Synthesis process of benzazon important intermediate 2-ethyl benzofuran

Abstract

The invention belongs to the technical field of chemical pharmaceuticals, and discloses a synthesis process of a benzazin heavy key intermediate 2-ethyl benzofuran, which comprises the following steps: step S10, taking salicylaldehyde SM1 and chloroacetone SM2 as initial raw materials, and adding an alcohol solvent and a strong alkali solution to synthesize a compound A; step S20, carrying out hydrogenation reduction reaction on the compound A to obtain 2-ethylbenzofuran TM; raw materials used in the scheme are cheap and easy to obtain, reaction steps are few, and synchronous recovery of the solvent is facilitated; reaction conditions are mild, equipment requirements are low, and production cost is low; the method is simple to operate, small in environmental pollution and suitable for industrial large-scale production; the invention solves the problem that the existing benzarone synthesis process is difficult for industrial scale production.

Description

Technical Field

[0001] The present invention belongs to the field of chemical pharmaceutical technology, and specifically relates to a synthesis process of 2-ethylbenzofuran, an important intermediate of benzalone. Background Art

[0002] Benzalone, chemical name 2-ethyl-3-(4-hydroxybenzoyl)benzofuran, molecular formula C 17 H 14 O 3， It is a compound that is structurally similar to benzbromarone but does not contain bromine. As a highly effective anti-hemorrhagic drug, it has a significant effect on the treatment of bleeding diseases caused by impaired hemostasis, which are caused by decreased platelet count or dysfunction, vascular wall damage, or abnormal coagulation function. In addition to its application in the treatment of blood diseases, benzbromarone can also bind to multifunctional proteins to form effective anti-cancer inhibitors, especially showing potential in the treatment of ovarian cancer and breast cancer. In addition, benzbromarone can inhibit uric acid synthesis, so it is also used to treat kidney diseases.

[0003] In the production process of benzalone, 2-ethylbenzofuran is a key intermediate. Referring to the existing existing publication (announcement) number CN106065010A, a compound for treating or preventing hyperuricemia or gout is disclosed, salicylaldehyde (SM1) is used as a starting material, reacts with chloroacetone (SM2) to generate compound A, and then 2-ethylbenzofuran is obtained by hydrazine hydrate reaction. Referring to the existing existing publication (announcement) number CN109734686A, a catalytic synthesis method of 2-substituted benzofuran compounds is disclosed, using 2-(2-ethyl) ethynylphenol, 2-ethylbenzofuran is synthesized under the catalysis of cuprous chloride and cesium carbonate. Pu Shouzhi, Wang Renjie, Liu Gang, Liu Weijun, Cui Shiqiang, Yan Peijian and others published a method for synthesizing 2-ethylbenzofuran by reacting benzofuran with ethyl bromide under the catalysis of n-butyl lithium; disclosed the synthesis of 2-ethylbenzofuran, an important intermediate of benzalone, using salicylaldehyde SM1 as the starting material and chloroacetone SM2 to synthesize compound A; compound A was reacted with hydrazine hydrate to obtain 2-ethylbenzofuran. After the method uses hydrazine hydrate reaction, a large amount of wastewater that needs to be treated is generated, and there is a large amount of waste gas, which has safety hazards and is difficult to treat, and it is difficult to meet the requirements of large-scale industrial production. Summary of the invention

[0004] The purpose of this scheme is to provide a synthesis process of 2-ethylbenzofuran, an important intermediate of benzalone, so as to solve the problem that the existing benzalone synthesis process is difficult to produce on an industrial scale.

[0005] In order to achieve the above object, the present invention provides a synthesis process of 2-ethylbenzofuran, an important intermediate of benzalone, comprising the following steps:

[0006] Step S10: using salicylaldehyde SM1 and chloroacetone SM2 as starting materials, adding an alcohol solvent and a strong base solution to synthesize compound A;

[0007] Step S20: Compound A is subjected to hydrogenation reduction reaction to obtain 2-ethylbenzofuran TM.

[0008] The effects of this scheme are: the raw materials used in this scheme are cheap and easy to obtain, and the fewer reaction steps are more conducive to the simultaneous recovery of the solvent; the reaction conditions are mild, the equipment requirements are low, and the production cost is low; the operation is simple, the environmental pollution is small, and it is suitable for large-scale industrial production.

[0009] Furthermore, in step S10, the alcohol solvent is one of methanol, ethanol, isopropanol, and ethylene glycol; and the strong alkaline solution is sodium hydroxide or potassium hydroxide.

[0010] Furthermore, the alcohol solvent is ethylene glycol; and the strong alkaline solution is sodium hydroxide.

[0011] Furthermore, the molar ratio of salicylaldehyde SM1, chloroacetone SM2 and sodium hydroxide is 1:1.1-1.8:1-1.5.

[0012] Furthermore, the molar ratio of salicylaldehyde SM1, chloroacetone SM2 and sodium hydroxide is 1:1.3-1.5:1-1.3.

[0013] Furthermore, the ratio of the alcohol solvent is 1:5-10.

[0014] Furthermore, the ratio of the alcohol solvent is 1:5 to 8.

[0015] Furthermore, the hydrogenation reduction catalyst is Raney nickel or Pd / C.

[0016] Furthermore, the hydrogenation reduction catalyst is Pd / C.

[0017] Furthermore, in step S20, the weight ratio of compound A to catalyst is 1:0.01 to 0.1.

[0018] Furthermore, in step S20, the weight ratio of compound A to catalyst is 1:0.05 to 0.1.

[0019] Furthermore, the ratio of the solvent in step S20 is 1:8-15.

[0020] Furthermore, the ratio of the solvent in step S20 is 1:8-10. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is a schematic diagram of the liquid phase purity of the finished product of Example 1 of the present invention;

[0022] Figure 2 This is a schematic diagram of the gas phase purity of the finished product of Example 1 of the present invention;

[0023] Figure 3 This is a schematic diagram of the liquid phase purity of the finished product of Example 2 of the present invention;

[0024] Figure 4 This is a schematic diagram of the gas phase purity of the finished product of Example 2 of the present invention. DETAILED DESCRIPTION

[0025] The following will be combined with the embodiments to clearly and completely describe the concept of the present invention and the technical effects produced, so as to fully understand the purpose, characteristics and effects of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative work are all within the scope of protection of the present invention.

[0026] If the specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. If the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0027] Embodiment 1:

[0028] A synthesis process of 2-ethylbenzofuran, an important intermediate of benzalone, comprises the following steps:

[0029] The synthetic route of compound A is as follows:

[0030]

[0031] Step S10: 2500 g of ethylene glycol and 190 g of sodium hydroxide were added to a 5 L dry and clean three-necked flask in sequence, and the mixture was stirred for 10 minutes. Then, 500 g of salicylaldehyde SM1 (1.0 mol) was added, and the mixture was stirred for 10 minutes. The temperature was controlled at 50-55° C., and 492.5 g of chloroacetone SM2 (1.3 mol) was added dropwise. After the addition was completed, the mixture was kept warm for 4-6 hours. The reaction was completed by liquid phase monitoring. Insoluble matter was removed by filtration, and water was added for washing. After separation, the mixture was concentrated to obtain 594.8 g of compound A with a purity of 92.5% and a yield of 90.7%.

[0032] The reaction route of TM is as follows:

[0033] Step S20: Add 50g of the above compound A, 300g of ethanol, 20g of acetic acid, 5g of 10% Pd / C, and 29.5g of anhydrous sodium acetate into a 2L autoclave, replace with nitrogen, introduce hydrogen, maintain the hydrogen pressure at 25 kg, raise the temperature to 95-110°C, react for 18-20 hours, take a sample to control the reaction of compound A, cool it down, filter out the catalyst,

[0034]

[0035] The mixture was added with activated carbon for decolorization, and the ethanol was evaporated. After high vacuum distillation, the fraction at 80-90°C was collected under a vacuum of 200-300 mmHg to obtain 31.7 g of a colorless transparent liquid with a purity of 99.2% and a yield of 69.7%.

[0036] Embodiment 2:

[0037] A synthesis process of 2-ethylbenzofuran, an important intermediate of benzalone, comprises the following steps:

[0038] Step S10: 2500 g of ethylene glycol and 205 g of potassium hydroxide were added to a 5 L dry and clean three-necked flask in sequence, and stirred for 10 minutes. Then, 500 g of salicylaldehyde SM1 (1.0 mol) was added, and stirred for 10 minutes. The temperature was controlled at 50-55° C., and 550 g of chloroacetone SM2 (1.45 mol) was added dropwise. After the addition was completed, the mixture was kept warm for 5 hours. The reaction was completed by liquid phase monitoring. Insoluble matter was removed by filtration, and water was added for washing. After separation, the mixture was concentrated to obtain 587.5 g of compound A with a purity of 93.9% and a yield of 89.6%.

[0039] Step S20: Add 50 g of the above-mentioned compound A, 500 g of ethanol, 20 g of sodium acetate, and 9.5 g of Raney nickel into a 2L autoclave, replace with nitrogen, introduce hydrogen, maintain the hydrogen pressure at 25 kg, raise the temperature to 95-110 ° C, and react for 25-30 hours. Take a sample to control the completion of the reaction of compound A, cool it, filter out the catalyst, add activated carbon for decolorization, and then evaporate the ethanol. After high vacuum distillation, collect the 80-90 ° C fraction under a vacuum of 200-300 mmHg to obtain 33.1 g of colorless and transparent liquid with a purity of 98.7% and a yield of 72.5%.

[0040] The above is only an embodiment of the present invention, and the common knowledge such as the known specific structure and characteristics in the scheme is not described in detail here. It should be pointed out that for those skilled in the art, several deformations and improvements can be made without departing from the structure of the present invention, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicality of the patent. The scope of protection required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to interpret the content of the claims.

Claims

1. A synthesis process for 2-ethylbenzofuran, an important intermediate of benzalone, characterized in that: The steps include: Step S10: using salicylaldehyde SM1 and chloroacetone SM2 as starting materials, adding an alcohol solvent and a strong base solution to synthesize compound A; Step S20: Compound A is subjected to hydrogenation reduction reaction to obtain 2-ethylbenzofuran TM.

2. A synthesis process for 2-ethylbenzofuran, an important intermediate of benzalone according to claim 1, characterized in that: In the step S10, the alcohol solvent is one of methanol, ethanol, isopropanol, and ethylene glycol; and the strong alkaline solution is sodium hydroxide or potassium hydroxide.

3. A synthesis process for the important intermediate 2-ethylbenzofuran of benzalone according to claim 3, characterized in that: The alcohol solvent is ethylene glycol; the strong alkali solution is sodium hydroxide.

4. A synthesis process for 2-ethylbenzofuran, an important intermediate of benzalone according to claim 4, characterized in that: The molar ratio of the salicylaldehyde SM1, chloroacetone SM2 and sodium hydroxide is 1:1.1-1.8:1-1.

5.

5. A synthesis process for the important intermediate 2-ethylbenzofuran of benzalone according to claim 5, characterized in that: The molar ratio of the salicylaldehyde SM1, chloroacetone SM2 and sodium hydroxide is 1:1.3-1.5:1-1.

3.

6. A synthesis process for 2-ethylbenzofuran, an important intermediate of benzalone according to claim 1, characterized in that: The multiple of the alcohol solvent is 1:5-10.

7. A synthesis process for 2-ethylbenzofuran, an important intermediate of benzalone according to claim 1, characterized in that: The hydrogenation reduction catalyst is Raney nickel or Pd / C.

8. A synthesis process for 2-ethylbenzofuran, an important intermediate of benzalone according to claim 1, characterized in that: The hydrogenation reduction catalyst is Pd / C.

9. The synthesis process of 2-ethylbenzofuran, an important intermediate of benzalone according to claim 1, is characterized in that: In the step S20, the weight ratio of the compound A to the catalyst is 1:0.01 to 0.

1.

10. The synthesis process of 2-ethylbenzofuran, an important intermediate of benzalone according to claim 1, characterized in that: The multiple of the solvent in step S20 is 1:8-15.

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