Preparation method of nedoromil intermediate

Abstract

The invention relates to the field of organic chemical synthesis, in particular to a preparation method of a nedoromil intermediate. Specifically, m-chlorophenol is used as an initial raw material, 3-chlorophenyl allyl ether is obtained through an etherification reaction, then 3-chloro-4, 6-diacetyl phenyl allyl ether is obtained through a Friedel-Crafts acylation reaction, and finally 3-allyloxy-4, 6-diacetyl-N-ethylaniline is obtained through a substitution reaction. Appropriate solvents and reaction conditions are selected, the method has the advantages of being novel in route, mild in reaction condition, simple and convenient in post-treatment method, stable in process, capable of achieving industrial production and the like, and a new thought is provided for preparation of nedoromil.

Description

Technical Field

[0001] The present invention relates to the field of organic chemical synthesis, and more particularly to a method for preparing a nedocromil intermediate. Background Art

[0002] Nedocromil is a drug with anti-inflammatory effects, which mainly exerts its effects by inhibiting the release of various inflammatory mediators. It is commonly used clinically for the prevention and treatment of bronchial asthma. Especially for the long-term maintenance treatment of mild and moderate asthma patients, it has good effects. It can also be used to relieve some symptoms of allergic rhinitis. It can reduce the inflammation of the nasal mucosa, reduce discomfort manifestations such as runny nose, sneezing, and nasal itching, and help patients improve the related symptoms of the nose. 3-Allyloxy-4,6-diacetyl-N-ethylaniline is an important intermediate for the synthesis of nedocromil, with the molecular formula C 15 H 19 NO3 and a molecular weight of 261.32.

[0003] Its structural formula is:

[0004]

[0005] The existing preparation methods of 3-allyloxy-4,6-diacetyl-N-ethylaniline mainly include the following several:

[0006] (1) The preparation method of the European patent: Using m-methoxyaniline as the starting material, through N-acylation reaction, Friedel-Crafts acylation reaction, demethylation reaction, Friedel-Crafts acylation reaction, substitution reaction, and etherification reaction to prepare 3-allyloxy-4,6-diacetyl-N-ethylaniline. In this method, the first Friedel-Crafts acylation product was not separated to remove the by-products therein, and the ether bond cleavage was incomplete, resulting in a final product yield of less than 20%. Reference: EP0030423

[0007]

[0008] (2) The preparation method of the domestic patent: Using m-methoxyaniline as the starting material, through N-acylation reaction, Friedel-Crafts acylation reaction, demethylation reaction, Friedel-Crafts acylation reaction, substitution reaction, and etherification reaction to prepare 3-allyloxy-4,6-diacetyl-N-ethylaniline. Although this method separated the by-products of the first Friedel-Crafts acylation reaction, due to the long route, complex operation, and the total yield of less than 40%. Reference: CN2011104389087

[0009]

[0010] (3) Preparation method of other references: Using m-methoxyaniline as the starting material, 3-allyloxy-4,6-diacetyl-N-ethylaniline is prepared through N-acylation reaction, Friedel-Crafts acylation reaction, substitution reaction, and etherification reaction. In this method, both the Friedel-Crafts acylation reaction and the ether bond cleavage reaction are incomplete, resulting in low purity of the final product and an actual total yield of less than 15%. Reference: Modern Drugs & Clinical Medicine, 2011, Vol. 25, No. 2 (P142-144)

[0011]

[0012] According to the above literature reports, the existing preparation methods have long steps and low yields. Now, a new preparation method for nadolemy intermediate is needed, which is novel in process, convenient to operate, high in safety, high in yield, and more suitable for large-scale production. Summary of the Invention

[0013] The present invention provides a new preparation method for nadolemy intermediate in view of the above problems.

[0014] The object of the present invention can be achieved by the following technical solutions:

[0015] A preparation method for nadolemy intermediate, the reaction formula is as follows:

[0016]

[0017] Using m-chlorophenol as the starting material, 3-chlorophenyl allyl ether is obtained through etherification reaction, 3-chloro-4,6-diacetylphenyl allyl ether is obtained through Friedel-Crafts acylation reaction, and finally 3-allyloxy-4,6-diacetyl-N-ethylaniline is obtained through substitution reaction.

[0018] Furthermore,

[0019] Step 1) Preparation of 3-chlorophenyl allyl ether: Using m-chlorophenol as the raw material, under alkaline conditions, allyl bromide is added dropwise at 20-80 °C with stirring for 1-5 h for etherification reaction, and 3-chlorophenyl allyl ether is obtained after the reaction;

[0020] Step 2) Preparation of 3-chloro-4,6-diacetylphenyl allyl ether: Mixing a Lewis acid and an aprotic solvent to obtain a mixed solution A, slowly adding an acylating agent dropwise to the mixed solution A at -10-10 °C to obtain a mixed solution B. After the addition is complete, a mixed solvent of 3-chlorophenyl allyl ether and an aprotic solvent is added dropwise to the mixed solution B. After the addition is complete, the reaction is stirred under nitrogen protection at 30-60 °C for 12-48 h for Friedel-Crafts acylation reaction, and 3-chloro-4,6-diacetylphenyl allyl ether is obtained after purification of the reaction;

[0021] Step 3) Preparation of 3-allyloxy-4,6-diacetyl-N-ethylaniline: 3-chloro-4,6-diacetylphenyl allyl ether is added dropwise with an aqueous solution of ethylamine under stirring at room temperature in the presence of a base. After the addition, it is sealed and reacted at 70 - 100 °C for 2 - 8 h for a substitution reaction, and then purified to obtain 3-allyloxy-4,6-diacetyl-N-ethylaniline.

[0022] In the said Step 1) and Step 3), the base can be the same or different and is selected from one or several mixtures of potassium carbonate, sodium hydroxide, and potassium hydroxide. The preferred base is potassium carbonate.

[0023] The said Step 1) etherification reaction: m-chlorophenol and a base are added to DMF, and after heating to 20 - 80 °C (preferably 50 - 70 °C) and stirring for 30 min, allyl bromide is added dropwise to the reaction solution, and the reaction continues to stir at this temperature for 1 - 5 h (preferably the reaction time is 2 - 4 h). After the reaction, it is cooled to room temperature and then poured into water under stirring. It is extracted three times with ethyl acetate. The organic phases are combined, washed with saturated brine until neutral, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, and the solvent is concentrated to obtain 3-chlorophenyl allyl ether.

[0024] The molar ratio of m-chlorophenol, the base, and allyl bromide in the said Step 1) is 1:2:1 - 2, and the preferred molar ratio is 1:2:1 - 1.5.

[0025] The said Step 2) Mix the Lewis acid and an aprotic solvent to obtain a mixed solution A. Slowly add the acylating reagent dropwise to the mixed solution A at -10 - 10 °C to obtain a mixed solution B. After the addition, add a mixed solvent of 3-chlorophenyl allyl ether and an aprotic solvent dropwise to the mixed solution B, and then stir at 30 - 60 °C (preferably the reaction temperature is 40 - 50 °C) under nitrogen protection for a Friedel-Crafts acylation reaction for 12 - 48 h (preferably the reaction time is 24 - 36 h). After the reaction is completed, pour the reaction solution into ice water under stirring, and a solid precipitates. The solid is filtered off, and the aqueous phase is repeatedly extracted with an aprotic solvent (usually three times). The organic phases are combined, washed with saturated sodium bicarbonate aqueous solution until neutral, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, and the solvent is concentrated to remove to obtain 3-chloro-4,6-diacetylphenyl allyl ether.

[0026] The molar ratio of 3-chlorophenyl allyl ether, the Lewis acid, and the acylating reagent in the said Step 2) is 1:10:5 - 25, and the preferred molar ratio is 1:10:15 - 25; among them, the Lewis acid is one or several mixtures of anhydrous zinc chloride, anhydrous aluminum chloride, and anhydrous iron chloride; the acylating reagent is one or several mixtures of acetyl chloride and acetic anhydride; the aprotic solvent is one or several mixtures of dichloromethane, chloroform, and 1,2-dichloroethane.

[0027] The above 3-chlorophenyl allyl ether: aprotic solvent = 1 mol: 500 ml, Lewis acid: aprotic solvent = 1 mol: 200 ml; during extraction, 3-chlorophenyl allyl ether: aprotic solvent = 1 mol: 2000 ml.

[0028] In the substitution reaction of step 3): Add 3-chloro-4,6-diacetylphenyl allyl ether and a base to DMF, stir at room temperature for 1 h, dropwise add an aqueous solution of ethylamine to the reaction solution, raise the temperature of the reaction solution to 70 - 100 °C (preferably the reaction temperature is 70 - 90 °C) under sealed conditions, stir for the substitution reaction for 2 - 8 h (preferably the reaction time is 6 - 8 h). After the reaction, cool the reaction solution to room temperature, pour it into water with stirring, a solid will precipitate, filter, wash with pure water, dry under reduced pressure, and recrystallize with absolute ethanol to obtain 3-allyloxy-4,6-diacetylaniline.

[0029] The molar ratio of the 3-chloro-4,6-diacetylphenyl allyl ether, the base and ethylamine is 1: 1.1: 2 - 6, preferably the molar ratio is 1: 1.1: 4 - 6; wherein, the concentration of the aqueous solution of ethylamine is 40 - 80% (preferably the concentration of the aqueous solution of ethylamine is 50 - 80%).

[0030] In the recrystallization in step 3), the feeding ratio of 3-chloro-4,6-diacetylphenyl allyl ether to absolute ethanol is 1 g: 5 - 10 ml, preferably the feeding ratio is 1 g: 5 - 7 ml.

[0031] Advantages of the present invention:

[0032] The present invention selects appropriate solvents and reaction conditions, and has the advantages of novel route, mild reaction conditions, simple post-treatment method, stable process, and industrial production feasibility, providing a new idea for the preparation of nedocromil. Specific examples

[0033] The exemplary embodiments of the present disclosure will be described in more detail below with reference to the examples. Although the exemplary embodiments of the present disclosure are shown, it should be understood that the present disclosure can be implemented in various forms and should not be limited by the embodiments set forth herein. On the contrary, these embodiments are provided so that the present disclosure can be more thoroughly understood and the scope of the present disclosure can be fully communicated to those skilled in the art.

[0034] The present invention selects appropriate solvents and reaction conditions, and has the advantages of novel route, mild reaction conditions, simple post-treatment method, stable process, and industrial production feasibility, providing a new idea for the preparation of nedocromil.

[0035] Investigation of influencing factors of etherification reaction

[0036] Example 1

[0037] 12.85 g (0.1 mol) of m-chlorophenol and 27.6 g (0.2 mol) of potassium carbonate were added to 200 ml of DMF. After the reaction solution was heated to 60 °C and stirred for 30 min, 13.31 g (0.11 mol) of allyl bromide was added dropwise to the reaction solution, and stirring was continued for 3 h until the end point. After the reaction solution was cooled to room temperature, it was poured into 2 L of water with stirring. The aqueous solution was extracted with ethyl acetate (3 × 100 ml). The combined organic phases were washed with 100 ml of saturated brine until the pH was neutral, dried over 20 g of anhydrous sodium sulfate for 8 h. Sodium sulfate was removed by filtration, and the solvent was concentrated to obtain 16.56 g of 3-chlorophenyl allyl ether, with a yield of 97.3% and a purity of 99.0%.

[0038] Example 2

[0039] The difference from Example 1 was that the feeding amounts of m-chlorophenol, potassium carbonate and allyl bromide were 12.85 g (0.1 mol): 27.6 g (0.2 mol): 12.1 g (0.1 mol) or 12.85 g (0.1 mol): 27.6 g (0.2 mol): 18.15 g (0.15 mol) respectively. Other conditions were the same as in Example 1. 16.40 g of 3-chlorophenyl allyl ether was obtained, with a yield of 95.6% and a purity of 98.2% (1:2:1), and 16.51 g, with a yield of 97.1% and a purity of 99.1% (1:2:1.5).

[0040] Example 3

[0041] The difference from Example 1 was that the reaction temperatures were 50 °C or 70 °C respectively. Other conditions were the same as in Example 1. 16.44 g of 3-chlorophenyl allyl ether was obtained, with a yield of 96.5% and a purity of 98.9% (50 °C), and 16.54 g, with a yield of 97.2% and a purity of 99.0% (70 °C).

[0042] Example 4

[0043] The difference from Example 1 was that the reaction times were 2 h or 4 h respectively. Other conditions were the same as in Example 1. 14.37 g of 3-chlorophenyl allyl ether was obtained, with a yield of 84.0% and a purity of 98.5% (2 h), and 16.54 g, with a yield of 97.0% and a purity of 98.8% (4 h).

[0044] Through the above experiments, the effects of factors such as feeding ratio, reaction temperature and reaction time on the yield and purity of the etherification reaction were investigated respectively. When the molar ratio of m-chlorophenol, potassium carbonate and allyl bromide was 1:2:1.1, the reaction temperature was 60 °C, and the reaction time was 3 h, the yield of the product was greater than 97%, and the purity was greater than 99%. Considering the comprehensive cost factors, under these conditions, the yield and purity were optimal.

[0045] Investigation of Influencing Factors on Friedel-Crafts Acylation Reaction

[0046] Example 5

[0047] 133.5 g (1.0 mol) of anhydrous aluminum trichloride and 200 ml of dichloromethane were added to a reaction flask. At -5 °C, 157.0 g (2.0 mol) of acetyl chloride was slowly added dropwise to the reaction solution. After the addition was complete, a mixed solvent of 17.02 g (99%, 0.1 mol) of 3-chlorophenyl allyl ether obtained under the above optimal etherification reaction conditions and 50 ml of dichloromethane was added dropwise to the reaction solution. After the addition was complete, the reaction solution was raised to 45 °C and stirred under nitrogen protection for 30 h until the end point. After the reaction was completed, the reaction solution was poured into 2 L of ice water with stirring, and a solid precipitated. The solution was filtered to remove the solid, and the aqueous phase was extracted with dichloromethane (2 × 100 ml). The organic phases were combined, washed with 200 ml of saturated sodium bicarbonate aqueous solution until neutral, and dried over 30 g of anhydrous sodium sulfate for 8 h. The sodium sulfate was filtered off, and the solvent was concentrated to obtain 18.67 g of 3-chloro-4,6-diacetylphenyl allyl ether, with a yield of 73.5% and a purity of 99.4%.

[0048] Example 6

[0049] The Lewis acid was changed from anhydrous aluminum trichloride to anhydrous zinc chloride or anhydrous iron chloride respectively, and other conditions were the same as in Example 5. The obtained 3-chloro-4,6-diacetylphenyl allyl ether was 7.64 g, with a yield of 24.6% and a purity of 81.3% (anhydrous zinc chloride) and 13.51 g, with a yield of 51.2% and a purity of 95.7% (anhydrous iron chloride).

[0050] Example 7

[0051] The acylating agent was changed to acetic anhydride, and other conditions were the same as in Example 5. The obtained 3-chloro-4,6-diacetylphenyl allyl ether was 12.82 g, with a yield of 48.8% and a purity of 96.1%.

[0052] Example 8

[0053] The feeding amounts of 3-chlorophenyl allyl ether, anhydrous aluminum trichloride and acetyl chloride were 17.02 g (99%, 0.1 mol): 133.5 g (1.0 mol): 117.75 g (1.5 mol) or 17.02 g (99%, 0.1 mol): 133.5 g (1.0 mol): 196.25 g (2.5 mol) respectively, and other conditions were the same as in Example 5. The obtained 3-chloro-4,6-diacetylphenyl allyl ether was 13.86 g, with a yield of 53.7% and a purity of 97.8% (1:10:15) and 18.63 g, with a yield of 72.9% and a purity of 98.8%

[0054] Example 9

[0055] The reaction temperatures were 40 °C or 50 °C respectively, and other conditions were the same as in Example 5. The obtained 3-chloro-4,6-diacetylphenyl allyl ether was 15.81 g respectively, with a yield of 61.1% and a purity of 97.6% (40 °C), and 23.94 g, with a yield of 78.4% and a purity of 82.7%.

[0056] Example 10

[0057] The reaction times were 24 h or 36 h respectively, and other conditions were the same as in Example 5. The obtained 3-chloro-4,6-diacetylphenyl allyl ether was 16.43 g respectively, with a yield of 64.3% and a purity of 98.8% (reaction time was 24 h), and 18.84 g, with a yield of 74.1% and a purity of 99.3% (reaction time was 36 h).

[0058] Through the above experiments, the effects of factors such as Lewis acid, acylating agent, feeding ratio, reaction temperature and reaction time on the yield and purity of the Friedel-Crafts acylation reaction were investigated respectively. When anhydrous aluminum chloride was used as the Lewis acid, both the yield and purity were the best; when acetyl chloride was used as the acylating agent, both the yield and purity were better than those when acetic anhydride was used as the acylating agent; when the molar feeding ratio of 3-chlorophenyl allyl ether, anhydrous aluminum chloride and acetyl chloride was 1:10:20, the reaction temperature was 45 °C, and the reaction time was 30 h, the yield of the product was greater than 70%, and the purity was greater than 99%. Considering the cost and other factors, under these conditions, the yield and purity were the optimal.

[0059] Investigation of influencing factors of substitution reaction

[0060] Example 11

[0061] 15.3 g (99%, 0.06 mol) of 3-chloro-4,6-diacetylphenyl allyl ether obtained under the optimal reaction conditions of the above Friedel-Crafts acylation and 2.64 g (0.066 mol) of sodium hydroxide were added to 150 ml of DMF, and stirred at room temperature for 1 h. 19.3 g (70%, 0.3 mol) of aqueous ethylamine solution was added dropwise to the reaction solution. The reaction flask was sealed, and the reaction solution was heated to 80 °C and stirred for 7 h until the end point. After the reaction solution was cooled to room temperature, it was poured into 1 L of water with stirring, and a solid precipitated. It was filtered, washed with pure water, dried under reduced pressure, and recrystallized from absolute ethanol to obtain 13.98 g of 3-allyloxy-4,6-diacetyl-N-ethylaniline, with a yield of 88.9% and a purity of 99.6%. 11H-NMR (600 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.27 (s, 1H), 6.20 (s, 1H), 6.16 - 5.48 (dd, J = 17.3, 1.5 Hz, 1H), 5.34 (dd, J = 10.6, 1.3 Hz, 1H), 4.78 (d, J = 5.4 Hz, 2H), 3.30 (dd, J = 7.1, 5.4 Hz, 2H), 3.30 (dd, J = 7.1, 5.4 Hz, 6H), 2.49 (d, J = 12.1 Hz, 9H), 1.22 (t, J = 7.2 Hz, 4H).

[0062] Example 12

[0063] The feeding amounts of 3-chloro-4,6-diacetylphenyl allyl ether, sodium hydroxide and ethylamine were 15.3 g (99%, 0.06 mol): 2.64 g (0.066 mol): 15.43 g (70%, 0.24 mol) or 15.3 g (99%, 0.06 mol): 2.64 g (0.066 mol): 23.14 g (70%, 0.36 mol) respectively. Under other conditions the same as in Example 11, 3-allyloxy-4,6-diacetyl-N-ethylaniline obtained was 13.04 g with a yield of 82.6% and a purity of 99.2% and 14.05 g with a yield of 89.2% and a purity of 99.4% respectively.

[0064] Example 13

[0065] The reaction temperatures were 70 °C or 90 °C respectively. Under other conditions the same as in Example 11, 3-allyloxy-4,6-diacetyl-N-ethylaniline obtained was 12.94 g with a yield of 81.8% and a purity of 99.0% and 14.01 g with a yield of 89.0% and a purity of 99.5% respectively.

[0066] Example 14

[0067] The reaction times were 6 h or 8 h respectively. Under other conditions the same as in Example 11, 3-allyloxy-4,6-diacetyl-N-ethylaniline obtained was 12.54 g with a yield of 79.1% and a purity of 98.8% and 14.05 g with a yield of 89.1% and a purity of 99.3% respectively.

[0068] Example 15

[0069] 14.12 g (92.4%, 0.05 mol) of the crude product of 3-allyloxy-4,6-diacetyl-N-ethylaniline was recrystallized with absolute ethanol at a ratio of 1 g : 4 ml, 1 g : 5 ml, or 1 g : 6 ml, respectively, to obtain 12.35 g of 3-allyloxy-4,6-diacetyl-N-ethylaniline with a yield of 93.3% and a purity of 98.6% (1 g : 4 ml); 12.04 g with a yield of 91.9% and a purity of 99.6% (1 g : 5 ml); and 11.44 g with a yield of 87.4% and a purity of 99.7% (1 g : 6 ml).

[0070] Through the above experiments, the effects of factors such as the feed ratio, reaction temperature, reaction time, and recrystallization conditions on the yield and purity of the substitution reaction were investigated. When the molar ratio of 3-chloro-4,6-diacetylphenyl allyl ether, sodium hydroxide, and ethylamine was 1 : 1.1 : 5, the reaction temperature was 80 °C, and the reaction time was 7 h, both the yield and purity were the best; when the feed ratio for recrystallization was 1 g : 5 ml, the recrystallization effect was the best. Considering the cost and other factors, the above reaction conditions, yield, and purity were the optimal ones.

[0071] The above are only the preferred specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, making equivalent substitutions or changes, should be covered by the protection scope of the present invention.

Claims

1. A method for preparing a nedocromil intermediate, characterized in that, The reaction formula is as follows: Using m-chlorophenol as the starting material, 3-chlorophenyl allyl ether is obtained through an etherification reaction, then 3-chloro-4,6-diacetylphenyl allyl ether is obtained through a Friedel-Crafts acylation reaction, and finally 3-allyloxy-4,6-diacetyl-N-ethylaniline is obtained through a substitution reaction.

2. The preparation method of the nedocromil intermediate according to claim 1, wherein Step 1) Preparation of 3-chlorophenyl allyl ether: Using m-chlorophenol as the raw material, under alkaline conditions, allyl bromide is added dropwise at 20-80 °C with stirring for 1-5 h for the etherification reaction, and 3-chlorophenyl allyl ether is obtained after the reaction. Step 2) Preparation of 3-chloro-4,6-diacetylphenyl allyl ether: Mix a Lewis acid and an aprotic solvent to obtain a mixed solution A. At -10-10 °C, the acylating reagent is slowly added dropwise to the mixed solution A to obtain a mixed solution B. After the addition is complete, a mixed solvent of 3-chlorophenyl allyl ether and an aprotic solvent is added dropwise to the mixed solution B, and then the Friedel-Crafts acylation reaction is carried out with stirring under nitrogen protection at 30-60 °C for 12-48 h. After the reaction, it is purified to obtain 3-chloro-4,6-diacetylphenyl allyl ether. Step 3) Preparation of 3-allyloxy-4,6-diacetyl-N-ethylaniline: In the presence of a base, an aqueous solution of ethylamine is added dropwise to 3-chloro-4,6-diacetylphenyl allyl ether with stirring at room temperature. After the addition, it is sealed at 70-100 °C for the substitution reaction for 2-8 h, and after purification, 3-allyloxy-4,6-diacetyl-N-ethylaniline is obtained.

3. The preparation method of the nedocromil intermediate according to claim 2, characterized in that, The base in the said Step 1) and Step 3) can be the same or different and is selected from one or several mixtures of potassium carbonate, sodium hydroxide, and potassium hydroxide.

4. The method for preparing the nedocromil intermediate according to claim 2 or 3, characterized in that, The etherification reaction in the said Step 1): Add m-chlorophenol and the base to DMF, raise the temperature to 20-80 °C and stir for 30 min, then add allyl bromide dropwise to the reaction solution, continue to stir at this temperature for the etherification reaction for 1-5 h. After the reaction, cool to room temperature and stir and pour into water, extract three times with ethyl acetate, combine the organic phases, wash with saturated brine until neutral, dry with anhydrous sodium sulfate, filter to remove sodium sulfate, and concentrate the solvent to obtain 3-chlorophenyl allyl ether.

5. The preparation method of the nedocromil intermediate according to claim 4, characterized in that, The molar ratio of m-chlorophenol, the base, and allyl bromide in the said Step 1) is 1:2:1-2.

6. The preparation method of the nedocromil intermediate according to claim 2, characterized in that, In the said Step 2), mix a Lewis acid and an aprotic solvent to obtain a mixed solution A. At -10-10 °C, the acylating reagent is slowly added dropwise to the mixed solution A to obtain a mixed solution B. After the addition is complete, a mixed solvent of 3-chlorophenyl allyl ether and an aprotic solvent is added dropwise to the mixed solution B, and then the Friedel-Crafts acylation reaction is carried out with stirring under nitrogen protection at 30-60 °C for 12-48 h. After the reaction is completed, stir the reaction solution and pour it into ice water, and a solid precipitates. Filter the solution to remove the solid, and repeatedly extract the aqueous phase with an aprotic solvent. Combine the organic phases, wash with saturated sodium bicarbonate aqueous solution until neutral, dry with anhydrous sodium sulfate, filter to remove sodium sulfate, and concentrate to remove the solvent to obtain 3-chloro-4,6-diacetylphenyl allyl ether.

7. The method for preparing the nedocromil intermediate according to claim 2 or 6, characterized in that, The molar ratio of 3-chlorophenyl allyl ether, Lewis acid and acylating agent in the step 2) is 1:10:5-25; wherein, the Lewis acid is one or a mixture of several of anhydrous zinc chloride, anhydrous aluminum chloride and anhydrous iron chloride; the acylating agent is one or a mixture of several of acetyl chloride and acetic anhydride; the aprotic solvent is one or a mixture of several of dichloromethane, chloroform and 1,2-dichloroethane.

8. The preparation method of the nedocromil intermediate according to claim 2, characterized in that, The substitution reaction in the step 3): Add 3-chloro-4,6-diacetylphenyl allyl ether and base into DMF, stir at room temperature for 1 h, dropwise add aqueous ethylamine solution to the reaction solution, raise the temperature of the reaction solution to 70-100 °C under sealed conditions and stir for 2-8 h for the substitution reaction. After the reaction, cool the reaction solution to room temperature, pour it into water with stirring, and a solid will precipitate. Filter, wash with pure water, dry under reduced pressure, and recrystallize with absolute ethanol to obtain 3-allyloxy-4,6-diacetyl-N-ethylaniline.

9. The method for preparing the nedocromil intermediate according to claim 2 or 8, characterized in that, The molar ratio of 3-chloro-4,6-diacetylphenyl allyl ether, base and ethylamine is 1:1.1:2-6, wherein the concentration of the aqueous ethylamine solution is 40-80%.

10. The preparation method of the nedocromil intermediate according to claim 8, wherein, The feeding ratio of 3-chloro-4,6-diacetylphenyl allyl ether to absolute ethanol in the recrystallization in the step 3) is 1 g:5-10 ml.

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