CN112552261B - Preparation method of levofloxacin and its intermediates - Google Patents

Abstract

The invention relates to a preparation method of levofloxacin and an intermediate thereof, belonging to the field of pharmaceutical chemistry. The preparation method comprises the following steps: the fluorine substituted substrate is subjected to amino substitution and ring closure reaction, so that a plurality of intermediates can be integrated into one-pot reaction, and then the levofloxacin is obtained through hydrolysis under an acidic condition. The method of the invention simplifies the reaction operation, greatly shortens the production period, does not need multiple post-treatments, reduces the emission of three wastes, is more environment-friendly, improves the reaction yield by about 20 percent compared with the prior art, and is suitable for industrial amplification.

Description

Preparation method of levofloxacin and its intermediates

Technical Field

The invention relates to the field of pharmaceutical chemistry, and in particular to a preparation method of levofloxacin and an intermediate thereof.

Background Art

Levofloxacin is a chiral fluoroquinolone structure with high efficacy, broad spectrum and low toxicity antibacterial properties. Its chemical name is: (S)-(-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-[1,4]benzoxazine-6-carboxylic acid (CAS: 100986-85-4). The chemical structure of levofloxacin is shown in formula (I).

There are many public documents on the synthesis methods of levofloxacin and its intermediates. Among them, patent US5053407 discloses a synthesis route, which is long and requires the separation of multiple intermediate compounds. The operation is cumbersome and the yield is not ideal, only 50%-55%, which is low. This increases the cost of preparing levofloxacin and is not suitable for large-scale industrial production.

Therefore, there is still a need to study the preparation method of levofloxacin to obtain a method with safe and simple operation, short production cycle, low cost, high yield, high purity and environmental friendliness.

Summary of the invention

The object of the present invention is to solve the above problems and provide a method for preparing levofloxacin and its intermediates which is safe and simple to operate, has a short production cycle, low production cost and is suitable for industrial production.

In one aspect, the present invention provides a method for preparing a compound (B), comprising: reacting a compound (A) with N-methylpiperazine in a reaction solvent in the presence of an alkali reagent at a certain reaction temperature, and performing post-treatment to prepare a compound (B).

The reaction of preparing compound (B) of the present invention can be carried out in a single reaction solvent or in a mixed solvent of multiple reaction solvents. In some embodiments, the reaction solvent is selected from at least one of toluene, xylene, DMF, DMA, and DMSO. In some embodiments, the reaction solvent is toluene, which is conducive to the reaction and operation and the control of impurities.

In some embodiments, the reaction temperature of the above reaction is 20°C-120°C. In some embodiments, the reaction temperature of the above reaction is 20°C-40°C.

The alkaline agent is selected from at least one of triethylamine and N,N-diisopropylethylamine. In some embodiments, the alkaline agent is triethylamine.

In some embodiments, the molar ratio of the compound (A) to N-methylpiperazine is 1:1.5-1:5.0.

In some embodiments, the molar ratio of the compound (A) to the base is 1:2.0-1:10.

In some embodiments, the reaction time of the reaction of compound (A) with N-methylpiperazine is 5 h to 24 h; or the reaction time is 10 h to 20 h.

In some embodiments, the post-treatment includes: cooling to 20°C-30°C and directly proceeding to the next reaction.

In some embodiments, a method for preparing a levofloxacin intermediate compound (B) comprises: in a reaction solvent, compound (A) reacts with N-methylpiperazine in the presence of an alkaline reagent at 20°C-120°C, and after the reaction is completed, post-treatment is performed to obtain compound (B).

In some embodiments, a method for preparing a levofloxacin intermediate compound (B) comprises: reacting compound (A) with N-methylpiperazine in a reaction solvent at 20°C-120°C in the presence of an alkaline reagent; after the reaction is completed, cooling to 20°C-30°C to obtain a solution of compound (B).

In some embodiments, a method for preparing a levofloxacin intermediate compound (B) comprises: in a reaction solvent, stirring a compound (A) and an alkaline reagent at room temperature; then adding N-methylpiperazine and reacting at 20°C-40°C; after the reaction is completed, cooling to 20°C-30°C to obtain a solution of compound (B).

In some embodiments, a method for preparing a levofloxacin intermediate compound (B) comprises: in toluene, compound (A) and N-methylpiperazine are stirred at room temperature, and then triethylamine is added to react at 20°C-40°C. After the reaction is completed, post-treatment is performed to obtain compound (B).

In some embodiments, a method for preparing a levofloxacin intermediate compound (B) comprises: in toluene, compound (A) and N-methylpiperazine are stirred at room temperature, and then triethylamine is added to react at 20°C-40°C. After the reaction is completed, the temperature is lowered to 20-30°C to obtain a solution of compound (B).

In some embodiments, a method for preparing a levofloxacin intermediate compound (B) comprises: in toluene, compound (A) and N-methylpiperazine are stirred at room temperature, and then triethylamine is added, and the reaction is carried out at 20°C-40°C. After the reaction is completed, the temperature is lowered to 20°C-30°C to obtain compound (B); wherein the molar ratio of compound (A) to N-methylpiperazine is 1:1.5-1:5.0, and the molar ratio of compound (A) to triethylamine is 1:2.0-1:10.

The present invention further provides a method for preparing compound (A). A method for preparing compound (A), comprising: mixing compound 3-(N,N-dimethylamino) ethyl acrylate with triethylamine in toluene or xylene, and then adding 2,3,4,5-tetrafluorobenzoyl chloride to the system, stirring at 20°C-40°C for 2h-6h, and post-treating to obtain compound (A); the reaction route is as follows:

In some embodiments, a method for preparing compound (B) comprises: mixing compound 3-(N,N-dimethylamino) ethyl acrylate with triethylamine in toluene or xylene, and then dropping 2,3,4,5-tetrafluorobenzoyl chloride into the system, stirring at 20°C-40°C for 2h-6h to obtain a solution containing compound (A); stirring compound (A) and N-methylpiperazine at room temperature, and then adding triethylamine, reacting at 20°C-40°C, and after the reaction is completed, cooling to 20°C-30°C to obtain a solution of compound (B); wherein the molar ratio of compound (A) to N-methylpiperazine is 1:1.5-1:5.0, and the molar ratio of compound (A) to triethylamine is 1:2.0-1:10.

The above reaction can be monitored by high performance liquid chromatography (HPLC) to determine the end point of the reaction. The reaction is considered complete when the HPLC purity of compound (A) is less than or equal to 0.5%. The reaction time is usually 10 hours or less.

In the above reaction, compound (A) reacts with N-methylpiperazine to obtain compound (B). The reaction conditions are mild and easy to operate, and the yield is nearly 100%. Compound (B) does not need to be separated and can be directly used in the next step of synthesis, which is convenient for shortening the production cycle, saving post-processing solvents, being more environmentally friendly, and suitable for industrial production.

On the other hand, the present invention also provides a method for preparing compound (C), which comprises: in a reaction solvent, in the presence of an acidic reagent, under certain temperature conditions, reacting compound (B) with L-aminopropanol represented by formula (01), and after post-treatment, obtaining compound (C), the reaction is shown in the following formula:

In the preparation method of the above-mentioned compound (C) of the present invention, the reaction can be carried out in a reaction solvent or in a mixed solvent of multiple reaction solvents. In some embodiments, the reaction solvent is selected from at least one of toluene, xylene, DMF, DMA, and DMSO. In some embodiments, the reaction solvent is toluene, which is conducive to the reaction and operation and the control of impurities.

In some embodiments, in the method for preparing the above compound (C), the reaction temperature may be 20°C-60°C.

The acidic reagent is selected from at least one of acetic acid, hydrochloric acid and sulfuric acid. In some embodiments, the acidic reagent is acetic acid, which is conducive to the reaction and the acquisition of high-quality products.

In some embodiments, the molar ratio of the compound (B) to L-aminopropanol is 1:1-1:3; or the molar ratio is 1:1.5-1:2.5.

In some embodiments, the molar ratio of the compound (B) to the acidic reagent may be 1:3.5-1:16. In some embodiments, the molar ratio of the compound (B) to the acidic reagent is 1:4-1:15, which is conducive to the reaction.

In some embodiments, the reaction time of the compound (B) and the L-aminopropanol represented by formula (01) can be 20 min-2 h; or the reaction time can be 30 min-1 h.

In the preparation method of compound (C), the post-treatment comprises: stopping the reaction, adding water to the reaction system, stirring, separating the liquids, collecting the organic phase, and obtaining a solution of compound (C).

In some embodiments, a method for preparing a levofloxacin intermediate compound (C) comprises: in a reaction solvent, compound (B) reacts with L-aminopropanol at 20°C-60°C in the presence of an acidic reagent; after the reaction is completed, water is added, the mixture is stirred and separated, and the organic phase is collected to obtain a solution of compound (C).

In some embodiments, a method for preparing a levofloxacin intermediate compound (C) comprises: in a reaction solvent, compound (B) reacts with L-aminopropanol at 20°C-60°C in the presence of acetic acid; after the reaction is completed, water is added, the mixture is stirred and separated, and the organic phase is collected to obtain a solution of compound (C).

In some embodiments, a method for preparing a levofloxacin intermediate compound (C) comprises: reacting a compound (B) with L-aminopropanol in toluene in the presence of acetic acid at 20°C-60°C; after the reaction is completed, post-treatment is performed to obtain a solution of the compound (C).

In some embodiments, a method for preparing a levofloxacin intermediate compound (C) comprises: reacting a compound (B) with L-aminopropanol in the presence of acetic acid at 20°C-60°C in toluene; after the reaction is completed, adding water, stirring and then separating the liquids, collecting the organic phase, and concentrating the organic phase under reduced pressure to obtain a compound (C); wherein the molar ratio of the compound (B) to the acetic acid is 1:3.5-1:16, and the molar ratio of the compound (B) to the L-aminopropanol is 1:1-1:3.

In some embodiments, a method for preparing a levofloxacin intermediate compound (C) comprises: preparing a compound (B) according to the aforementioned method, and then reacting the compound (B) with L-aminopropanol represented by formula (01) in a reaction solvent in the presence of an acidic reagent under certain temperature conditions, and obtaining a compound (C) after post-treatment.

In some embodiments, a method for preparing a levofloxacin intermediate compound (C) comprises: stirring compound (A) and N-methylpiperazine at room temperature, then adding triethylamine, reacting at 20°C-40°C, and obtaining a solution of compound (B) after completion of the reaction; reacting compound (B) with L-aminopropanol in the presence of acetic acid at 20°C-60°C, and after completion of the reaction, adding water, stirring and separating the liquids, collecting the organic phase, and concentrating the organic phase under reduced pressure to obtain compound (C); wherein the molar ratio of compound (A) to N-methylpiperazine is 1:1.5-1:5.0, the molar ratio of compound (A) to triethylamine is 1:2.0-1:10, the molar ratio of compound (B) to acetic acid is 1:3.5-1:16, and the molar ratio of compound (B) to L-aminopropanol is 1:1-1:3.

In some embodiments, a method for preparing a levofloxacin intermediate compound (C) comprises: mixing the compound 3-(N,N-dimethylamino) ethyl acrylate with triethylamine in toluene or xylene, and then dropping 2,3,4,5-tetrafluorobenzoyl chloride into the system, stirring at 20°C-40°C for 2h-6h after the dropping, to obtain a solution containing the compound (A); stirring the compound (A) and N-methylpiperazine at room temperature, and then adding triethylamine, reacting at 20°C-40°C, and after the reaction is completed, obtaining a compound (B) ) solution; compound (B) reacts with L-aminopropanol in the presence of acetic acid at 20°C-60°C, after the reaction is completed, water is added, the mixture is stirred and separated, the organic phase is collected, and the organic phase is concentrated under reduced pressure to obtain compound (C); wherein the molar ratio of compound (A) to N-methylpiperazine is 1:1.5-1:5.0, the molar ratio of compound (A) to triethylamine is 1:2.0-1:10, the molar ratio of compound (B) to acetic acid is 1:3.5-1:16, and the molar ratio of compound (B) to L-aminopropanol is 1:1-1:3; the reaction route is as follows:

In the preparation method of the above compound (C) of the present invention, high performance liquid chromatography (HPLC) can be used to monitor the reaction endpoint. When the HPLC purity of compound (B) is less than or equal to 0.5%, the reaction is considered to be completed. The reaction time is usually 10 hours or less.

In the preparation method of the above-mentioned compound (C), the solvent of the preparation reaction of compound (B) can be the same as the solvent of the preparation reaction of compound (C). Compared with the published literature, the reaction does not require post-treatment and does not require replacement of the reaction solvent. It only requires feeding and monitoring the reaction to obtain compound (C) with high yield and high purity. The operation is convenient, environmentally friendly, easy to control, and suitable for industrial scale-up.

The present invention further provides a method for preparing a compound (D). A method for preparing a compound (D), comprising: reacting a compound (C) in the presence of a base in a reaction solvent at a certain temperature condition such as reflux temperature, and performing post-treatment to obtain a compound (D); the reaction route is as follows:

In some embodiments, a method for preparing compound (D) comprises: reacting compound (C) in a reaction solvent in the presence of a base at the reflux temperature of the solvent, and performing post-treatment to obtain compound (D); wherein the reaction solvent is toluene, xylene or a mixed solution thereof, and the base is one or more of potassium carbonate, sodium carbonate, and sodium ethoxide; the temperature is 120°C-140°C; the post-treatment comprises stopping the reaction, cooling the reaction system to room temperature, adding water and stirring, filtering, adding water to the filter cake and mixing, heating to 40°C-60°C, stirring for 1h-3h, cooling to room temperature, filtering, and drying the filter cake to obtain compound (D).

In some embodiments, a method for preparing compound (D) comprises: first preparing compound (C) according to the aforementioned method for preparing compound (C); then compound (C) reacts in the presence of a base in a reaction solvent at a certain temperature condition such as reflux temperature, and undergoes post-treatment to obtain compound (D). In some embodiments, a method for preparing compound (D) comprises: first preparing compound (B) according to the aforementioned method for preparing compound (B), and then preparing compound (C) according to the aforementioned method for preparing compound (C); compound (C) reacts in the presence of a base in a reaction solvent at a certain temperature condition such as reflux temperature, and undergoes post-treatment to obtain compound (D).

In some embodiments, a method for preparing compound (D) comprises: mixing compound 3-(N,N-dimethylamino) ethyl acrylate with triethylamine in toluene or xylene, and then dropping 2,3,4,5-tetrafluorobenzoyl chloride into the system, stirring at 20°C-40°C for 2h-6h after the dropping, to obtain a solution containing compound (A); stirring compound (A) and N-methylpiperazine at room temperature, and then adding triethylamine, reacting at 20°C-40°C, and after the reaction is completed, obtaining a solution of compound (B); reacting compound (B) with L-amino in the presence of acetic acid. Propanol, react at 20°C-60°C, after the reaction is completed, add water, stir and separate, collect the organic phase, and concentrate the organic phase under reduced pressure to obtain compound (C); compound (C) reacts at the reflux temperature of the solvent in the presence of a base, and after post-treatment, obtains compound (D); wherein the molar ratio of compound (A) to N-methylpiperazine is 1:1.5-1:5.0, the molar ratio of compound (A) to triethylamine is 1:2.0-1:10, the molar ratio of compound (B) to acetic acid is 1:3.5-1:16, and the molar ratio of compound (B) to L-aminopropanol is 1:1-1:3; the alkaline reagent is one or more of potassium carbonate, sodium carbonate, and sodium ethoxide; the solvent reflux temperature is 120°C-140°C.

In some embodiments, a method for preparing compound (D) comprises the following reaction steps:

a) ethyl 3-(N,N-dimethylamino)acrylate and triethylamine are added to toluene or xylene to dissolve, and then 2,3,4,5-tetrafluorobenzoyl chloride is added dropwise, and stirred at 20°C-30°C to obtain compound (A);

b) adding N-methylpiperazine to step a, and stirring at 20° C.-120° C. for 5 h-24 h to obtain compound (B);

c) adding acetic acid to step b at 20°C-40°C until the pH reaches 5-6, then adding L-aminopropanol, stirring while keeping warm, and post-treating the reaction solution to obtain a solution of compound (C);

d) adding a base to step c, raising the temperature to 120° C.-140° C., reflux reacting for 2 h-8 h, and performing post-treatment to obtain compound (D), wherein the base is one or more of potassium carbonate, sodium carbonate or sodium ethoxide.

Compound (D) can be hydrolyzed under the action of acid to obtain levofloxacin.

The intermediate and preparation method thereof provided by the present invention are as follows: the intermediate compound (A) reacts with N-methylpiperazine to obtain the intermediate compound (B); the compound (B) reacts with L-aminopropanol to obtain the compound (C); the compound (C) is cyclized under the action of a base to obtain the compound (D); the corresponding intermediate compounds (A), (B), (C), and (D) can be separated in the whole reaction process, or the three intermediate compounds (A), and/or the compound (B), and/or the compound (C) can be not separated, and only the intermediate compound (D) can be separated to realize a one-pot reaction, and finally levofloxacin is obtained by acid hydrolysis. Through technical improvements, we integrate multi-step reactions into a one-pot reaction, simplify the experimental operation, greatly shorten the production cycle, and increase the yield from the original 50-55% to about 75%, thereby reducing the cost, saving the multi-step post-processing process, having low energy consumption, reducing the three wastes, being environmentally friendly, and being conducive to large-scale industrial production.

In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

In the present invention, expressions such as "compound A" and "compound represented by formula A" refer to the same compound.

DETAILED DESCRIPTION

In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further describe the present invention in detail.

The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

In the present invention, DMF represents N,N-dimethylformamide, DMA represents N,N-dimethylacetamide, and DMSO represents dimethyl sulfoxide.

In the present invention, K ₂ CO ₃ represents potassium carbonate.

In the present invention, room temperature refers to ambient temperature, which is generally 20°C-40°C or 20°C-30°C.

1. Preparation of Levofloxacin

Add 3-(N,N-dimethylamino)ethyl acrylate (6.74 g), triethylamine (6.19 g) and toluene (90 mL) to the reaction bottle, start stirring, then drop 2,3,4,5-tetrafluorobenzoyl chloride (10 g) into the system, after the dropwise addition, continue stirring at 20°C-30°C for 4 h; add N-methylpiperazine (4.4 g), stir and react at 27°C for 16 h to obtain a solution of compound (B); add acetic acid at room temperature to adjust the pH to 5-6, then add L-aminopropanol to the system, keep warm and stir for 30 min, add 40 ml of water, stir for 15 min, separate the liquids, discard the lower aqueous phase, and the organic phase is the solution of compound (C); then add K ₂ CO ₃ to the solution of compound (C) (14.3 g, 2.2 eq), heated to 140 ° C, solid reflux water separation for 4 h, cooled to 25 ° C, added 56 mL of water, filtered, the filter cake was mixed with water, heated to 40 ° C-60 ° C, stirred for 1 h-3 h, cooled to room temperature, filtered, and the filter cake was dried under reduced pressure at 80 ° C to obtain compound (D); compound (D) was mixed with ethanol (29 mL), water (29 mL), and 30% hydrochloric acid HCl (70 g), dissolved, heated to 83 ° C and stirred for 36 h, cooled to crystallize, filtered, and levofloxacin was obtained: 12.4 g, the yield was 73.2%, and the detection: purity was 99.1%, LC-MS: m/z (ESI): 362.1511 (M+H) +.

2. Preparation of Levofloxacin

Add 3-(N,N-dimethylamino)ethyl acrylate (6.74 g), triethylamine (6.19 g) and toluene (90 mL) to the reaction bottle, start stirring, then drop 2,3,4,5-tetrafluorobenzoyl chloride (10 g) into the system, continue stirring at 27°C for 4 h; add N-methylpiperazine (4.4 g), raise the temperature to 50°C, stir and react for 16 h to obtain a solution of compound (B); add acetic acid at room temperature to adjust the pH to 5-6, then add L-aminopropanol to the system, keep warm and stir for 30 min, add 40 mL of water, stir for 15 min, separate the liquids, discard the lower aqueous phase, and the organic phase is the solution of compound (C); then add K ₂ CO ₃ to the solution of compound (C) (14.3g), heated to 140°C, refluxed the solid to separate water for 4h, cooled to 25°C, added 56ml of water, filtered, and the filter cake was dried under reduced pressure at 80°C to obtain compound (D); compound (D) was mixed with ethanol (29mL), water (29mL), and 30% hydrochloric acid HCl (70g), dissolved, heated to 83°C and stirred for 36h, cooled to crystallize, and filtered to obtain levofloxacin: 12.8g; the yield was 75.3%, the detection: purity was 99.2%, LC-MS: m/z (ESI): 362.1511 (M+H)+.

3. Preparation of compound (C)

3-(N,N-dimethylamino)ethyl acrylate (6.74 g), triethylamine (6.19 g) and toluene (90 mL) were added to the reaction flask, stirring was started, and 2,3,4,5-tetrafluorobenzoyl chloride (10 g) was added dropwise to the system. After the addition was completed, stirring was continued at 27° C. for 4 h; N-methylpiperazine (4.4 g) was added, the temperature was raised to 50° C., and the reaction was stirred for 16 h to obtain a solution of compound (B); acetic acid was added at room temperature to adjust the pH to 5-6, and L-aminopropanol was added to the system, the mixture was stirred for 30 min at this temperature, 40 ml of water was added, and the mixture was stirred for 15 min. The liquid was separated, and the lower aqueous phase was discarded. The organic phase was the solution of compound (C); the solution was concentrated to obtain 20.3 g of compound (C); the yield was 100%, and the purity was 91%, LC-MS: m/z (ESI): 430.1961 (M+H)+.

Example 4 Preparation of Compound (D)

Add 3-(N,N-dimethylamino)ethyl acrylate (6.74 g), triethylamine (6.19 g) and toluene (90 mL) to the reaction bottle, start stirring, then drop 2,3,4,5-tetrafluorobenzoyl chloride (10 g) into the system, continue stirring at 27°C for 4 h; add N-methylpiperazine (4.4 g), raise the temperature to 50°C, stir and react for 16 h to obtain a solution of compound (B); add acetic acid at room temperature to adjust the pH to 5-6, then add L-aminopropanol to the system, keep warm and stir for 30 min, add 40 ml of water, stir for 15 min, separate the liquids, discard the lower aqueous phase, and the organic phase is the solution of compound (C); then add K ₂ CO ₃ to the solution of compound (C) (14.3g), heated to 140°C, refluxed the solid to remove water for 4h, cooled to 25°C, added 56ml of water, filtered, and the filter cake was dried under reduced pressure at 80°C to obtain compound (D): 15.3g; the yield was 83.7%, detection: purity 90%, LC-MS: m/z (ESI): 390.1823 (M+H)+.

The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims (10)

1. A process for preparing compound (B) comprises reacting compound (A) with N-methylpiperazine in the presence of a base agent in a reaction solvent at 20-120 ℃ to obtain compound (B) by post-treatment, wherein the reaction formula is shown as follows:

wherein the alkaline reagent is at least one selected from triethylamine and N, N-diisopropylethylamine.

2. A process for producing compound (C), which comprises producing compound (B) according to the process of claim 1, then reacting compound (B) with L-aminopropanol represented by formula (01) in the presence of an acidic reagent at 20 ℃ to 60 ℃ in a reaction solvent, and subjecting to post-treatment to produce compound (C) represented by the following formula:

Wherein the acidic reagent is at least one selected from acetic acid, hydrochloric acid and sulfuric acid.

3. A process for preparing compound (D) comprising,

Step (1): in a reaction solvent, under the condition of 20-60 ℃ in the presence of an acidic reagent, reacting the compound (B) with L-aminopropanol shown in a formula (01), and carrying out post-treatment to obtain a compound (C), wherein the reaction formula is shown as follows:

wherein the acidic reagent is at least one selected from acetic acid, hydrochloric acid and sulfuric acid;

step (2): the compound (C) reacts in a reaction solvent at 120-140 ℃ in the presence of alkali, and the compound (D) is obtained through post-treatment,

Wherein the reaction solvent is toluene, xylene or a mixed solution thereof; the alkali is one or more of potassium carbonate, sodium carbonate and sodium ethoxide.

4. A process for producing compound (D) according to claim 3, wherein compound (B) is produced according to the process of claim 1.

5. The process for producing compound (D) according to claim 3 or 4, wherein the intermediate compound (C) or compound (B) is not isolated.

6. A process for preparing compound (D) according to claim 3, the post-treatment of step (2) comprising: stopping the reaction, cooling the reaction system to room temperature, adding water, stirring, filtering, mixing the filter cake with water, heating to 40-60 ℃, stirring for 1-3 h, cooling to room temperature, filtering, and drying the filter cake to obtain the compound (D).

7. The process of claim 1, wherein the molar ratio of compound (a) to N-methylpiperazine is from 1:1.5 to 1:5.0, or the molar ratio of compound (a) to alkaline agent is from 1:2.0 to 1:10.

8. The method according to claim 1 or 2, wherein the reaction solvent is at least one selected from toluene, xylene, DMF, DMA, and DMSO.

9. The process according to claim 2, wherein the molar ratio of compound (B) to L-aminopropanol is from 1:1 to 1:3, or the molar ratio of compound (B) to acidic reagent is from 1:3.5 to 1:16.

10. The method of any one of claims 1-2, 7 and 9, further comprising adding 2,3,4, 5-tetrafluorobenzoyl chloride to the system after the compound 3- (N, N-dimethylamino) ethyl acrylate is mixed with triethylamine in toluene or xylene, stirring for 2-6 hours at 20-40 ℃ after the addition, and obtaining a compound (a) through post-treatment; the reaction route is as follows: