of the present invention, the reaction temperature is 20-80℃, and the preferred temperature is 30-50℃.

[0024] The reaction time in step (1) of the present invention is 1-10h, preferably 3-6h.

[0025] Step (2) of the present invention can be carried out in solvent B, wherein solvent B is one of toluene, acetone, n-hexane, and DMF, preferably acetone or toluene.

[0026] In step (2) of the present invention, the weight ratio of compound 1 to solvent B is 1:(3-15), preferably 1:(6-10).

[0027] In step (2) of the present invention, the weight ratio of compound 1 to bromopropyne is 1:(2-10), preferably 1:(4-6).

[0028] In step (2) of the present invention, the reaction temperature is 60-160℃, and the preferred temperature is 80-120℃.

[0029] The reaction time in step (2) of the present invention is 1-8 hours, preferably 2-4 hours.

[0030] In step (3) of the present invention, the mass ratio of compound 2 and hydrogen peroxide with a concentration of 27.5%-35% is 1:(1-5), and the preferred mass ratio is 1:(2-3).

[0031] In step (3) of the present invention, the mass ratio of compound 2 to catalyst 2 is (100-700):1, preferably (300-500):1.

[0032] The catalyst 2 used in step (3) of the present invention is a palladium-based catalyst, which can be selected from palladium acetate, palladium nitrate, triphenylphosphine palladium, palladium sulfate, and preferably palladium acetate catalyst.

[0033] In step (3) of the present invention, the reaction temperature is 30-150℃, and the preferred temperature is 50-100℃.

[0034] The reaction time in step (3) of the present invention is 1-10h, and the preferred time is 4-6h.

[0035] In another aspect, the present invention applies the synthesized cyclic ether auxiliaries to the preparation of hydroxyanisole by hydroxylation of anisole.

[0036] A process for synthesizing hydroxyanisole, employing a continuous process, involves mixing anisole, hydrogen peroxide, and additives before feeding them into the process.

[0037] The catalyst used was a titanium-silicon molecular sieve, and the feed mass hourly space velocity (MHSV) was 0.01-0.2 h⁻¹. -1 The reaction temperature is 40-100℃, and the residence time is 2-6h;

[0038] The mass ratio of anisole to hydrogen peroxide (27.5%-35%) is (2-4):1, and the mass ratio of anisole to auxiliaries is 1:(0.01-0.5).

[0039] In this invention, different para- and ortho-para ratios of hydroxyanisole can be obtained by varying the ratio of anisole to cyclic ether auxiliaries. Cyclic ether auxiliaries help promote the formation of p-hydroxyanisole; to increase the para-position content in the reaction solution, the cyclic ether auxiliaries can be increased. Similarly, a lower formation of p-hydroxyanisole can be achieved by reducing the content of cyclic ether auxiliaries in the reaction solution.

[0040] The beneficial effects of this invention are:

[0041] This invention provides a novel cyclic ether auxiliaries for the hydroxylation of anisole to produce p- / o-hydroxyanisole. The cyclic ether compounds synthesized in this invention can effectively pair with groups such as anisole and hydrogen peroxide, fixing anisole and hydrogen peroxide near the catalyst, increasing the contact area, significantly improving reaction activity, and effectively reducing the reaction temperature. More importantly, the cyclic ether auxiliaries possess a certain site-limiting effect and a larger spatial structure, which can promote the production of the para-product, i.e., p-hydroxyanisole. Based on this, the ratio of p-hydroxyanisole to o-hydroxyanisole can be adjusted by controlling the content of the cyclic ether auxiliaries in the reaction solution according to market conditions. Detailed Implementation

[0042] The following embodiments will further illustrate the method provided by the present invention, but the present invention is not limited to the listed embodiments, and should also include any other known modifications within the scope of the claims of the present invention.

[0043] Example 1

[0044] Preparation of cyclic ether auxiliaries:

[0045] 50g of hydroxybenzothiophene, 50g of allyl chloride, 250g of DMF, 200g of 10% sodium hydroxide solution, and 0.2g of copper sulfate were added to a three-necked flask and reacted at 40℃ for 5 hours. After separation and purification, compound 1 was obtained. 40g of compound 1, 240g of acetone, and 160g of bromopropyne were added to a reaction flask and reacted at 80℃ for 4 hours. After subsequent separation, compound 2 was obtained. 30g of compound 2 was reacted with 60g of 27.5% hydrogen peroxide and 0.1g of palladium acetate at 80℃ for 5 hours. After separation and purification, compound 3, i.e., the cyclic ether auxiliary, was obtained.

[0046] Anisole, 27.5% hydrogen peroxide, and additives were mixed and fed into the feed at a ratio of 1:0.5:0.1. The catalyst was a titanium-silicon molecular sieve (Wuhan Shuer Biochemical Co., Ltd., grade SW-5, with a BET greater than 300 m² / g), and the mass hourly space velocity of the catalyst was 0.1 h⁻¹. -1 The reaction temperature was 70℃ and the residence time was 4h to obtain a mixed solution of o-hydroxyanisole and p-hydroxyanisole with a yield of 91.5% and a p-hydroxyanisole / o-hydroxyanisole ratio of 4.3.

[0047] Example 2

[0048] Preparation of cyclic ether auxiliaries:

[0049] 50g of hydroxybenzothiophene, 75g of allyl chloride, 400g of water, 400g of 5% sodium hydroxide solution, and 0.2g of cobalt sulfate were added to a three-necked flask and reacted at 25°C for 8 hours. After separation and purification, compound 1 was obtained. 40g of compound 1, 500g of toluene, and 120g of bromopropyne were added to a reaction flask and reacted at 130°C for 1.5 hours. After subsequent separation, compound 2 was obtained. 30g of compound 2 was reacted with 120g of 35% hydrogen peroxide and 0.1g of palladium nitrate at 120°C for 2 hours. After separation and purification, compound 3, i.e., the cyclic ether auxiliary, was obtained.

[0050] Anisole, 35% hydrogen peroxide, and additives were mixed and fed into the feed at a ratio of 1:0.28:0.05. The catalyst was a titanium-silicon molecular sieve (Wuhan Shuer Biochemical Co., Ltd., grade SW-5, with a BET greater than 300 m² / g), and the mass hourly space velocity of the catalyst was 0.06 h⁻¹. -1 The reaction temperature was 50℃ and the residence time was 5h to obtain a mixed solution of o-hydroxyanisole and p-hydroxyanisole with a yield of 92.2% and a p-hydroxyanisole / o-hydroxyanisole ratio of 2.9.

[0051] Example 3

[0052] Preparation of cyclic ether auxiliaries:

[0053] 50g of hydroxybenzothiophene, 35g of allyl chloride, 100g of tetrahydrofuran, 100g of 18% sodium hydroxide solution, and 0.2g of ferric sulfate were added to a three-necked flask and reacted at 70℃ for 2 hours. After separation and purification, compound 1 was obtained. 40g of compound 1, 150g of n-hexane, and 200g of bromopropyne were added to a reaction flask and reacted at 70℃ for 5 hours. After subsequent separation, compound 2 was obtained. 30g of compound 2 was reacted with 50g of 30% hydrogen peroxide and 0.1g of triphenylphosphine palladium at 80℃ for 5 hours. After separation and purification, compound 3, i.e., the cyclic ether auxiliary, was obtained.

[0054] Anisole, 30% hydrogen peroxide, and additives were mixed and fed into the feed at a ratio of 1:0.28:0.4. The catalyst was a titanium-silicon molecular sieve (Wuhan Shuer Biochemical Co., Ltd., grade SW-5, with a BET greater than 300 m² / g), and the mass hourly space velocity of the catalyst was 0.15 h⁻¹. -1 The reaction temperature was 85℃ and the residence time was 3h to obtain a mixed solution of o-hydroxyanisole and p-hydroxyanisole with a yield of 90.6% and a p-hydroxyanisole / o-hydroxyanisole ratio of 7.3.

[0055] Comparative Example

[0056] Anisole and 30% hydrogen peroxide were mixed and fed into the feed at a ratio of 1:0.28. The catalyst was a titanium-silicon molecular sieve (Wuhan Shuer Biochemical Co., Ltd., grade SW-5, with a BET greater than 300 m² / g), and the mass hourly space velocity of the catalyst was 0.15 h⁻¹. -1 The reaction temperature was 85℃ and the residence time was 3h to obtain a mixed solution of o-hydroxyanisole and p-hydroxyanisole with a yield of 87.6% and a p-hydroxyanisole / o-hydroxyanisole ratio of 0.95.

[0057] It is readily understood that the above embodiments are merely illustrative examples for clear explanation and do not imply that the invention is limited thereto. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. An adjuvant, with the following structural formula:

2. A method for preparing the adjuvant according to claim 1, comprising the following steps: (1) Hydroxybenzothiophene, allyl chloride, and alkaline solution were reacted with catalyst 1 to obtain compound 1; (2) Compound 1 was reacted with bromopropyne to obtain compound 2; (3) Compound 2 is reacted with hydrogen peroxide in the presence of catalyst 2 to generate compound 3; The synthesis route is shown below:

3. The preparation method according to claim 2, wherein, In step (1), the mass ratio of hydroxybenzothiophene to allyl chloride is 1:(0.5-3), preferably 1:(1-1.5).

4. The preparation method according to claim 2, wherein, In step (1), the alkaline solution is one of sodium hydroxide solution, potassium hydroxide solution, or ammonia water, and the mass concentration of the alkaline solution is 1%-20%, preferably 5%-10%. Preferably, the mass ratio of hydroxybenzothiophene to alkaline solution is 1:(2-10), more preferably 1:(4-8); Preferably, catalyst 1 in step (1) is at least one of ferric sulfate, manganese sulfate, cobalt sulfate and copper sulfate; Preferably, in step (1), the mass ratio of catalyst 1 to hydroxybenzothiophene is 1:(100-1000), more preferably 1:(200-600); Preferably, the reaction temperature in step (1) is 20-80℃, the preferred temperature is 30-50℃, and the reaction time is 1-10h, the preferred time is 3-6h.

5. The preparation method according to claim 2, wherein, In step (2), the weight ratio of compound 1 to bromopropyne is 1:(2-10), preferably 1:(4-6).

6. The preparation method according to claim 2 or 5, wherein, In step (2), the reaction temperature is 60-160℃, preferably 80-120℃, and the reaction time is 1-8h, preferably 2-4h.

7. The preparation method according to claim 2, wherein, In step (3), the mass ratio of compound 2 to hydrogen peroxide is 1:(1-5), and the preferred mass ratio is 1:(2-3). Preferably, the hydrogen peroxide concentration is 27.5%-35wt%; The mass ratio of compound 2 to catalyst 2 is (100-700):1, preferably (300-500):1; Preferably, catalyst 2 is a palladium-based catalyst, and can be selected from palladium acetate, palladium nitrate, triphenylphosphine palladium, and palladium sulfate.

8. A process for synthesizing hydroxyanisole, comprising a continuous process in which anisole, hydrogen peroxide, and auxiliaries are mixed and fed into the feed; wherein, The additive is the additive described in claim 1.

9. The synthesis process according to claim 8, wherein, The catalyst used was a titanium-silicon molecular sieve, and the feed mass hourly space velocity (MHSV) was 0.01–0.2 h⁻¹. -1 The reaction temperature is 40-100℃, and the residence time is 2-6h.

10. The synthesis process according to claim 8 or 9, wherein, The mass ratio of anisole to hydrogen peroxide (preferably 27.5%-35wt%) is (2-4):1, and the mass ratio of anisole to auxiliaries is 1:(0.01-0.5).

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