A process for the preparation of urapidil hydrochloride

Abstract

This invention discloses a method for preparing urapidil hydrochloride. The method uses 4-(3-hydroxypropylamino)-1,3-dimethyluracil as the starting material, and obtains urapidil hydrochloride through oxidation, reductive amination, and salt formation. By reconstructing the reactive groups of the intermediates, a mild and efficient reaction type is adopted, improving reaction selectivity, product yield, and purity. The raw materials are readily available, the operation is safer, more convenient, and environmentally friendly, and conventional production equipment and environment are sufficient, facilitating large-scale production.

Description

Technical Field

[0001] This invention relates to a method for preparing urapidil hydrochloride, and more particularly to a method for preparing urapidil hydrochloride based on a novel synthetic strategy, belonging to the pharmaceutical field. Background Technology

[0002] Urapidil hydrochloride, chemically named 6-[[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]amino]-1,3-dimethyl-2,4(1H,3H)-pyrimidinide hydrochloride, is a dual antihypertensive drug that acts on both the central and peripheral nervous systems. It is widely used clinically to treat hypertensive crisis, severe hypertension, and perioperative hypertension.

[0003] Currently, the synthetic route for urapidil hydrochloride typically uses 6-(3-chloropropyl)-1,3-dimethyluracil and 1-(2-methoxyphenyl)piperazine or its hydrochloride salt as starting materials, and obtains the free urapidil base through a condensation reaction, followed by salt formation with hydrochloric acid to obtain the target product. For example, the synthetic route for urapidil hydrochloride disclosed in US3957786A is as follows:

[0004] .

[0005] The above method uses strong halogen reagents such as thionyl chloride or phosphorus oxychloride to prepare 6-(3-chloropropylamino)-1,3-dimethyluracil. These reactions inherently have poor selectivity, produce numerous process byproducts, and make it difficult to guarantee product quality. Furthermore, the chlorination process is a hazardous chemical process, facing safety and environmental concerns. In addition, this method employs a large amount of phase transfer catalysts, particularly a significant amount of nonionic surfactants, which increases the difficulty of wastewater treatment.

[0006] The literature Arseim Forsch Drug, 1997, 10: 1895-187 also discloses a method for preparing urapidil hydrochloride using 6-chloro-1,3-dimethyluracil and 1-(3-amino-1-propyl)-4-(2-methoxyphenyl)piperazine or their hydrochloride salts as raw materials. However, the raw material 1-(3-amino-1-propyl)-4-(2-methoxyphenyl) is not readily available, has limited sources, and is expensive, which limits the industrial application of this method.

[0007] . Summary of the Invention

[0008] Purpose of the invention: The present invention aims to provide an industrial method for preparing urapidil hydrochloride that is easy to obtain, convenient to operate, safe and environmentally friendly.

[0009] Technical solution: The method for preparing urapidil hydrochloride according to the present invention includes the following steps:

[0010] ,

[0011] (1) Compound 4 is oxidized to give the free base of compound 3, and then the base is formed to give compound 3;

[0012] (2) Compound 3 and Compound 2 undergo a reducing amination reaction to obtain urapidil free base, which is then salted to obtain urapidil hydrochloride.

[0013] Preferably, the oxidant used in step (1) is selected from at least one of Des Martin reagent, dimethyl sulfoxide-oxalyl chloride, and 2-iodobenzoic acid.

[0014] Further preferred, the oxidant used in step (1) is the Des Martin reagent.

[0015] Further preferred, in step (1), the molar ratio of compound 4 to oxidant is 1:1.3 to 1:1.8.

[0016] Preferably, the reaction solvent used in step (1) is selected from at least one of acetonitrile, tetrahydrofuran, and dichloromethane.

[0017] Further preferred, the amount of reaction solvent used in step (1) is 5 times the weight of compound 4 by volume.

[0018] Further preferred, the reaction solvent used in step (1) is dichloromethane.

[0019] Preferably, the oxidation reaction temperature in step (1) is 5~10℃.

[0020] Preferably, the reducing amination reagent used in step (2) is selected from at least one of sodium triacetoxyborohydride, sodium cyanoborohydride, and sodium borohydride.

[0021] Further preferred, the reducing amination reagent used in step (2) is sodium triacetoxyborohydride or sodium cyanoborohydride.

[0022] Further preferred, in step (2), the molar ratio of compound 3 to the reducing amination reagent is 1:1.5 to 1:2.

[0023] Preferably, step (2) also uses an activating agent selected from at least one of triethylamine, N,N-diisopropylethylamine, methylamine, ethylamine, DBU, and pyrrole.

[0024] Further preferred, the activating agent used in step (2) is triethylamine or N,N-diisopropylethylamine.

[0025] Further preferred, step (2) uses sodium triacetoxyborohydride-N,N-diisopropylethylamine or sodium cyanoborohydride-triethylamine as the catalytic reaction.

[0026] Further preferred, in step (2), the molar ratio of compound 3 to activating reagent is 1:1.2 to 1:2.

[0027] Preferably, the molar ratio of compound 3 to compound 2 in step (2) is 1:1.1 to 1:1.3.

[0028] Preferably, the reaction solvent used in step (2) is selected from at least one of acetonitrile, tetrahydrofuran, dichloromethane, and N,N-dimethylformamide.

[0029] Further preferred, the amount of reaction solvent used in step (2) is 5 times the weight of compound 3 by volume.

[0030] Further preferred, the reaction solvent used in step (2) is tetrahydrofuran.

[0031] Preferably, the reductive amination reaction temperature in step (2) is 10~30℃.

[0032] Further preferred, the temperature of the reductive amination reaction in step (2) during the addition of the reductive amination reagent is 0~10℃, and the temperature of the heat preservation reaction after the addition of the reductive amination reagent is 10~30℃, more preferably 20~30℃.

[0033] Preferably, in steps (1) and (2), a hydrogen chloride-ethanol solution is used for salt formation.

[0034] Further optimization involves using a 30%~40% mass concentration hydrogen chloride-anhydrous ethanol solution for salt formation in steps (1) and (2).

[0035] Further preferred, the solvent for salt formation in steps (1) and (2) is anhydrous ethanol.

[0036] More preferably, in step (1), the amount of anhydrous ethanol, the salt-forming solvent, is 4 times the volume of compound 4.

[0037] More preferably, in step (2), the amount of anhydrous ethanol, the salt-forming solvent, is 5 times the volume of compound 3.

[0038] Further optimization involves salt formation in steps (1) and (2) at a pH of 1 to 2.

[0039] Further optimization involves salt formation in steps (1) and (2) at 60-70°C, followed by crystallization at 5-15°C.

[0040] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0041] This invention improves reaction selectivity, product yield, and purity by reconstructing the reactive groups of intermediates and employing a mild and efficient reaction type. The raw materials are readily available, and the operation is safer, more convenient, and more environmentally friendly. Conventional production equipment and environment can meet the requirements, which is conducive to large-scale production. Attached Figure Description

[0042] Figure 1 The liquid chromatography purity detection chromatogram of compound 3 prepared in Example 1 is shown.

[0043] Figure 2 The mass spectrum of compound 3 prepared in Example 1;

[0044] Figure 3 The 1H NMR spectrum of compound 3 prepared in Example 1;

[0045] Figure 4 The liquid chromatography purity determination chromatogram of urapidil hydrochloride prepared in Example 1;

[0046] Figure 5 The mass spectrum of urapidil hydrochloride prepared in Example 1;

[0047] Figure 6 The image shows the 1H NMR spectrum of urapidil hydrochloride prepared in Example 1. Detailed Implementation

[0048] The technical solution of the present invention will be further described below with reference to the embodiments.

[0049] Example 1

[0050] Step 1: Preparation of Compound 3

[0051] Dichloromethane (105 ml), 4-(3-hydroxypropylamino)-1,3-dimethyluracil (compound 4, 1.0 eq, 21 g), and Dys-Martin reagent (1.3 eq, 55.1 g) were added to a reaction flask. Stirring was initiated, and the mixture was cooled to 10 °C and maintained at this temperature for 1 h. After the reaction was complete, the reaction system was extracted sequentially with an aqueous solution of sodium thiosulfate (2.0 eq, 49.1 g dissolved in 105 ml of water) and saturated sodium bicarbonate (105 ml). The organic phase was concentrated to dryness. Anhydrous ethanol (84 ml) was added to the concentrate, and the mixture was heated to 70 °C to dissolve it. The pH was adjusted to 1.3 by slowly adding a 30% (w / w) hydrogen chloride-anhydrous ethanol solution. The mixture was maintained at 70 °C for 30 min, cooled to 15 °C, and crystallized for 3 h. The crystals were filtered and dried to obtain 22.16 g of a yellow solid, with a yield of 91.0% and a purity of 99.9%. The HPLC purity chromatogram is shown below. Figure 1 Mass spectrum (see) Figure 2 , 1The H-NMR spectrum is shown below. Figure 3 .

[0052] Step 2: Preparation of urapidil hydrochloride

[0053] Compound 3 (1.0 eq, 12.4 g), tetrahydrofuran (62 ml), and N,N-diisopropylethylamine (1.5 eq, 9.7 g) were added to a reaction flask. Stirring was initiated, and the temperature was raised to 20 °C and maintained for 10 min. Compound 2 (1.1 eq, 12.5 g) was added to the reaction flask, and the temperature was maintained at 20 °C for 30 min. The temperature was lowered to 0 °C, and sodium triacetoxyborohydride (1.5 eq, 15.9 g) was added. The temperature was maintained at 0 °C, then raised to 20 °C and maintained at 20 °C for 1 h. After the reaction was complete, water (62 ml) was added to quench the reaction, and dichloromethane (62 ml) was added for extraction twice. The organic phase was concentrated to dryness. Anhydrous ethanol (62 ml) was added to the concentrate and the mixture was heated to 70 °C to dissolve it. A 30% (w / w) hydrogen chloride-anhydrous ethanol solution was slowly added dropwise to adjust the pH to 1.4. The mixture was kept at 70 °C for 30 min, then cooled to 15 °C and kept at this temperature for 3 h to allow crystals to crystallize. The crystals were filtered and dried to obtain 18.8 g of a white solid, with a yield of 88.5% and a purity of 99.7%. The purity chromatogram is shown below. Figure 4 Mass spectrum (see) Figure 5 , 1 The H-NMR spectrum is shown below. Figure 6 .

[0054] Example 2

[0055] Step 1: Preparation of Compound 3

[0056] Dichloromethane (50 ml), 4-(3-hydroxypropylamino)-1,3-dimethyluracil (1.0 eq, 10.5 g), and Dysmartin reagent (1.8 eq, 38.1 g) were added to a reaction flask. Stirring was started, and the mixture was cooled to 5 °C and maintained at this temperature for 1 h. After the reaction was complete, the reaction mixture was extracted sequentially with an aqueous solution of sodium thiosulfate (2.0 eq, 24.5 g dissolved in 105 ml of water) and saturated sodium bicarbonate (50 ml). The organic phase was concentrated to dryness. Anhydrous ethanol (42 ml) was added to the concentrate, and the mixture was heated to 60 °C to dissolve the solid. The pH was adjusted to 1.6 by slowly adding a 40% (w / w) hydrogen chloride-anhydrous ethanol solution. The mixture was maintained at 60 °C for 30 min, cooled to 5 °C, and crystallized for 3 h. The crystals were filtered and dried to obtain 11.16 g of a yellow solid, with a yield of 91.6% and a purity of 98.8%.

[0057] Step 2: Preparation of urapidil hydrochloride

[0058] Compound 3 (1.0 eq, 6.2 g), tetrahydrofuran (31 ml), and triethylamine (2.0 eq, 5.0 g) were added to the reaction flask. Stirring was initiated, and the temperature was raised to 30 °C and maintained for 10 min. Compound 2 (1.1 eq, 12.5 g) was added to the reaction flask, and the temperature was maintained at 30 °C for 30 min. The temperature was lowered to 10 °C, and sodium cyanoborohydride (2.0 eq, 3.2 g) was added. The temperature was maintained at 10 °C, then raised to 30 °C and maintained at 30 °C for 1 h. After the reaction was complete, water (31 ml) was added to quench the reaction, and dichloromethane (31 ml) was added for extraction twice. The organic phase was concentrated to dryness. Anhydrous ethanol (31 ml) was added to the concentrate and heated to 60 °C to dissolve it. The pH was adjusted to 1.2 by slowly adding 40% hydrogen chloride-anhydrous ethanol solution. The solution was kept at 60 °C for 30 min, then cooled to 5 °C and kept at this temperature for 3 h to allow crystals to precipitate. The solution was then filtered and dried to obtain 9.24 g of off-white solid, with a yield of 87.1% and a purity of 99.7%.

[0059] Comparative Example 1

[0060]

[0061] Add purified water (105.0 g) to the reaction flask, and then add 6-(3-chloropropyl)-1,3-dimethyluracil (21.0 g) and 1-(2-methoxyphenyl)piperazine hydrochloride (16.1 g) to the reaction flask in sequence; add potassium carbonate (16.2 g) in batches slowly, raise the temperature to 100°C, and keep the reaction at this temperature for 5 h.

[0062] After the incubation period, the reaction solution was cooled to 20°C and extracted twice with dichloromethane (117.4 g). The organic phase was collected and concentrated under reduced pressure at 40°C until dry. Anhydrous ethanol (100.8 g) was transferred to a reaction flask, heated to 70°C, and stirred until dissolved. A 30% (w / w) solution of hydrogen chloride in anhydrous ethanol was slowly added dropwise at 70°C to adjust the pH to 2.0. The temperature was maintained at 70°C, and the mixture was stirred for 30 min. The mixture was then cooled to 5°C and stirred for 2 h. The mixture was filtered, the filter cake was collected, and dried to obtain 26.5 g of a white solid, yield: 79.88%, purity: 99.3%.

[0063] The previous preparation method involved a high reaction temperature and a slow reaction rate, resulting in high energy consumption. Furthermore, the yield and purity of the final product were lower than those of the method described in this invention. Additionally, the preparation of 6-(3-chloropropyl)-1,3-dimethyluracil requires the use of highly corrosive halogenated reagents such as phosphorus oxychloride or thionyl chloride. The reaction process is highly corrosive to equipment, and the concentrated halogenated reagents undergo violent exothermic and gaseous processes, posing safety risks.

[0064] Comparative Example 2

[0065]

[0066] 3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamine (50.0 g), 6-chloro-1,3-dimethyluracil (35.0 g), sodium hydroxide (24.0 g), and purified water (500 ml) were added to a three-necked reaction flask. The mixture was mechanically stirred and heated to 60 °C for 2 hours. After cooling to room temperature, the mixture was filtered. The filter cake was dried at 50 °C for 6 hours to obtain 41.2 g of urapidil, with a yield of 53.0%. Anhydrous ethanol (200.0 g) and urapidil (20.0 g) were added to a three-necked reaction flask. The mixture was heated to 70 °C, and a mixture of hydrochloric acid and ethanol solution (7.32 g concentrated hydrochloric acid and 8.00 g anhydrous ethanol) was added dropwise. After the addition was complete, the mixture was stirred at 70 °C for 1 hour. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with anhydrous ethanol (40.00 g). The filter cake was dried at 50°C for 4 hours to obtain 18.30 g of urapidil hydrochloride, with a yield of 83.6% and a purity of 99.7%.

[0067] In this preparation method, the overall reaction yield is 40% lower than that of the method of the present invention, and the production cost is higher. At the same time, the preparation route and each step of the starting material 1-(3-amino)-4-(2-methoxyphenyl)piperazine are long, energy-intensive, and difficult to obtain. In addition, the synthesis process uses hydrazine hydrate, which is easily explosive, and the post-processing extraction step also uses chloroform, a type II solvent. Therefore, this route is not suitable for large-scale production.

Claims

1. A method for preparing urapidil hydrochloride, characterized in that, Includes the following steps: ， (1) Compound 4 is oxidized to give the free base of compound 3, and then the base is formed to give compound 3; (2) Compound 3 and Compound 2 undergo a reducing amination reaction to obtain urapidil free base, which is then salted to obtain urapidil hydrochloride.

2. The method for preparing urapidil hydrochloride according to claim 1, characterized in that, The oxidant used in step (1) is selected from at least one of the following: Des Martin reagent, dimethyl sulfoxide-oxalyl chloride, and 2-iodobenzoic acid.

3. The method for preparing urapidil hydrochloride according to claim 2, characterized in that, In step (1), the molar ratio of compound 4 to oxidant is 1:1.3 to 1:1.

8.

4. The method for preparing urapidil hydrochloride according to claim 1, characterized in that, The reaction solvent used in step (1) is selected from at least one of acetonitrile, tetrahydrofuran, and dichloromethane.

5. The method for preparing urapidil hydrochloride according to claim 1, characterized in that, The reducing amination reagent used in step (2) is selected from at least one of sodium triacetoxyborohydride, sodium cyanoborohydride, and sodium borohydride.

6. The method for preparing urapidil hydrochloride according to claim 5, characterized in that, In step (2), the molar ratio of compound 3 to the reducing amination reagent is 1:1.5 to 1:

2.

7. The method for preparing urapidil hydrochloride according to claim 1, characterized in that, Step (2) also uses an activating agent selected from at least one of triethylamine, N,N-diisopropylethylamine, methylamine, ethylamine, DBU, and pyrrole.

8. The method for preparing urapidil hydrochloride according to claim 7, characterized in that, In step (2), the molar ratio of compound 3 to the activating reagent is 1:1.2 to 1:

2.

9. The method for preparing urapidil hydrochloride according to claim 1, characterized in that, The reaction solvent used in step (2) is selected from at least one of acetonitrile, tetrahydrofuran, dichloromethane, and N,N-dimethylformamide.

10. The method for preparing urapidil hydrochloride according to claim 1, characterized in that, In steps (1) and (2), a hydrogen chloride-ethanol solution is used for salt formation.

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