Preparation method of (2-hydroxy isopropyl) acetophenone

Abstract

The invention provides a method for preparing (2-hydroxy isopropyl) acetophenone, which comprises the following steps of: (1) reacting diisopropylbenzene and oxygen-containing gas in the presence of an initiator and a reaction aid to obtain a reaction solution containing (2-peroxyhydroxy-2-propyl) acetophenone; (2) mixing the reaction liquid obtained in the step (1) with alkali, and extracting (2-peroxyhydroxy-2-propyl) acetophenone to an alkali layer; and (3) heating the alkali layer to obtain (2-hydroxy isopropyl) acetophenone, wherein the initiator comprises one or more of azodiisobutyronitrile, benzoyl peroxide, benzoic acid peroxide, tert-butyl hydroperoxide, diisopropylbenzene dihydroperoxide and dicumyl peroxide, the reaction aid comprises one or more of sulfuric acid type, phosphoric acid type and chlorinated metal Lewis acid, and the alkali comprises sodium hydroxide, potassium hydroxide or a combination thereof.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a method for preparing (2-hydroxyisopropyl)acetophenone, in particular to a method for preparing 3-(2-hydroxyisopropyl)acetophenone and 4-(2-hydroxyisopropyl)acetophenone. Background Art

[0002] (2-Hydroxyisopropyl)acetophenone (KCL) is an important organic intermediate with a wide range of applications in antibacterial, antifungal, glycosidase inhibition, anti-inflammatory, anti-tumor, antioxidant and neuroactive properties. It includes 2-(2-hydroxyisopropyl)acetophenone (o-KCL), 3-(2-hydroxyisopropyl)acetophenone (m-KCL) and 4-(2-hydroxyisopropyl)acetophenone (p-KCL).

[0003] (2-Hydroxyisopropyl)acetophenone can be synthesized by reacting acetophenone with 2-hydroxypropanol, reacting under alkaline conditions at room temperature to appropriate heating conditions, and then crystallizing and purifying the product. Another method for synthesizing 2-hydroxyisopropyl substituted acetophenone is to use, for example, trimethylsilyl trifluoromethanesulfonate (TMSOTF), triphenylphosphine (PPh3) or triethylphosphine (PEt3) as a ketone protective agent, and then react with a Grignard reagent to prepare (2-hydroxyisopropyl)acetophenone, but this type of ketone protective agent contains phosphorus, which is not environmentally friendly, and has a high cost, and is not economical for industrial-grade mass production.

[0004] Therefore, there is still a need in the art for a new method for preparing (2-hydroxyisopropyl)acetophenone, which has a short process flow, can obtain (2-hydroxyisopropyl)acetophenone in high yield and high selectivity, is clean and environmentally friendly, has mild reaction conditions, is easy to control, and is suitable for industrialization. Summary of the invention

[0005] The inventors of the present application have found that (2-hydroxyperoxy-2-propyl)acetophenone is synthesized by co-catalysis of diisopropylbenzene as a raw material through an initiator and a Lewis acid-type reaction aid, and then extracted with an alkali solution, heated to generate (2-hydroxyisopropyl)acetophenone, and a high-purity product is obtained after crystallization. The process is short, and (2-hydroxyisopropyl)acetophenone can be obtained with high yield and high selectivity. It is clean and environmentally friendly, has mild reaction conditions, and is easy to control, making it suitable for industrialization.

[0006] On the one hand, the present application provides a method for preparing (2-hydroxyisopropyl)acetophenone, the method comprising the following steps:

[0007] (1) reacting diisopropylbenzene and an oxygen-containing gas in the presence of an initiator and a reaction aid to obtain a reaction solution containing (2-peroxyhydroxy-2-propyl)acetophenone;

[0008] (2) mixing the reaction solution obtained in step (1) with a base to extract (2-hydroxyperoxy-2-propyl)acetophenone into the base layer; and

[0009] (3) heating the alkaline layer to obtain (2-hydroxyisopropyl)acetophenone;

[0010] The initiator comprises one or more of azobisisobutyronitrile, benzoyl peroxide, benzoic acid peroxide, tert-butyl peroxide, diisopropylbenzene dipydroperoxide and diisopropylbenzene peroxide.

[0011] The reaction aid includes one or more of sulfuric acid type, phosphoric acid type, and chlorinated metal Lewis acid.

[0012] The base includes sodium hydroxide, potassium hydroxide or a combination thereof.

[0013] On the other hand, the present application provides a (2-hydroxyisopropyl)acetophenone product prepared by the method of the present application. DETAILED DESCRIPTION

[0014] "Scope" disclosed herein is defined in the form of lower limit and upper limit, and a given range is defined by selecting a lower limit and an upper limit, and the selected lower limit and upper limit define the boundary of a particular range. The scope defined in this way can be including end values ​​or not including end values, and can be arbitrarily combined, that is, any lower limit can be combined with any upper limit to form a scope. For example, if the scope of 60-120 and 80-110 is listed for a particular parameter, it is understood that the scope of 60-110 and 80-120 is also expected. In addition, if the minimum range values ​​1 and 2 are listed, and if the maximum range values ​​3, 4 and 5 are listed, the following scope can all be expected: 1-3, 1-4, 1-5, 2-3, 2-4 and 2-5. In this application, unless otherwise specified, the numerical range "ab" represents the abbreviation of any real number combination between a and b, wherein a and b are real numbers. For example, the numerical range "0-5" means that all real numbers between "0-5" are listed in this document, and "0-5" is just an abbreviation of these numerical combinations. In addition, when a parameter is expressed as an integer ≥ 2, it is equivalent to disclosing that the parameter is, for example, an integer of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0015] In this application, unless otherwise specified, all embodiments and preferred embodiments mentioned herein can be combined with each other to form a new technical solution.

[0016] In this application, unless otherwise specified, all technical features and preferred features mentioned herein can be combined with each other to form a new technical solution.

[0017] In the present application, unless otherwise specified, all steps mentioned herein may be performed sequentially or randomly, but are preferably performed sequentially. For example, the method includes steps (a) and (b), which means that the method may include steps (a) and (b) performed sequentially, or may include steps (b) and (a) performed sequentially. For example, the method may further include step (c), which means that step (c) may be added to the method in any order, for example, the method may include steps (a), (b) and (c), or may include steps (a), (c) and (b), or may include steps (c), (a) and (b), etc.

[0018] In this application, unless otherwise specified, the terms "include" and "comprising" mentioned herein may be open-ended or closed-ended. For example, the terms "include" and "comprising" may mean that other components not listed may also be included or only the listed components may be included or only the listed components may be included.

[0019] In the description of this article, it should be noted that, unless otherwise specified, "above" and "below" are inclusive of the number itself, and "several" in "one or several" means two or more.

[0020] In the description herein, unless otherwise specified, the term "or" is inclusive. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, any of the following conditions satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist).

[0021] Herein, unless otherwise specified, percentage (%) or part refers to percentage by weight or part by weight relative to the composition.

[0022] Herein, if there is no contrary description, the sum of the contents of the various components in the composition is 100%.

[0023] Herein, if there is no contrary description, the sum of the parts of each component in the composition may be 100 parts by weight.

[0024] In this context, unless otherwise specified, "a combination thereof" means a multi-component mixture of the elements described, for example a mixture of two, three, four and up to the maximum possible multi-component mixture.

[0025] If not specifically stated, the terms "a" or "an" used in the present specification means "at least one".

[0026] Herein, unless otherwise stated, all reactions are carried out at normal temperature and pressure.

[0027] On the one hand, the present application provides a method for preparing (2-hydroxyisopropyl)acetophenone, the method comprising the following steps:

[0028] (1) reacting diisopropylbenzene and an oxygen-containing gas in the presence of an initiator and a reaction aid to obtain a reaction solution containing (2-peroxyhydroxy-2-propyl)acetophenone;

[0029] (2) mixing the reaction solution obtained in step (1) with a base to extract (2-hydroxyperoxy-2-propyl)acetophenone into the base layer; and

[0030] (3) heating the alkaline layer to obtain (2-hydroxyisopropyl)acetophenone;

[0031] The initiator comprises one or more of azobisisobutyronitrile, benzoyl peroxide, benzoic acid peroxide, tert-butyl peroxide, diisopropylbenzene dipydroperoxide and diisopropylbenzene peroxide.

[0032] The reaction aid includes one or more of sulfuric acid type, phosphoric acid type, and chlorinated metal Lewis acid.

[0033] The base includes sodium hydroxide, potassium hydroxide or a combination thereof.

[0034] In the present application, the diisopropylbenzene may be a diisopropylbenzene product commonly used in the art, including o-diisopropylbenzene, m-diisopropylbenzene and p-diisopropylbenzene, which may be prepared according to a commonly used method in the art, or may be a commercially available product. Typically, diisopropylbenzene is in liquid form or in solution form.

[0035] Taking m-diisopropylbenzene as a starting material, m-diisopropylbenzene reacts with an oxygen-containing gas in the presence of an initiator and a reaction aid to generate m-(2-hydroxyperoxy-2-propyl)acetophenone (i.e., 1-hydroperoxide-3-ethyl ketone diisopropylbenzene (KHP)), and then the hydrogen peroxide is partially decomposed by heating to generate (2-hydroxyisopropyl)acetophenone. The reactions involved are as follows:

[0036]

[0037] In the present application, the initiator includes one or more of azobisisobutyronitrile, benzoyl peroxide, benzoic acid peroxide, tert-butyl peroxide, diisopropylbenzene dipydroperoxide, and diisopropylbenzene peroxide. Preferably, the initiator includes at least one initiator selected from the group consisting of tert-butyl peroxide, 1,4-diisopropylbenzene dipydroperoxide, azobisisobutyronitrile, and 1,4-monoisopropylbenzene hydroperoxide. The present application selects an initiator having a similar structure to the raw material diisopropylbenzene, and during the reaction, its oxidation activity is higher, thereby improving the selectivity and yield of the product.

[0038] In one example of the present application, the amount of the initiator can be 0.01%-20%, preferably 0.05-15%, and more preferably 0.1-10%, based on the weight of the diisopropylbenzene.

[0039] In the present application, the oxygen-containing gas represents any gas containing oxygen, for example, a gas containing 1-100% by volume of oxygen, and also includes a gas that can produce oxygen in the reaction process. In one example of the present application, the oxygen-containing gas represents a gas containing 10-100% by volume of oxygen. In another example of the present application, the oxygen-containing gas represents air.

[0040] In the present application, based on the weight of oxygen in the oxygen-containing gas, the amount of oxygen used is 0.2-10 times, such as 0.3-8 times or 0.4-6 times, the weight of diisopropylbenzene.

[0041] In the present application, the reaction aid includes one or more of sulfuric acid type, phosphoric acid type, and chlorinated metal Lewis acid. Specifically, the reaction aid includes one or more of ferric sulfate, cupric chloride, ferric phosphate, aluminum chloride, and ferric chloride. More preferably, the reaction aid includes ferric sulfate and / or ferric chloride.

[0042] In one example of the present application, the amount of the reaction aid can be 0.01%-20%, preferably 0.05-15%, and more preferably 0.1-10%, based on the weight of the diisopropylbenzene.

[0043] In the present application, the base is a strong base to increase the reaction activity, such as improving the selectivity, yield and conversion rate of the reaction. In one example of the present application, the base includes sodium hydroxide, potassium hydroxide or a combination thereof. The base can be in the form of a solution of the base or a solid. In the case of an alkaline solution, the solvent can be a commonly used solvent in the art, including but not limited to water. In a preferred example of the present application, the base is an aqueous solution of sodium hydroxide and potassium hydroxide, with a mass content of 5 to 30%. Based on the weight of diisopropylbenzene, the amount of the base (in the case of an alkaline solution, based on the weight of the base in the solution) is 10%-100% of the weight of diisopropylbenzene, preferably 20-90%, and more preferably 30-70%.

[0044] In the method of the present application, in order to obtain better results, the reaction temperature in step (1) is 80-150°C, preferably 70-120°C, more preferably 80-110°C, and the pressure is 0.1-10MPa, preferably 0.4-2MPa, more preferably 0.5-1.5MPa.

[0045] In the method of the present application, the extraction step in step (2) can be carried out by methods commonly used in the art, including but not limited to vigorous stirring, shaking, etc.

[0046] In the method of the present application, the step (3) is to heat the OH in (2-hydroxyperoxy-2-propyl) acetophenone to - Remove to obtain (2-hydroxyisopropyl)acetophenone. The heating temperature is 25-100°C and the time is 1-120h.

[0047] The (2-hydroxyisopropyl)acetophenone obtained in step (3) can be subjected to a purification treatment, and the purification treatment can be a purification method commonly used in the art, including but not limited to recrystallization, etc. The recrystallization method can be carried out using a solvent commonly used in the art, including but not limited to one or more combinations of methanol, ethanol, acetone, methyl isobutyl ketone, methyl acetate, ethyl acetate, and butyl acetate, with an amount of 1 to 10 times the weight of the product, and a crystallization temperature of 30 to 80° C., preferably 50 to 70° C.

[0048] In step (2) of the method of the present application, unreacted diisopropylbenzene can be recovered and added back to the oxidation reaction process of step 1. The recovery method can be carried out by methods known in the art.

[0049] On the other hand, the present application provides a (2-hydroxyisopropyl)acetophenone product, which is prepared by the method of the present application.

[0050] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0051] Main reagents for the experiment

[0052] Reagents type Manufacturer p-Diisopropylbenzene 98％ Jiaozhou Futian Chemical Co., Ltd. m-Diisopropylbenzene 98％ Jiaozhou Futian Chemical Co., Ltd. Azobisisobutyronitrile 99％ Zhejiang Guangwei Chemical Co., Ltd. Ferrous Sulfate Analytical grade Langfang Pengcai Fine Chemical Co., Ltd. Ferrous chloride Analytical grade Langfang Pengcai Fine Chemical Co., Ltd. Benzoyl peroxide 99％ Jinan Hengda Chemical Additives Co., Ltd. Benzoic acid peroxide 99％ Jiangsu Qiangsheng Functional Chemicals Co., Ltd. Tert-Butyl Peroxide 99％ Jiangsu Qiangsheng Functional Chemicals Co., Ltd. 1,4-Diisopropylbenzene hydroperoxide 98％ Suzhou Senfida Chemical Co., Ltd. 1,4-Diisopropylbenzene monohydroperoxide 98％ Suzhou Senfeida Chemical Co., Ltd. Ferrous Sulfate Analytical grade Langfang Pengcai Fine Chemical Co., Ltd. Cupric chloride Analytical grade Langfang Pengcai Fine Chemical Co., Ltd. Iron phosphate Analytical grade Langfang Pengcai Fine Chemical Co., Ltd. Aluminum Chloride Analytical grade Langfang Pengcai Fine Chemical Co., Ltd. Ferric chloride Analytical grade Langfang Pengcai Fine Chemical Co., Ltd. 15% sodium hydroxide aqueous solution 15％ Langfang Pengcai Fine Chemical Co., Ltd. Ethanol Analytical grade Langfang Pengcai Fine Chemical Co., Ltd. Methanol Analytical grade Langfang Pengcai Fine Chemical Co., Ltd. acetone Analytical grade Langfang Pengcai Fine Chemical Co., Ltd. Methyl isobutyl ketone Analytical grade Langfang Pengcai Fine Chemical Co., Ltd. Methyl acetate Analytical grade Langfang Pengcai Fine Chemical Co., Ltd. Ethyl acetate Analytical grade Langfang Pengcai Fine Chemical Co., Ltd. Butyl acetate Analytical grade Langfang Pengcai Fine Chemical Co., Ltd.

[0053] Main experimental instruments

[0054] Instrument Name model Manufacturer Electronic balance JA31002 Shanghai Yitian Scientific Instrument Co., Ltd., etc. 1L Reactor J2-04 Yantai Songling Chemical Equipment Co., Ltd., etc. Liquid Chromatograph LC Agilent Technologies, etc.

[0055] Calculation method of conversion, selectivity and yield:

[0056] Diisopropylbenzene conversion rate: (the amount of diisopropylbenzene substance converted / the amount of diisopropylbenzene substance put into the total reaction)*100%

[0057] (2-Hydroxyisopropyl)acetophenone selectivity: (the amount of (2-hydroxyisopropyl)acetophenone actually produced / the amount of diisopropylbenzene converted)*100%

[0058] (2-Hydroxyisopropyl)acetophenone yield: (diisopropylbenzene conversion rate*(2-Hydroxyisopropyl)acetophenone selectivity)

[0059] (2-Hydroxyisopropyl)acetophenone crystallization yield: (mass of (2-hydroxyisopropyl)acetophenone after recrystallization) / (mass of (2-hydroxyisopropyl)acetophenone before recrystallization)*100%

[0060] Example 1

[0061] 162.2g of m-diisopropylbenzene, 0.2g of azobisisobutylonitrile, and 0.2g of ferrous sulfate were placed in a 1L reactor. The reaction temperature was raised to 85°C, and 4055.0g of air was introduced at 0.4MPa for 12h. The reaction was stopped to obtain a reaction liquid rich in m-KHP, which was then fully mixed with 81.6g of 15% liquid caustic soda to extract the m-KHP in the system to the alkali layer. The unreacted diisopropylbenzene was recycled to the reactor, and the conversion rate of m-diisopropylbenzene was 97%;

[0062] The alkaline layer was heated at 85°C for 12 hours to obtain a crude 3-(2-hydroxyisopropyl)acetophenone, which was recrystallized from ethanol to obtain 178.8 g of 3-(2-hydroxyisopropyl)acetophenone, with a crystallization yield of 96.0%, a total yield of 92.2%, and a product purity of 99.98%. The selectivity of 3-(2-hydroxyisopropyl)acetophenone was 99%, and the yield of 3-(2-hydroxyisopropyl)acetophenone was 96.0%.

[0063] Example 2

[0064] 162.4 g of p-diisopropylbenzene, 0.2 g of azobisisobutylonitrile, and 0.2 g of ferrous chloride were put into a 1 L reactor, the reaction temperature was raised to 85°C, 4055.6 g of air was introduced at 0.4 MPa for 12 h, the reaction was stopped, and a reaction liquid rich in p-KHP was obtained, which was then fully mixed with 81.6 g of 15% liquid caustic soda to extract p-KHP in the system to the alkali layer, and the unreacted diisopropylbenzene was recycled to the reactor, and the conversion rate of p-diisopropylbenzene was 98.2%;

[0065] The alkaline layer was heated at 85°C for 12 hours to obtain a crude 4-(2-hydroxyisopropyl)acetophenone, which was recrystallized from methanol to obtain 169.8 g of 4-(2-hydroxyisopropyl)acetophenone benzene, with a crystallization yield of 95.0%, a total yield of 87.5%, and a product purity of 99.96%. The selectivity of 4-(2-hydroxyisopropyl)acetophenone was 98.9%, and the yield of 4-(2-hydroxyisopropyl)acetophenone was 97.1%.

[0066] Embodiments 3 to 12

[0067] Different initiators were replaced based on Example 1:

[0068] Table 1 Initiator evaluation results

[0069]

[0070] From the data in Table 1, it can be seen that azobisisobutyronitrile, 1,4-diisopropylbenzene hydroperoxide and 1,4-diisopropylbenzene monoperoxide have high oxidation activity and selectivity for 3-(2-hydroxyisopropyl)acetophenone, indicating that free radical initiators can promote the oxidation reaction, and initiators with similar structures to the raw materials can improve the reaction activity.

[0071] Embodiments 13 to 17

[0072] Different Lewis acid reaction aids were replaced on the basis of Example 1:

[0073] Table 2 Evaluation results of reaction aids

[0074]

[0075]

[0076] It can be seen from the data in Table 2 that when Lewis acid reaction aid is used, the conversion rate of raw material diisopropylbenzene and the selectivity of product (2-hydroxyisopropyl)acetophenone are higher.

[0077] Embodiments 18 to 30

[0078] On the basis of Example 1, different reaction temperatures and pressures were changed:

[0079] Table 3 Evaluation results of temperature and pressure

[0080]

[0081] It can be seen from the data in Table 3 that when the reaction temperature is 80-110°C and the pressure is 0.5-1.5 MPa, the conversion rate of the raw material diisopropylbenzene and the selectivity of the product (2-hydroxyisopropyl) acetophenone are relatively high.

[0082] Examples 31 to 40

[0083] On the basis of Example 1, different crystallization temperatures and solvents were replaced:

[0084] Table 4: Evaluation results of the effects of temperature and solvent on crystallization

[0085]

[0086]

[0087] From the results in Table 4, it can be seen that the crystallization temperature is preferably 50-70°C.

[0088] The above are only preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be regarded as limiting the present invention, and the protection scope of the present invention should be based on the scope defined by the claims. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing (2-hydroxyisopropyl)acetophenone, the method comprising the steps of: (1) reacting diisopropylbenzene and an oxygen-containing gas in the presence of an initiator and a reaction aid to obtain a reaction solution containing (2-peroxyhydroxy-2-propyl)acetophenone; (2) mixing the reaction solution obtained in step (1) with a base to extract (2-hydroxyperoxy-2-propyl)acetophenone into the base layer; and (3) heating the alkaline layer to obtain (2-hydroxyisopropyl)acetophenone; The initiator comprises one or more of azobisisobutyronitrile, benzoyl peroxide, benzoic acid peroxide, tert-butyl peroxide, diisopropylbenzene dipydroperoxide and diisopropylbenzene peroxide. The reaction aid includes one or more of sulfuric acid type, phosphoric acid type, and chlorinated metal Lewis acid. The base includes sodium hydroxide, potassium hydroxide or a combination thereof.

2. The method of claim 1, wherein: The reaction temperature in step (1) is 80-150° C., preferably 70-120° C., and the pressure is 0.1-10 MPa, preferably 0.4-2 MPa.

3. The method of claim 1, wherein: The amount of the initiator is 0.01%-20%, preferably 0.05-15%, and more preferably 0.1-10%, based on the weight of the diisopropylbenzene; and / or The dosage of the reaction aid is 0.01%-20%, preferably 0.05-15%, more preferably 0.1-10%.

4. The method of claim 1, wherein: The oxygen-containing gas refers to a gas containing oxygen or a gas that can generate oxygen during the reaction, such as a gas containing 1-100 volume % oxygen; preferably, the oxygen-containing gas refers to a gas containing 10-100 volume % oxygen; preferably, the oxygen-containing gas refers to air.

5. The method of claim 1, wherein: Calculated by the weight of oxygen in the oxygen-containing gas, the amount of oxygen used is 0.2-10 times, such as 0.3-8 times or 0.4-6 times, the weight of diisopropylbenzene.

6. The method of claim 1, wherein: The alkali is a strong alkali; preferably, the alkali includes sodium hydroxide, potassium hydroxide or a combination thereof; preferably, the alkali is in the form of a solution of alkali with a mass concentration of 5%-30%; preferably, the alkali is an aqueous solution of sodium hydroxide and potassium hydroxide; preferably, based on the weight of diisopropylbenzene, the amount of the alkali is 10%-100%, preferably 20-90%, and more preferably 30-70% of the weight of diisopropylbenzene.

7. The method of claim 1, wherein: The heating temperature of step (3) is 25 to 100° C., and / or the heating time is 1 to 120 hours.

8. The method of claim 1, wherein: The method further comprises the step (4) of recrystallizing the (2-hydroxyisopropyl)acetophenone obtained in the step (3).

9. The method of claim 8, wherein: The crystallization solvent used in step (4) includes one or more combinations of methanol, ethanol, acetone, methyl isobutyl ketone, methyl acetate, ethyl acetate, and butyl acetate; and / or In the step (4), the crystallization temperature is 30-100°C, preferably 40-80°C.

10. A (2-hydroxyisopropyl)acetophenone product, wherein the (2-hydroxyisopropyl)acetophenone product is prepared by the method according to any one of claims 1 to 9.

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