Process for the preparation of an intermediate of urapidil

Abstract

The application belongs to the technical field of medicine, and particularly relates to a preparation method of an urapidil intermediate. Piperazine and o-chlorophenol are subjected to a substitution reaction in a first organic solvent to obtain a compound shown in formula II; the compound shown in formula II and a methylating agent are subjected to a methylation reaction under alkaline conditions in a second organic solvent to obtain the urapidil intermediate shown in formula I, and the methylating agent includes dimethyl carbonate and / or dimethyl sulfate. The preparation method provided by the application selects suitable raw materials, first performs a substitution reaction, and then performs a methylation reaction, and by reasonably setting the preparation route of the urapidil intermediate, the yield and product purity of the urapidil intermediate are significantly improved, so that the production cost is greatly reduced.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a preparation method of an urapidil intermediate. Background Art

[0002] Urapidil is suitable for the treatment of essential hypertension, renal hypertension and hypertension caused by pheochromocytoma. Its structural formula is as follows:

[0003] .

[0004] The compound of formula I is a key intermediate in the preparation of urapidil:

[0005] .

[0006] The preparation method of the urapidil intermediate of the structure represented by Formula I reported in the relevant art mainly comprises: cyclizing o-anisidine and bis(2-chloroethyl)amine hydrochloride under high temperature conditions to obtain the urapidil intermediate of the structure represented by Formula I. However, it was found during the preparation process that the cyclization reaction was incomplete, and a large amount of intermediate remained, resulting in a reduced yield of the target product (urapidil intermediate of the structure represented by Formula I), thereby increasing the production cost. Summary of the Invention

[0007] The object of the present invention is to provide a method for preparing an urapidil intermediate. The urapidil intermediate having a structure represented by formula I obtained by the preparation method provided by the present invention has a high total yield and high product purity, effectively reduces production costs, and is more suitable for industrial production.

[0008] In order to achieve the above object, the present invention provides the following technical solutions:

[0009] The present invention provides a method for preparing an urapidil intermediate, comprising the following steps:

[0010] Piperazine and o-chlorophenol are subjected to a substitution reaction in a first organic solvent to obtain a compound having a structure shown in Formula II;

[0011] ;

[0012] A compound represented by Formula II and a methylating agent are subjected to a methylation reaction in a second organic solvent under alkaline conditions to obtain a methylation reaction solution, and the methylation reaction solution is cooled and then mixed with hydrochloric acid to obtain an urapidil intermediate represented by Formula I, wherein the methylating agent comprises dimethyl carbonate and / or dimethyl sulfate;

[0013] .

[0014] Preferably, the molar ratio of the o-chlorophenol to the piperazine is 1:1.4-1.8.

[0015] Preferably, the substitution reaction comprises the following steps:

[0016] dissolving piperazine in a first organic solvent to obtain a piperazine solution;

[0017] o-chlorophenol is added dropwise to the piperazine solution under a first temperature condition, and after the addition is completed, a first-stage substitution reaction is carried out under a second temperature condition to obtain a first-stage substitution reaction liquid; the first-stage substitution reaction liquid is subjected to a second-stage substitution reaction under a third temperature condition; the first temperature is 30-35° C., the second temperature is 35-45° C., the first-stage substitution reaction time is 3-5 hours, the third temperature is 55-75° C., and the second-stage substitution reaction time is 1-3 hours.

[0018] Preferably, the first organic solvent is dimethyl sulfoxide.

[0019] Preferably, the molar ratio of the compound represented by formula II to the methylating agent is 1:1.2-1.5.

[0020] Preferably, the alkaline condition is provided by an alkaline reagent, and the alkaline reagent comprises an alkali metal hydroxide;

[0021] The molar ratio of the compound of formula II to the alkaline reagent is 1:2-2.5.

[0022] Preferably, the methylation reaction temperature is 110-130° C., and the time is 5-8 hours.

[0023] Preferably, the second organic solvent includes dimethylformamide and / or dimethylacetamide.

[0024] Preferably, the methylation reaction liquid is cooled and mixed with hydrochloric acid to adjust the pH value to 1-2, and then continued to stir and mix to obtain a mixed reaction liquid; the mixed reaction liquid is sequentially subjected to solid-liquid separation and dried to obtain the urapidil intermediate with the structure shown in Formula I.

[0025] Preferably, the substitution reaction liquid is directly obtained after the substitution reaction is completed, and the method further comprises: cooling the substitution reaction liquid and then performing solid-liquid separation, and drying the obtained solid product under reduced pressure to obtain the compound with the structure represented by Formula II; the temperature of the reduced pressure drying is 40-50° C., and the time is 12-24 hours.

[0026] The present invention provides a method for preparing an urapidil intermediate, comprising the following steps: subjecting piperazine and o-chlorophenol to a substitution reaction in a first organic solvent to obtain a compound having a structure shown in Formula II; subjecting the compound having a structure shown in Formula II to a methylating agent in a second organic solvent under alkaline conditions to a methylation reaction to obtain a methylation reaction liquid; cooling the methylation reaction liquid and mixing it with hydrochloric acid to obtain an urapidil intermediate having a structure shown in Formula I, wherein the methylating agent comprises dimethyl carbonate and / or dimethyl sulfate. The preparation method provided by the present invention selects suitable raw materials for preparation, first performs a substitution reaction, and then performs a methylation reaction. By rationally setting the preparation route of the urapidil intermediate, the yield and product purity of the urapidil intermediate are significantly improved, thereby greatly reducing production costs.

[0027] At the same time, the preparation method provided by the present invention uses piperazine and o-chlorophenol as starting reaction raw materials. Both starting reaction raw materials can be produced on a large scale industrially and are relatively inexpensive. Neither the substitution reaction nor the methylation reaction in the present invention requires the addition of expensive catalysts. The substitution reaction and methylation reaction provided by the present invention are both conventional production reactions, which greatly reduces the requirements for production equipment and is more suitable for industrial production. In summary, the preparation method provided by the present invention has a simple operation process, simple reaction operation, avoids the use of expensive catalysts or reagents and special production equipment, greatly reduces production costs, is more suitable for industrial production, and thus reduces the production cost of urapidil.

[0028] Furthermore, in the present invention, the substitution reaction includes the following steps: dissolving piperazine in a first organic solvent to obtain a piperazine solution; adding o-chlorophenol dropwise to the piperazine solution under a first temperature condition; and after the addition is complete, performing a first-stage substitution reaction under a second temperature condition to obtain a first-stage substitution reaction liquid; and performing a second-stage substitution reaction on the first-stage substitution reaction liquid under a third temperature condition; the first temperature is 30-35°C, the second temperature is 35-45°C, the first-stage substitution reaction lasts for 3-5 hours, the third temperature is 55-75°C, and the second-stage substitution reaction lasts for 1-3 hours. The present invention further ensures that o-chlorophenol fully reacts by gradiently controlling the temperature of each post-reaction stage of the substitution reaction, thereby increasing the yield of the compound of Formula II and ultimately obtaining the total yield of the target product.

[0029] Furthermore, in the present invention, the alkaline conditions are provided by an alkaline reagent comprising an alkali metal hydroxide; the molar ratio of the compound of the structure represented by Formula II to the alkaline reagent is 1:2.2-2.5; the temperature of the methylation reaction is 110-130°C, and the time is 5-8 hours. During the methylation reaction, the present invention optimizes the amount of the alkaline reagent to ensure sufficient reaction of the compound of Formula II and avoids the generation of a large number of impurities during methylation. Furthermore, by optimizing the reaction temperature and reaction time of the methylation reaction, the present invention ensures sufficient reaction of the compound of Formula II, thereby improving the purity and yield of the compound of Formula I. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The H NMR spectrum of the compound of formula II in Example 1;

[0031] Figure 2 The mass spectrum of the compound of formula II in Example 1;

[0032] Figure 3 This is a liquid chromatography spectrum of the urapidil intermediate of the structure shown in Formula I in Example 1;

[0033] Figure 4 This is the H NMR spectrum of the urapidil intermediate of formula I in Example 1;

[0034] Figure 5 This is the mass spectrum of the urapidil intermediate of the structure shown in Formula I in Example 1;

[0035] Figure 6 This is a liquid chromatography spectrum of the urapidil intermediate of the structure described in Formula I in Example 2;

[0036] Figure 7 This is a flow chart for the preparation of the urapidil intermediate of the structure described in Formula I in the embodiment of the present invention. DETAILED DESCRIPTION

[0037] The present invention provides a method for preparing an urapidil intermediate, comprising the following steps:

[0038] Piperazine and o-chlorophenol are subjected to a substitution reaction in a first organic solvent to obtain a compound having a structure shown in Formula II;

[0039] ;

[0040] A compound represented by Formula II and a methylating agent are subjected to a methylation reaction in a second organic solvent under alkaline conditions to obtain a methylation reaction solution, and the methylation reaction solution is cooled and then mixed with hydrochloric acid to obtain an urapidil intermediate represented by Formula I, wherein the methylating agent comprises dimethyl carbonate and / or dimethyl sulfate;

[0041] .

[0042] In the present invention, unless otherwise specified, all preparation raw materials / components are commercially available products well known to those skilled in the art.

[0043] The present invention conducts a substitution reaction between piperazine and o-chlorophenol in a first organic solvent to obtain a compound having a structure shown in Formula II. In the present invention, the compound having a structure shown in Formula II is 1-(2-hydroxyphenyl)piperazine hydrochloride.

[0044] In the present invention, the first organic solvent is preferably dimethyl sulfoxide (DMSO). The molar ratio of o-chlorophenol to piperazine is preferably 1:1.4-1.8, more preferably 1:1.5-1.8, and in embodiments, may be 4:6 or 40:72. The present invention has no specific requirements for the amount of the first organic solvent used, as long as the substitution reaction proceeds smoothly.

[0045] In the present invention, the substitution reaction preferably comprises the following steps:

[0046] dissolving piperazine in a first organic solvent to obtain a piperazine solution;

[0047] o-chlorophenol is added dropwise to the piperazine solution at a first temperature. After the addition is complete, a first-stage substitution reaction is performed at a second temperature to obtain a first-stage substitution reaction liquid. The first-stage substitution reaction liquid is then subjected to a second-stage substitution reaction at a third temperature. The first temperature is preferably 30-35°C. The second temperature is preferably 35-45°C, more preferably 35-40°C or 40-45°C. The first-stage substitution reaction is preferably performed for 3-5 hours, and in embodiments, may be 3 hours or 5 hours. The third temperature is preferably 55-75°C, more preferably 55-65°C or 65-75°C. The second-stage substitution reaction is preferably performed for 1-3 hours, and in embodiments, may be 1 hour or 3 hours.

[0048] The present invention has no special requirements for the specific implementation process of the dropwise addition, and in the embodiment of the present invention, uniform speed dropwise addition is sufficient. In the present invention, a solid product is precipitated in the first stage substitution reaction liquid.

[0049] In the present invention, the substitution reaction liquid is directly obtained after the substitution reaction is completed. The present invention preferably further comprises: cooling the substitution reaction liquid and then performing solid-liquid separation, and drying the obtained solid product under reduced pressure to obtain the compound with the structure represented by Formula II. In the present invention, the solid-liquid separation is preferably filtration. The solid product obtained by the solid-liquid separation does not need to be washed and is directly dried under reduced pressure. The temperature of the substitution reaction liquid after cooling is preferably 10-20°C, more preferably 15-20°C or 10-15°C. The temperature of the reduced pressure drying is preferably 40-50°C, and the time is preferably 12-24h, and in the embodiment, it can be 16h or 24h.

[0050] After obtaining the compound of formula II, the present invention conducts a methylation reaction between the compound of formula II and a methylating agent in a second organic solvent under alkaline conditions to obtain a methylation reaction liquid. The methylation reaction liquid is cooled and then mixed with hydrochloric acid to obtain an urapidil intermediate of formula I. The methylating agent includes dimethyl carbonate and / or dimethyl sulfate.

[0051] In the present invention, the second organic solvent preferably comprises dimethylformamide (DMF) and / or dimethylacetamide (DMAC). In embodiments, the methylating agent may be dimethyl carbonate. The molar ratio of the compound represented by Formula II to the methylating agent is preferably 1:1.2-1.5, and in embodiments, it may be 3.49:4.19 or 35.87:53.8. The alkaline conditions are preferably provided by an alkaline agent, preferably an alkali metal hydroxide, more preferably sodium hydroxide and / or potassium hydroxide. The molar ratio of the compound represented by Formula II to the alkaline agent is preferably 1:2-2.5, more preferably 1:2.2-2.5, and in embodiments, it may be 3.49:7.68 or 35.87:89.68. The present invention does not require any specific amount of the second organic solvent; it only requires an amount that ensures the methylation reaction proceeds smoothly.

[0052] In the present invention, the raw materials for the methylation reaction preferably include a compound of Formula II, a methylating agent, an alkaline agent, and a second organic solvent. During the methylation reaction, mixing the raw materials preferably comprises: dissolving the compound of Formula II in the second organic solvent to obtain a solution of the compound of Formula II; stirring and mixing the solution of the compound of Formula II with the alkaline agent to obtain a mixed solution; and mixing the mixed solution with the methylating agent. The stirring and mixing time is preferably 30 to 40 minutes. The mixing of the raw materials during the methylation reaction is preferably performed at room temperature.

[0053] In the present invention, the temperature of the methylation reaction is preferably 110-130° C., more preferably 110-120° C. or 120-130° C. The time of the methylation reaction is preferably 5-8 hours, and in the embodiment, it can be 5 hours or 8 hours.

[0054] In the present invention, a methylation reaction liquid is directly obtained after the methylation reaction is completed. The present invention further comprises: cooling the methylation reaction liquid, mixing it with hydrochloric acid, adjusting the pH to 1-2, and then continuing to stir and mix to obtain a mixed reaction liquid; and sequentially subjecting the mixed reaction liquid to solid-liquid separation and drying to obtain the urapidil intermediate having the structure represented by Formula I. In the present invention, the temperature of the cooled methylation reaction liquid is preferably 20-30°C. The present invention has no particular requirements for the molar concentration of the hydrochloric acid. The stirring and mixing time is preferably 1-2 hours. The solid-liquid separation is preferably performed by suction filtration. The drying temperature is preferably 40-50°C, and the drying time is preferably 12-24 hours, more preferably 16 hours or 24 hours.

[0055] In the present invention, the intermediate urapidil of formula I is 1-(2-methoxyphenyl)piperazine hydrochloride. The total yield of the intermediate urapidil of formula I obtained by the preparation method provided by the present invention is above 83% and the purity is above 99.5%.

[0056] In order to further illustrate the present invention, the technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0057] The following examples are based on Figure 7 The preparation process synthesizes the urapidil intermediate having the structure shown in formula I.

[0058] Example 1:

[0059] (1) Preparation of the compound represented by formula II

[0060] To a 3 L reaction flask, 3.45 L of DMSO and 516.84 g (6.0 mol) of piperazine were added, the temperature was raised to 30-35°C, and 514.24 g (4.0 mol) of o-chlorophenol was added dropwise. After the addition was complete, the temperature was controlled at 35-45°C and the reaction was carried out for 3 hours. Solids gradually precipitated during the reaction. The temperature was then raised to 55-65°C and the reaction was carried out for 1 hour. After the reaction was completed, the temperature was lowered to 15-20°C, filtered, and dried under reduced pressure at 50°C for 16 hours to obtain 758.8 g of the compound represented by the structure of Formula II, with a yield of 88.4%.

[0061] The H NMR spectrum of the compound of formula II (see Figure 1 ): 1H NMR δ8.809 (s, 1H), δ6.863~6.715 (m, 4H), δ3.432 (s, 2H), δ2.86 (s, 8H); mass spectrum (see Figure 2 ):[M+H] + :179.1.

[0062] (2) Preparation of the Urapidil Intermediate with the Structure of Formula I

[0063] 750.0 g (3.49 mol) of the compound represented by formula II was added to 3 L of DMF, stirred and then 307.2 g (7.68 mol) of sodium hydroxide was added. After stirring for 30 minutes, 377.1 g (4.19 mol) of dimethyl carbonate was added. The mixture was heated to 110-120°C for 5 hours, cooled to 20-30°C, and hydrochloric acid was added to adjust the pH to 1-2. The mixture was stirred for 2 hours, filtered, and dried under reduced pressure at 50°C for 16 hours to obtain 760.2 g of the intermediate represented by formula I. The yield of this step was 95.2%, the total yield of the two steps was 84.2%, and the purity was 99.65% (see Figure 3 ).

[0064] The H NMR spectrum of the urapidil intermediate of formula I (see Figure 4 ): 1 H NMR δ9.485 (s, 2H), δ7.024~6.887 (m, 4H), δ3.790 (s, 3H), δ3.183 (s, 8H); mass spectrum (see Figure 5 ):[M+H] + :193.1.

[0065] Example 2:

[0066] (1) Preparation of the compound represented by formula II

[0067] To a 50 L glass reactor, 34.5 L of DMSO and 6.2 kg (72.0 mol) of piperazine were added, the temperature was raised to 30-35 ° C, and 5.14 kg (40.0 mol) of o-chlorophenol was added dropwise. After the addition was complete, the temperature was controlled at 40-45 ° C and the reaction was carried out for 5 hours. Solids gradually precipitated during the reaction. The temperature was then raised to 65-75 ° C and the reaction was carried out for 3 hours. After the reaction was completed, the temperature was lowered to 10-15 ° C, centrifuged, and dried under reduced pressure at 50 ° C for 24 hours to obtain 7.72 kg of the compound represented by the structure of Formula II, with a yield of 89.9% for this step.

[0068] (2) Preparation of the Urapidil Intermediate with the Structure of Formula I

[0069] 7.7 kg (35.87 mol) of the compound represented by formula II was added to 30.8 L of DMAC, stirred and then added with 5.02 kg (89.68 mol) of potassium hydroxide. After stirring for 30 minutes, 4.84 kg (53.80 mol) of dimethyl carbonate was added. The mixture was heated to 120-130°C for 8 hours, cooled to 20-30°C, and hydrochloric acid was added to adjust the pH to 1-2. The mixture was stirred for 2 hours, filtered, and dried under reduced pressure at 50°C for 24 hours to obtain 7.62 kg of the intermediate represented by formula I. The yield of this step was 92.9%, the total yield of the two steps was 83.5%, and the purity was 99.61% (see Figure 6 ).

[0070] Example 3:

[0071] Compared with Example 1, the difference is:

[0072] (1) Preparation of the compound of formula II (the molar equivalent of piperazine is 1.4 eq, and the amount of piperazine used is reduced)

[0073] To a 3 L reaction flask, 3.45 L of DMSO and 482.38 g (5.6 mol) of piperazine were added, the temperature was raised to 30-35 ° C, and 514.24 g (4.0 mol) of o-chlorophenol was added dropwise. After the addition was complete, the temperature was controlled at 35-40 ° C and the reaction was carried out for 3 hours. Solids gradually precipitated during the reaction. The temperature was then raised to 55-65 ° C and the reaction was carried out for 1 hour. After the reaction was completed, the temperature was lowered to 15-20 ° C, filtered, and dried under reduced pressure at 50 ° C for 16 hours to obtain 689.6 g of compound II, with a yield of 80.3%.

[0074] Compared with Example 1, Example 3 reduces the amount of piperazine used in Example 3, resulting in a lower yield of step (1) in Example 3 compared with Example 1.

[0075] Example 4:

[0076] Compared with Example 1, the difference is:

[0077] (1) Preparation of the compound of formula II (without subsequent temperature-raising reaction)

[0078] To a 3 L reaction flask, 3.45 L of DMSO and 516.84 g (6.0 mol) of piperazine were added, the temperature was raised to 30-35°C, and 514.24 g (4.0 mol) of o-chlorophenol was added dropwise. After the addition was complete, the temperature was controlled at 35-45°C and the reaction was carried out for 5 hours. During the reaction, a solid gradually precipitated. The reaction was cooled to 15-20°C, filtered, and dried under reduced pressure at 50°C for 16 hours to obtain 631.2 g of compound II, with a yield of 73.5%.

[0079] Compared with Example 1, in Example 4, the reaction of step (1) in Example 4 was only carried out at 35-45°C for 5 hours, and the subsequent reaction step of raising the temperature to 55-65°C was not performed. Although the total reaction time at 35-45°C was extended, the yield of step (1) in Example 4 was lower than that in Example 1.

[0080] Example 5:

[0081] Compared with Example 1, the difference is:

[0082] (2) Preparation of the intermediate of Urapidil of the structure shown in Formula I (base dosage 2.0eq)

[0083] 750.0 g (3.49 mol) of the compound of formula II was added to 3 L of DMF, stirred, and then 279.2 g (6.98 mol) of sodium hydroxide was added. After stirring for 30 minutes, 377.1 g (4.19 mol) of dimethyl carbonate was added. The mixture was heated to 110-120°C for reaction for 5 hours, cooled to 20-30°C, and hydrochloric acid was added to adjust the pH to 1-2. The mixture was stirred for 2 hours, filtered, and dried at 50°C for 16 hours to obtain 699.3 g of the compound of formula I. The yield of this step was 87.6%.

[0084] In Example 5, compared with Example 1, the amount of alkaline reagent used in step (2) of Example 4 is reduced, resulting in a lower reaction yield in step (2).

[0085] Example 6:

[0086] Compared with Example 1, the difference is:

[0087] (2) Preparation of the compound of formula I (lowering the reaction temperature)

[0088] 750.0 g (3.49 mol) of the compound of formula II was added to 3 L of DMF, stirred well, and then 307.2 g (7.68 mol) of sodium hydroxide was added. After stirring for 30 minutes, 377.1 g (4.19 mol) of dimethyl carbonate was added. The mixture was heated to 100-105°C and reacted for 8 hours. The temperature was then lowered to 20-30°C, and hydrochloric acid was added to adjust the pH to 1-2. The mixture was stirred for another 2 hours, filtered, and dried at 50°C for 16 hours to obtain 660.1 g of the compound of formula I. The yield of this step was 82.7%.

[0089] Compared with Example 1, Example 6 lowers the temperature of the methylation reaction, resulting in a lower reaction yield in step (2).

[0090] From the above examples, it can be seen that the preparation method provided by the present invention has the following effects: (1) The starting materials used in the present invention are large-scale industrial production and are relatively cheap. The reagents and solvents used are all conventional reagents and solvents, and no expensive catalysts are used, which greatly reduces the production cost. (2) The route adopted by the present invention improves the total process yield by first performing the substitution reaction and then the methylation reaction, thereby greatly reducing the production cost. (3) During the substitution reaction of the present invention, the gradient temperature control can ensure that o-chlorophenol is fully reacted, thereby improving the yield of the compound of formula II. (4) During the methylation reaction of the present invention, the appropriate amount of alkaline reagent can ensure that the compound of formula II is fully reacted and avoids the generation of more impurities. The appropriate reaction temperature and reaction time can ensure that the compound of formula II is fully reacted, thereby improving the purity and yield of the compound of formula I. (5) The reaction conditions involved in the reaction steps of the present invention are all conventional production conditions, which greatly reduces the requirements for production equipment and is more suitable for industrial production. (6) The total yield of the product obtained by the present invention is above 83%, and the purity is above 99.5%. In summary, the process of the present invention is simple in operation flow and reaction operation, avoids the use of expensive catalysts or reagents and special production equipment, greatly reduces production costs, is more suitable for industrial production, and thus reduces the production cost of urapidil.

[0091] Although the above embodiment provides a detailed description of the present invention, it is only a part of the embodiments of the present invention, not all of the embodiments. Other embodiments can be obtained based on this embodiment without creativity, and these embodiments all fall within the scope of protection of the present invention.

Claims

1. A method for preparing an urapidil intermediate, characterized in that: The following steps are involved: Piperazine and o-chlorophenol are subjected to a substitution reaction in a first organic solvent to obtain a compound having a structure shown in Formula II; the substitution reaction comprises the following steps: dissolving piperazine in a first organic solvent to obtain a piperazine solution, wherein the first organic solvent is dimethyl sulfoxide; Add o-chlorophenol dropwise to the piperazine solution at a first temperature, and after the addition is complete, perform a first-stage substitution reaction at a second temperature to obtain a first-stage substitution reaction liquid; and perform a second-stage substitution reaction on the first-stage substitution reaction liquid at a third temperature; the first temperature is 30-35° C., the second temperature is 35-45° C., the first-stage substitution reaction time is 3-5 hours, and the third temperature is 55-75° C., the second-stage substitution reaction time is 1-3 hours; ； A compound represented by Formula II and a methylating agent are subjected to a methylation reaction in a second organic solvent under alkaline conditions to obtain a methylation reaction solution, and the methylation reaction solution is cooled and then mixed with hydrochloric acid to obtain an urapidil intermediate represented by Formula I, wherein the methylating agent comprises dimethyl carbonate and / or dimethyl sulfate; 。 2. The preparation method according to claim 1, characterized in that The molar ratio of the o-chlorophenol to the piperazine is 1:1.4-1.

8.

3. The preparation method according to claim 1, characterized in that The molar ratio of the compound represented by the structure of Formula II to the methylating agent is 1:1.2-1.

5.

4. The preparation method according to claim 1, characterized in that The alkaline conditions are provided by an alkaline reagent, and the alkaline reagent includes an alkali metal hydroxide; The molar ratio of the compound of formula II to the alkaline reagent is 1:2-2.

5.

5. The preparation method according to claim 1, characterized in that The methylation reaction temperature is 110-130° C., and the reaction time is 5-8 hours.

6. The preparation method according to claim 1, characterized in that The second organic solvent includes dimethylformamide and / or dimethylacetamide.

7. The preparation method according to claim 1, characterized in that After cooling, the methylation reaction liquid is mixed with hydrochloric acid to adjust the pH value to 1-2, and then continued to stir and mix to obtain a mixed reaction liquid; the mixed reaction liquid is sequentially subjected to solid-liquid separation and drying to obtain the urapidil intermediate with the structure shown in Formula I.

8. The preparation method according to claim 1, characterized in that After the substitution reaction is completed, a substitution reaction liquid is directly obtained, and the method further comprises: cooling the substitution reaction liquid and then performing solid-liquid separation, and drying the obtained solid product under reduced pressure to obtain the compound with the structure represented by Formula II; the temperature of the reduced pressure drying is 40-50° C., and the time is 12-24 hours.

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