A preparation method of 1-acetyl-4-(4-hydroxyphenyl)piperazine

Abstract

The present invention discloses a preparation method of 1-acetyl-4-(4-hydroxyphenyl)piperazine. This method undergoes two-step reactions in a reaction kettle. In the step of preparing compound III from bis(2-bromoethyl)amine hydrobromide (compound II), first add a reaction solvent and compound II, stir, add base 1 in batches, control the internal temperature, and dropwise add a solution of acetyl chloride and the reaction solvent until the reaction is complete; add water, stir, stand still, and separate layers, and leave the organic layer in the kettle. In the step of preparing compound I from compound III, under nitrogen protection, add base 2, tetrabutylammonium iodide, and p-aminophenol to the reaction kettle, stir, and heat until the reaction is complete; after treatment, 1-acetyl-4-(4-hydroxyphenyl)piperazine (compound I) is obtained. The reaction of the present invention is simple and easy to operate, has a high yield, the total yield can reach 88%, the purity can be greater than 99.5%, and there is no high-risk reaction, which is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of synthesis of pharmaceutical intermediates, and particularly to a method for preparing 1-acetyl-4-(4-hydroxyphenyl)piperazine. Background Art

[0002] Fungal infections are relatively common in dermatology. Clinically, superficial and deep mycosis can be caused after fungal infection. In recent years, the incidence of fungal infections has been increasing year by year. In particular, deep fungal infections are increasingly threatening the health and lives of patients. Ketoconazole is an imidazole broad-spectrum antifungal drug that highly selectively interferes with the activity of fungal cytochrome P-450, thereby inhibiting the biosynthesis of ergosterol on the fungal cell membrane. It is effective against both superficial and deep fungal infections, can not only inhibit the growth of fungi, but also inhibit the transformation of spores into hyphae to prevent further infection. Itraconazole is a synthetic triazole broad-spectrum antifungal drug that exerts antibacterial activity by changing the permeability of the fungal cell membrane. It has antibacterial activity against the pathogens of both superficial and deep fungal infections, and its antibacterial spectrum is wider and stronger than that of ketoconazole. It can inhibit the synthesis of ergosterol in the fungal cell membrane, thereby exerting an antifungal effect.

[0003] 1-Acetyl-4-(4-hydroxyphenyl)piperazine (Compound 1) is a key intermediate for the synthesis of itraconazole and ketoconazole. Studying the preparation method of 1-acetyl-4-(4-hydroxyphenyl)piperazine is of great significance.

[0004] Patent CN1257163C discloses a synthesis method of 1-acetyl-4-(4-hydroxyphenyl)piperazine as follows:

[0005]

[0006] Reagents and conditions: (a) Acetone, 40% HBr, yield: 51.2%; (b) MeOH, n-butanol, acetone, p-anisidine, anhydrous NaCO 3 , yield: 60%-66%; (c) Acetone, 40% HBr, yield: 78.6%; (d) EtOH, K 2 CO 3 , acetic anhydride, yield: 85%.

[0007] This route has the following problems: Steps a and c use 40% HBr, which is highly corrosive; the total yield of Compound I obtained by the above method is only 21%-23%, the yield is low, not suitable for large-scale production, and will also cause great pollution to the environment.

[0008] The literature Yang Jiqiu, Liu Lilin, Wang Xiaoyan, Lv Jiaguo, Sun Changsheng, & Zhang Huanxiang et al. (1984). Synthesis of the antifungal drug ketoconazole reported the following synthesis method:

[0009]

[0010] Reagents and conditions: (e) p-nitrochlorobenzene, anhydrous potassium carbonate, n-butanol, dilute hydrochloric acid, 40% NaOH, yield: 75%; (f) 95% EtOH, pyridine, acetic anhydride, yield: 90%; (g) ethanol, 85% hydrazine hydrate, active nickel, yield: 84%; (h) 7.5% sulfuric acid, sodium nitrite, copper nitrate, copper powder, NaHCO 3 , ethyl acetate, yield: 57%.

[0011] This method has multiple steps, complex operations, highly hazardous reactions, harsh reaction conditions, large equipment investment, potential safety hazards, and a risk of hydrazine genotoxic impurities, with a generally low overall yield. Summary of the Invention

[0012] Object of the Invention: To overcome the defects of the prior art, the present invention discloses a method for preparing 1-acetyl-4-(4-hydroxyphenyl)piperazine. This method is carried out in a single reaction kettle, with short steps and simple and convenient operations; there are no high-risk reactions, avoiding large equipment cost investments; through route design, the generation of phenolic ester impurities and hydrazine genotoxic impurities is avoided, the purity is improved, meeting the requirements of the pharmaceutical industry, the yield can reach 88%, and it can be industrially produced.

[0013] The present invention is achieved by the following technical means:

[0014]

[0015] This method undergoes two-step reactions in a single reaction kettle. In the step of preparing compound Ⅲ from compound Ⅱ, first add the reaction solvent and bis(2-bromoethyl)amine hydrobromide, stir, add base 1 in batches, control the internal temperature, and dropwise add a solution of acetyl chloride and the reaction solvent until the reaction is complete; add water, stir, stand, and separate layers, and leave the organic layer in the reaction kettle; in the step of preparing compound Ⅰ from compound Ⅲ, under nitrogen protection, add base 2, tetrabutylammonium iodide, and p-aminophenol to the reaction kettle, stir, and heat until the reaction is complete; perform post-treatment to obtain compound Ⅰ.

[0016] For the above-mentioned method for preparing 1-acetyl-4-(4-hydroxyphenyl)piperazine, the reaction solvent is one of methyl tert-butyl ether and 2-methyltetrahydrofuran.

[0017] Furthermore, in the step of preparing compound Ⅲ from compound Ⅱ, the base 1 is one of sodium carbonate and potassium carbonate.

[0018] Furthermore, in the step of preparing compound Ⅲ from compound Ⅱ, the molar ratio of compound Ⅱ, base 1, and acetyl chloride is 1:1.3 - 1.6:1.1 - 1.3.

[0019] Furthermore, in the step of preparing Compound III from Compound II, when dropping the solution of acetyl chloride, the internal temperature is controlled at 0 - 10°C. After the dropping is completed, the reaction temperature is controlled at 10 - 35°C, and the reaction is carried out for 4 - 8 hours.

[0020] Furthermore, in the step of preparing Compound I from Compound III, the base 2 is one of sodium carbonate, sodium bicarbonate, and potassium bicarbonate.

[0021] Furthermore, in the step of preparing Compound I from Compound III, the molar ratio of Compound III, p - aminophenol, tetrabutylammonium iodide to base 2 is 1:1 - 1.2:0.03 - 0.1:1.5 - 5.

[0022] Furthermore, in the step of preparing Compound I from Compound III, the reaction temperature is 60 - 90°C, and the reaction time is 8h - 26h.

[0023] Furthermore, in the step of preparing Compound I from Compound III, the post - treatment steps are as follows: first, the solvent is removed by vacuum distillation; water is added, cooled, filtered by suction, the filter cake is recrystallized with 95% ethanol, and dried in vacuum to obtain Compound I.

[0024] Beneficial Effects

[0025] In this paper, bis(2 - bromoethyl)amine hydrobromide (Compound II) is used as the starting material. First, it reacts to obtain Compound III; then it reacts with p - aminophenol to obtain 1 - acetyl - 4-(4 - hydroxyphenyl)piperazine (Compound I). The total yield of the two - step reaction for the preparation of Compound I can reach 89.1%, and the purity can be greater than 99.5%. This method is carried out in a single reaction kettle, with short steps, simple and convenient operation; there is no high - risk reaction, avoiding large equipment costs, and is suitable for industrial production. The present invention solves the problems of complex operation, large equipment investment, and potential safety hazards in the currently known synthesis processes. Description of the Drawings

[0026] Figure 1 For Example 1, HPLC purity chart of 1 - acetyl - 4-(4 - hydroxyphenyl)piperazine;

[0027] Figure 2 For Example 1, 1H - NMR chart of 1 - acetyl - 4-(4 - hydroxyphenyl)piperazine. Detailed Embodiments

[0028] The following detailed embodiments further elaborate on the purpose, technical solutions, and beneficial effects of this application. It should be understood that the following are only the detailed embodiments of this application and are not used to limit the protection scope of this application. Any modifications, equivalent replacements, improvements, etc. made on the basis of the technical solutions of this application should be included within the protection scope of this application.

[0029] Example 1:

[0030] In a dry reaction kettle equipped with a thermometer, stirrer, and reflux condenser, add methyl tert-butyl ether (800 mL) and bis(2-bromoethyl)amine hydrobromide (155.9 g, 0.5 mol, 1.0 e.q.). Start stirring, and add sodium carbonate (68.9 g, 0.65 mol, 1.3 e.q.) in batches. Cool to control the internal temperature at 0 - 10 °C, and dropwise add acetyl chloride (43.2 g, 0.55 mol, 1.1 e.q.) and 45 mL of methyl tert-butyl ether solution. After dropping, react at 25 °C for 8 hours, and monitor the reaction by TLC until the raw materials are completely reacted; add water (250 mL), stir, let stand, and separate the layers. Keep the organic layer in the kettle; under nitrogen protection, add sodium bicarbonate (126.0 g, 1.5 mol, 3 e.q.), tetrabutylammonium iodide (5.54 g, 0.015 mol, 0.03 e.q.), and p-aminophenol (54.6 g, 0.5 mol, 1 e.q.). Stir, heat, and keep the reaction at 60 °C for 20 hours, and monitor the reaction by TLC until the raw materials are completely reacted; recover methyl tert-butyl ether by vacuum distillation; add water (600 mL), cool, filter by suction, recrystallize the filter cake with 95% ethanol, and dry it under vacuum to obtain 98.7 g of white crystals, with an HPLC purity of 99.7% and a yield of 89.6% (calculated based on bis(2-bromoethyl)amine hydrobromide). The HPLC purity chart of 1-acetyl-4-(4-hydroxyphenyl)piperazine is as shown in Figure 1 shown; the hydrogen NMR chart of 1-acetyl-4-(4-hydroxyphenyl)piperazine is as shown in Figure 2 shown, 1 HNMR(400MHz,DMSO-d 6 )δ: 8.90(s,1H),6.82 - 6.78(m,2H),6.68 - 6.64(m,2H),3.56 - 3.52(m,4H),2.95 - 2.86(m,4H),2.02(s,3H).

[0031] Example 2:

[0032] In a dry reaction kettle equipped with a thermometer, a stirrer, and a reflux condenser, add 2-methyltetrahydrofuran (800 mL) and bis(2-bromoethyl)amine hydrobromide (155.9 g, 0.5 mol, 1.0 e.q.). Start stirring, and add sodium carbonate (68.9 g, 0.65 mol, 1.3 e.q.) in batches. Cool to control the internal temperature at 0 - 10 °C, and dropwise add acetyl chloride (43.2 g, 0.55 mol, 1.1 e.q.) and 45 mL of 2-methyltetrahydrofuran solution. After dropping, react at 35 °C for 4 hours, and monitor the reaction by TLC. When the raw materials have completely reacted; add water (250 mL), stir, let stand, and separate the layers. Keep the organic layer in the kettle; under nitrogen protection, add sodium bicarbonate (84.1 g, 1.0 mol, 2 e.q.), tetrabutylammonium iodide (9.24 g, 0.025 mol, 0.05 e.q.), and p-aminophenol (57.3 g, 0.525 mol, 1.05 e.q.), stir, heat, and keep the reaction at 80 °C for 12 hours. Monitor the reaction by TLC. When the raw materials have completely reacted; recover 2-methyltetrahydrofuran by vacuum distillation; add water (600 mL), cool, filter by suction, recrystallize the filter cake with 95% ethanol, and dry it under vacuum to obtain 97.5 g of white crystals, with an HPLC purity of 99.6% and a yield of 88.5% (calculated based on bis(2-bromoethyl)amine hydrobromide).

[0033] Example 3:

[0034] In a dry reaction kettle equipped with a thermometer, a stirrer, and a reflux condenser, add methyl tert-butyl ether (800 mL) and bis(2-bromoethyl)amine hydrobromide (155.9 g, 0.5 mol, 1.0 e.q.). Start stirring, and add potassium carbonate (110.6 g, 0.8 mol, 1.6 e.q.) in batches. Cool to control the internal temperature at 0 - 10 °C, and dropwise add acetyl chloride (51 g, 0.65 mol, 1.3 e.q.) and 45 mL of methyl tert-butyl ether solution. After dropping, react at 25 °C for 8 hours, and monitor the reaction by TLC. When the raw materials have completely reacted; add water (350 mL), stir, let stand, and separate the layers. Keep the organic layer in the kettle; under nitrogen protection, add potassium bicarbonate (250.3 g, 2.5 mol, 5 e.q.), tetrabutylammonium iodide (18.5 g, 0.05 mol, 0.1 e.q.), and p-aminophenol (60.0 g, 0.55 mol, 1.1 e.q.), stir, heat, and keep the reaction at 60 °C for 26 hours. Monitor the reaction by TLC. When the raw materials have completely reacted; recover methyl tert-butyl ether by vacuum distillation; add water (1000 mL), cool, filter by suction, recrystallize the filter cake with 95% ethanol, and dry it under vacuum to obtain 97.7 g of white crystals, with an HPLC purity of 99.6% and a yield of 88.7% (calculated based on bis(2-bromoethyl)amine hydrobromide).

[0035] Example 4:

[0036] In a dry reaction kettle equipped with a thermometer, a stirrer, and a reflux condenser, add 2-methyltetrahydrofuran (800 mL) and bis(2-bromoethyl)amine hydrobromide (155.9 g, 0.5 mol, 1.0 e.q.). Start stirring and add sodium carbonate (68.9 g, 0.65 mol, 1.3 e.q.) in batches. Cool to control the internal temperature at 0 - 10 °C, and dropwise add acetyl chloride (43.2 g, 0.55 mol, 1.1 e.q.) and 45 mL of 2-methyltetrahydrofuran solution. After dropping, react at 10 °C for 8 hours, and monitor the reaction by TLC until the raw materials are completely reacted; add water (250 mL), stir, let stand, and separate the layers. Keep the organic layer in the kettle; under nitrogen protection, add sodium carbonate (79.5 g, 0.75 mol, 1.5 e.q.), tetrabutylammonium iodide (9.24 g, 0.025 mol, 0.05 e.q.), and p-aminophenol (65.5 g, 0.6 mol, 1.2 e.q.), stir, heat, and hold the reaction at 90 °C for 8 hours. Monitor the reaction by TLC until the raw materials are completely reacted; recover 2-methyltetrahydrofuran by vacuum distillation; add water (600 mL), cool, filter by suction, recrystallize the filter cake with 95% ethanol, and dry it under vacuum to obtain 98.1 g of white crystals with an HPLC purity of 99.5% and a yield of 89.1% (calculated based on bis(2-bromoethyl)amine hydrobromide).

Claims

1. A preparation method of 1-acetyl-4-(4-hydroxyphenyl)piperazine, characterized in that, it includes: Among them, this method undergoes two-step reactions in a reaction kettle. In the step of preparing compound Ⅲ from compound Ⅱ, first add a reaction solvent and bis(2-bromoethyl)amine hydrobromide, stir, add base 1 in batches, control the internal temperature at 0-10 °C, dropwise add a solution of acetyl chloride and the reaction solvent. After the dropwise addition is completed, control the reaction temperature at 10-35 °C, and react for 4-8 hours until the reaction is complete; add water, stir, stand still, and separate layers, and leave the organic layer in the reaction kettle; The reaction solvent is one of methyl tert-butyl ether and 2-methyltetrahydrofuran; the base 1 is one of sodium carbonate and potassium carbonate; the molar ratio of compound Ⅱ, base 1 and acetyl chloride is 1:1.3-1.6:1.1-1.3; In the step of preparing compound Ⅰ from compound Ⅲ, under nitrogen protection, add base 2, tetrabutylammonium iodide, and p-aminophenol to the reaction kettle, stir, heat until the reaction is complete; perform post-treatment to obtain compound Ⅰ; The steps of the post-treatment are to first remove the solvent by vacuum distillation, then add water, cool, filter by suction, recrystallize the filter cake with 95% ethanol, and dry it under vacuum to obtain compound Ⅰ.

2. The preparation method of 1-acetyl-4-(4-hydroxyphenyl)piperazine according to claim 1, characterized in that, In the step of preparing compound Ⅰ from compound Ⅲ, the base 2 is one of sodium carbonate, sodium bicarbonate, and potassium bicarbonate.

3. The preparation method of 1-acetyl-4-(4-hydroxyphenyl)piperazine according to claim 1 or 2, characterized in that, In the step of preparing compound Ⅰ from compound Ⅲ, the molar ratio of compound Ⅲ, p-aminophenol, tetrabutylammonium iodide and base 2 is 1:1-1.2:0.03-0.1:1.5-5.

4. The preparation method of 1-acetyl-4-(4-hydroxyphenyl)piperazine according to claim 1, characterized in that, In the step of preparing compound Ⅰ from compound Ⅲ, the reaction temperature is 60-90 °C, and the reaction time is 8h-26h.

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