Synthetic method of azatinib intermediate 2-(4-ethyl-3-iodophenyl)-2-methyl propionic acid

Abstract

The invention discloses a synthesis method of an azatinib intermediate compound as shown in a formula III, a compound as shown in a formula II and halogenated carboxylic ester react under a strong alkali condition to generate the compound as shown in the formula III, and the invention provides a synthesis method of an azatinib key intermediate 2-(4-ethyl-3-iodophenyl)-2-methylpropanoic acid. The cyano compound is prepared from 2-(4-ethylphenyl) propionaldehyde, methyl is added to dimethyl sulfate, and the cyano group is hydrolyzed and iodinated to obtain the target compound, so that the reaction speed is high, the operation is simple, the route yield is increased, the production cost is greatly reduced, and the obtained product has high purity and is more suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the pharmaceutical field, and in particular to a method for synthesizing an alectinib intermediate 2-(4-ethyl-3-iodophenyl)-2-methylpropionic acid. Background Art

[0002] Alectinib hydrochloride is an anaplastic lymphoma kinase inhibitor mainly used to treat patients with ALK-positive non-small cell lung cancer, especially for patients who have deteriorated after treatment with crizotinib or are intolerant to it.

[0003]

[0004] 2-(4-Ethyl-3-iodophenyl)-2-methylpropanoic acid is an important intermediate of alectinib hydrochloride.

[0005]

[0006] At present, there are many methods for preparing 2-(4-ethyl-3-iodophenyl)-2-methylpropionic acid, mainly by the following methods:

[0007] 1. CN106946650A discloses the following preparation method:

[0008]

[0009] This patent uses bromobutyric acid as the starting material and thionyl chloride to prepare bromoisobutyryl chloride. The acyl chloride intermediate is difficult to purify. The one-pot method is used for Friedel-Crafts reaction to obtain the product compound 2 with many impurities and low yield, resulting in poor atom economy. In addition, the rearrangement reaction uses a large excess of zinc chloride catalyst, and a large amount of tarry viscous mixture is produced after the reaction, which is highly corrosive to traditional equipment, is not conducive to product purification, is not conducive to equipment cleaning, and produces a large amount of acidic wastewater (forming complex acid when in contact with water), which is difficult to scale up commercial production.

[0010] 2. CN112047829 discloses the following preparation method:

[0011]

[0012] This patent uses benzyl halides, which are very easy to eliminate during the synthesis of Grignard reagents to form conjugated stable olefin byproducts, resulting in low yields, difficult product purification, and increased costs.

[0013] 3. CN109438218 discloses the following contents:

[0014]

[0015] This patent uses halogenated alkenes and Lewis acid catalysis to complete the Friedel-Crafts reaction with carbon cations, but the reaction regioselectivity is not high, there is positional isomerism, and there are halogenated alkanes as by-products of the Friedel-Crafts reaction. The intermediates are difficult to separate due to the presence of isomers, and the purity improvement is limited, making it difficult to obtain high-purity products. Secondly, the subsequent reaction involves two oxidations, the first of which requires the use of a Grignard reagent and oxygen. This type of reaction requires very low temperatures and is difficult to control. There are few reports in the literature and very few industrial applications, so this route has no commercial value.

[0016] The preparation of 2-(4-ethyl-3-iodophenyl)-2-methylpropionic acid requires avoiding the use of special raw materials and reagents, and using cheap and readily available raw materials on the market to prepare a high-purity product, so the existing technology has the defect of being difficult to scale up industrially. In view of the defects of the existing technology, a new preparation method is needed. Summary of the invention

[0017] In order to achieve the above invention objectives, the present invention provides a method for preparing an alectinib intermediate 2-(4-ethyl-3-iodophenyl)-2-methylpropionic acid. This method uses ethylbenzene, which is easily available, as a raw material, reacts with acetic anhydride, and then reacts with an α-haloacetic acid ester to obtain an intermediate III. The reaction conditions of this step are simple and the yield is high. The route chemical reaction type of the present invention is simple, the reaction conditions have low requirements on equipment, the raw materials and reagents used are easy to obtain and low in cost, and a high-purity product can be obtained at a high yield, which is conducive to commercial production.

[0018] The technical solution of this application is as follows:

[0019] The first object of the present invention is to provide a method for synthesizing an alectinib intermediate compound of formula III:

[0020] The compound of formula II reacts with a halogenated carboxylic acid ester under strong alkaline conditions to generate a compound of formula III,

[0021]

[0022] Among them, X is Cl, Br, I; R1 is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl.

[0023] Furthermore, the molar ratio of the compound of formula II to the strong base is 1:1-5, preferably 1:1-2.

[0024] Further, the molar ratio of the compound of formula II to the halogenated carboxylic acid ester is 1:1-5, preferably 1:1-2, further: 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0.

[0025] Furthermore, the halogenated carboxylic acid ester includes ethyl chloroacetate, methyl bromoacetate, ethyl bromoacetate, and methyl chloroacetate.

[0026] Furthermore, the strong base includes potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, LDA, and n-butyllithium.

[0027] Furthermore, the reaction temperature is -30 to 30°C. Furthermore, the reaction temperature is -20 to 5°C.

[0028] The second object of the present invention is to provide a method for synthesizing an alectinib intermediate 2-(4-ethyl-3-iodophenyl)-2-methylpropionic acid:

[0029] (a) the compound of formula II reacts with a halogenated carboxylic acid ester under strong alkaline conditions to generate a compound of formula III,

[0030]

[0031] X is Cl, Br, I; R1 is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl;

[0032] (b) the compound of formula III is hydrolyzed under alkaline conditions to generate the compound of formula IV,

[0033]

[0034] (c) reacting the compound of formula IV with a cyanation reagent to obtain a compound of formula V,

[0035]

[0036] (d) the compound of formula V is subjected to methylation to obtain the compound of formula VI,

[0037]

[0038] (e) hydrolyzing the compound of formula VI to obtain a compound of formula VII,

[0039]

[0040] (f) iodine the compound of formula VII to obtain the compound of formula VIII,

[0041]

[0042] Furthermore, in step (c), the molar ratio of the compound of formula IV to the cyanation reagent is 1:1-2; in step (d), the molar ratio of the compound of formula V to the methyl source reagent is 1:1-8; and in step (f), the molar ratio of the compound of formula VII to the iodine compound is 1:1-2.

[0043] Furthermore, the reaction temperature of step (b) is 20-35°C; the reaction temperature of step (c) is 60-70°C; the reaction temperature of step (d) is -20-20°C; the reaction temperature of step (e) is 100-140°C; and the reaction temperature of step (f) is 20-40°C.

[0044] Furthermore, the compound of formula II is prepared from ethylbenzene and acetic anhydride, the molar mass ratio of ethylbenzene to acetic anhydride is 1:1-2, and the reaction temperature is -20-30°C.

[0045] The invention provides a method for synthesizing 2-(4-ethyl-3-iodophenyl)-2-methylpropionic acid, a key intermediate of alectinib. A cyano compound is prepared by using 2-(4-ethylphenyl) propionaldehyde, a methyl group is added by dimethyl sulfate, and then the cyano group is hydrolyzed and iodinated to obtain a target compound. The method has fast reaction speed, simple operation, improved route yield, greatly reduced production cost, high purity of the obtained product, and is more suitable for industrial production.

[0046] This method uses ethylbenzene, which is easily available, as a raw material, and undergoes a Friedel-Crafts acylation reaction with acetic anhydride, with high regioselectivity and high conversion rate; in the second step, a strong base such as sodium methoxide is used to react with an α-haloacetic acid ester to undergo a Darson reaction, and the intermediate III obtained can be simply treated to obtain a compound of formula IV. The aldehyde group of the compound of formula IV is converted into a cyano group using raw materials such as formic acid and sodium acetate, with a fast conversion rate and high yield, and then methylated under alkaline conditions of dimethyl sulfate to obtain a compound of formula VI, which is subsequently hydrolyzed and iodinated to obtain a compound of formula VIII. This synthetic method has a simple chemical reaction type, and the reaction conditions are equipment-friendly. The reagents used are all common, cheap, and readily available raw materials and reagents on the market. At the same time, a high-purity product can be obtained at a high yield, which is conducive to commercial production. Specific embodiments

[0047] The route of the present invention is as follows:

[0048]

[0049] Formula I compound ethylbenzene and acetic anhydride react to prepare formula II compound, wherein the molar mass ratio of ethylbenzene to acetic anhydride is 1:1-2, the reaction temperature is -20-30°C, and the further reaction temperature is -20-0°C. Formula I compound ethylbenzene and acetic anhydride react to add Lewis acid, Lewis acid includes: aluminum chloride, ferric chloride, zinc chloride, titanium tetrachloride, copper chloride; preferably aluminum chloride; ethylbenzene and Lewis acid molar ratio is 1:2-5, preferably 1:2-3, preferably 1:2.5. The reaction solvent can be one of dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dioxane, preferably DCM (dichloromethane).

[0050] Step (a) The compound of formula II reacts with a halogenated carboxylic acid ester under strong base conditions to generate a compound of formula III, the molar ratio of the compound of formula II to the strong base is 1:1-5, preferably 1:1-2. The molar ratio of the compound of formula II to the halogenated carboxylic acid ester is 1:1-5, preferably 1:1-3. The halogenated carboxylic acid ester is an α-halogenated carboxylic acid ester, including ethyl chloroacetate, methyl bromoacetate, ethyl bromoacetate, and methyl chloroacetate. The strong base includes potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, LDA, and n-butyl lithium. The reaction temperature is -30 to 30°C. Further, the reaction temperature is -20 to 0°C. Further, the reaction temperature is -10 to 0°C.

[0051] The reaction solvent can be one of n-hexane, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, n-hexane, n-heptane, methanol, toluene, acetonitrile, ethanol, isopropanol, n-butanol, tert-butanol, and dioxane.

[0052] Step (b) The compound of formula III is hydrolyzed under alkaline conditions to generate a compound of formula IV. The base can be potassium carbonate, sodium carbonate, sodium acetate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, LDA, n-butyl lithium. Furthermore, the alkaline condition is preferably hydrolyzed under a sodium alcohol / alcohol system, wherein the alcohol includes methanol and ethanol, and the sodium alcohol includes sodium methoxide and sodium ethoxide. The molar ratio of the compound of formula III to the sodium alcohol is 1:1 to 3, preferably 1:1 to 2; the reaction solvent can be replaced by water, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, acetonitrile, methanol, isopropanol, n-butanol, tert-butanol, dioxane. The reaction temperature is 20 to 35°C;

[0053] Step (c) The compound of formula IV reacts with a cyanation agent to obtain a compound of formula V, wherein the molar ratio of the compound of formula IV to the cyanation agent is 1:1-2; the preferred cyanation agent includes hydroxylamine hydrochloride. The reaction conditions also include a dehydrating agent, which includes sodium acetate, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, and the reaction solvent includes anhydrous formic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, oxalic acid, and phosphoric acid. The reaction temperature is 20-80°C, preferably 60-70°C;

[0054] Step (d) The compound of formula V is subjected to methylation to obtain the compound of formula VI, wherein the methyl source reagent includes dimethyl sulfate, methyl iodide, dimethyl carbonate, triethyl orthoformate, and dimethyl phosphate, and the base potassium tert-butoxide can be replaced by potassium carbonate, sodium carbonate, sodium acetate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, triethylamine, diisopropylethylamine, LDA, and n-butyl lithium; the solvent can be replaced by DMF, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dioxane, isopropyl acetate, methyl tert-butyl ether, or a mixed solvent of any two or more thereof. The reaction temperature is -20-20°C; the molar ratio of the compound of formula V to the methyl source reagent is 1:1-8;

[0055] Step (e) The compound of formula VI is hydrolyzed to obtain the compound of formula VII, and the solvent includes any one of n-butanol, ethylene glycol, water, N,N-dimethylformamide, N,N-dimethylacetamide, tert-butanol, ammonium acetate, ammonium formate, toluene, and dioxane. The recrystallization system includes a methanol / water system, ethyl acetate, isopropyl acetate, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, methanol, ethanol, isopropanol, n-butanol, tert-butanol, dioxane, isopropyl acetate, methyl tert-butyl ether, or a mixed solvent of any two or more thereof. The reaction temperature is 100-140°C;

[0056] Step (f) Compound VII is subjected to iodination to obtain compound VIII. The iodine source can be any one of N-iododiformimide, elemental iodine, and potassium iodide. The reaction also includes one of methanesulfonic acid, sulfuric acid, and acetic acid. The solvent includes one of acetonitrile, ethanol, isopropanol, n-butanol, tert-butanol, ethylene glycol, dioxane, toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, N,N-dimethylformamide, and N,N-dimethylacetamide. The reaction temperature is 20 to 40° C. The molar ratio of compound VII to iodinated compound is 1:1 to 2.

[0057] Example 1

[0058]

[0059] Aluminum chloride (310 g, 2.35 mol) and DCM (1325 g) were added to a four-necked flask, and a mixed solution of ethylbenzene (100 g, 0.94 mol) and acetic anhydride (100.96 g, 0.99 mol) was slowly dripped into the reaction bottle, maintaining the temperature at -20 to -5°C for 1 to 1.5 hours. After the addition was completed, the temperature was maintained at -5 to 0°C for 1 to 3 hours. After the reaction was completed, the reaction solution was poured into crushed ice (1000 g) for quenching, washed with saturated sodium bicarbonate to a pH of 5-7, and the aqueous phase was extracted with DCM (500 mL × 3) and the organic phase was dried over anhydrous sodium sulfate. The inorganic salt was removed by filtration under reduced pressure, and the filter cake was rinsed with DCM (50 g). The organic phases were combined and concentrated to remove the solvent to obtain a brown-red liquid product 2 (134.00 g, yield 95.99%).

[0060] Example 2

[0061]

[0062] 4-Ethylacetophenone (134 g, 0.76 mol) and n-hexane (371.45 g) were added to a three-necked flask and stirred to dissolve. Methyl chloroacetate (148.36 g, 1.37 mol) was then added. Sodium methoxide (82.06 g, 1.52 mol) was slowly added and stirred to dissolve while maintaining an internal temperature of -20 to -5°C. The temperature was raised to an internal temperature of -5 to 0°C and the reaction was performed for 1 to 2 hours. After the reaction was completed, 371.45 g of n-hexane was added to the reaction flask, and 1340 g of tap water was added. The system was cooled to -5 to 0°C while stirring continuously. Stirring was continued for 1 hour and then the liquids were separated. The aqueous phase was extracted with EA (500 mL × 3). The organic phase was dried over anhydrous sodium sulfate. The inorganic salt was removed by filtration under reduced pressure. The filter cake was rinsed with EA (67 g). The organic phases were combined and concentrated to remove the solvent to obtain a brown-red liquid product 3 (166.00 g, yield 99.23%).

[0063] MS (ESI) m / z = 163.3 [M + H] +

[0064] Example 3

[0065]

[0066] 3-(4-ethylphenyl)-3-methyloxirane-2-carboxylic acid methyl ester (10 g, 45 mmol) and ethanol (79 g) were added to a three-necked flask, followed by sodium ethoxide (3.4 g, 50 mmol) and water (0.98 g, 54 mmol). The reaction was stirred at 20-35°C for 4-6 h. After the reaction was completed, the reaction system was cooled to an internal temperature of -5-0°C and stirred for 1 h. An off-white solid was precipitated, which was filtered and dried to obtain a light yellow solid product 4 as a sodium salt (7.13 g, yield 96.80%).

[0067] Example 4

[0068]

[0069] 2-(4-ethylphenyl)propanal (53.85 g, 0.33 mol) and anhydrous formic acid (218.09 g) were added to a three-necked flask and stirred to dissolve. Hydroxylamine hydrochloride (24.38 g, 0.35 mol), anhydrous sodium acetate (47.96 g, 0.58 mol) and acetic anhydride (44.76 g, 0.44 mol) were then added. The mixture was heated to 60-70°C and stirred for 2-3 h. After the reaction, the reaction system was cooled to an internal temperature of 25-30°C, water (150 g) was added, the pH was adjusted to 9, MTBE (150 mL) was added, and the mixture was stirred for 1 h before separation. The aqueous phase was extracted with MTBE (100 mL × 3), the organic phase was dried over anhydrous sodium sulfate, and the inorganic salt was removed by filtration under reduced pressure. The filter cake was then rinsed with MTBE (53 g), the organic phases were combined, and the solvent was removed by concentration to obtain a brown-red liquid product 5 (52.11 g, yield 98.6%).

[0070] Example 5

[0071]

[0072] 2-(4-ethylphenyl)propionitrile (30.0 g, 0.19 mol) and DMF (282 g) were added to a three-necked flask, the reaction system was cooled to -20-0°C, potassium tert-butoxide (42.28 g, 0.38 mol) was added and stirred for 0.5 h, and then dimethyl sulfate (118.82 g, 0.94 mol) was added and stirred for 0.5 h, and then the temperature was controlled to -5-0°C and stirred for 0.5-1 h. After the reaction, water (100 g) was added to the reaction flask for quenching, the pH was adjusted to 9-10, MTBE (150 mL) was added, and the mixture was separated after stirring for 1 h. The aqueous phase was extracted with MTBE (100 mL×3), the organic phase was dried over anhydrous sodium sulfate, and the inorganic salt was removed by filtration under reduced pressure. The filter cake was rinsed with MTBE (30 g), the organic phases were combined, and the solvent was removed by concentration to obtain a brown-red liquid product 6 (32.00 g, yield 98.01%).

[0073] 1H NMR (400MHz, DMSO) δ = 7.72 (d, J = 2.0, 1H), 7.31 (dd, J = 8.0, 2.0, 1H), 7.24 (d, J = 8.1, 1H), 2.63 (q, J = 7.5, 2H), 1.44 (s, 6H), 1.11 (t, J = 7.5, 3H).

[0074] Example 6

[0075]

[0076] Add 2-(4-ethylphenyl)-2-methylpropionitrile (35 g, 0.20 mol) to a three-necked flask, add n-butanol (28.35 g), water (30 g), and then add potassium hydroxide (68 g, 1.21 mol) and heat to 100-125°C and stir to dissolve. Control the system temperature between 110 and 125°C to react for 12-15 hours. After the reaction is completed, cool the reaction system to 25-30°C, add MTBE (100 mL) to the reaction flask, and continue to heat. After stirring for 1 h, the liquids were separated, the organic phase was extracted with water (100 mL×3), the aqueous phases were combined and the pH was adjusted to 1 with hydrochloric acid, MTBE (300 mL) was added to the aqueous phase and stirring was continued for 1 h, the liquids were separated, the aqueous phase was extracted with MTBE (100 mL×3), the organic phase was dried over anhydrous sodium sulfate, the inorganic salt was removed by filtration under reduced pressure, the filter cake was rinsed with MTBE (35 g), the organic phases were combined and concentrated to remove the solvent to obtain a red crystalline solid product 7 (37.09 g, yield 95.60%).

[0077] MS (ESI) m / z = 191.0 [M + H] -

[0078] Example 7

[0079]

[0080] 2-(4-Ethylphenyl)-2-methylpropanoic acid 7 (1 g, 5.2 mmol), acetonitrile (2.37 g), NIS (1.29 g, 5.7 mmol) and methanesulfonic acid (0.72 g, 7.8 mmol) were added to the reaction bottle, and the mixture was stirred at 20-35°C for 12-16 h. After the reaction was completed, the reaction was quenched with 10% sodium bisulfite, and stirred at -5-0°C for 1 h. The mixture was allowed to stand for 0.5 h, and filtered under reduced pressure to collect the filter cake. The filter cake was washed with acetonitrile (2 mL×3), and the filter cake was recrystallized from acetonitrile to obtain white crystalline solid compound 8 (1.54 g, yield 93.06%).

[0081] MS (ESI) m / z = 317.0 [M + H] - .

Claims

1. A method for synthesizing an alectinib intermediate compound of formula III, characterized in that: The compound of formula II reacts with a halogenated carboxylic acid ester under strong alkaline conditions to generate a compound of formula III, Among them, X is Cl, Br, I; R1 is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl.

2. The synthesis method according to claim 1, characterized in that: The molar ratio of the compound of formula II to the strong base is 1:1-5.

3. The synthesis method according to claim 1, characterized in that: The molar ratio of the compound of formula II to the halogenated carboxylic acid ester is 1:1-5.

4. The synthesis method according to claim 3, characterized in that: The halogenated carboxylic acid ester includes any one of ethyl chloroacetate, methyl bromoacetate, ethyl bromoacetate and methyl chloroacetate.

5. The synthesis method according to claim 4, characterized in that: The strong base includes any one of potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, LDA, and n-butyllithium.

6. The synthesis method according to claim 5, characterized in that: The reaction temperature is -30 to 30°C.

7. A method for synthesizing an alectinib intermediate 2-(4-ethyl-3-iodophenyl)-2-methylpropionic acid, characterized in that: (a) the compound of formula II reacts with a halogenated carboxylic acid ester under strong alkaline conditions to produce a compound of formula III, X is Cl, Br, I; R1 is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl; (b) the compound of formula III is hydrolyzed under alkaline conditions to generate the compound of formula IV, (c) reacting the compound of formula IV with a cyanation reagent to obtain a compound of formula V, (d) the compound of formula V is subjected to methylation to obtain the compound of formula VI, (e) hydrolyzing the compound of formula VI to obtain a compound of formula VII, (f) iodine the compound of formula VII to obtain the compound of formula VIII, 8. A method for synthesizing an alectinib intermediate 2-(4-ethyl-3-iodophenyl)-2-methylpropionic acid according to claim 7, characterized in that: The molar ratio of the compound of formula IV in step (c) to the cyanation reagent is 1:1-2; the molar ratio of the compound of formula V in step (d) to the methyl source reagent is 1:1-8; and the molar ratio of the compound of formula VII in step (f) to the iodine compound is 1:1-2.

9. A method for synthesizing an alectinib intermediate 2-(4-ethyl-3-iodophenyl)-2-methylpropionic acid according to claim 8, characterized in that: The reaction temperature of step (b) is 20-35°C; the reaction temperature of step (c) is 60-70°C; the reaction temperature of step (d) is -20-20°C; the reaction temperature of step (e) is 100-140°C; and the reaction temperature of step (f) is 20-40°C.

10. The synthesis method according to any one of claims 7 to 9, characterized in that: The compound of formula II is prepared from ethylbenzene and acetic anhydride, the molar mass ratio of ethylbenzene to acetic anhydride is 1:1-2, and the reaction temperature is -20-30°C.

Images