A preparation method of ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate

Abstract

The present invention discloses a preparation method of ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate. Using compound II as a raw material, the present invention reacts with compound III in an acetic acid / sodium dihydrogen phosphate system for selective monoethoxycarbonylation to obtain compound IV, and compound IV then reacts with 4-bromophenol to generate ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate (compound I). This method produces fewer diethoxycarbonyl impurities and can be directly used in the next reaction without purification to remove them; it avoids rectification and purification, has fewer synthesis steps, low losses, and simple operation; it avoids the generation of phenol ester impurities, and the obtained compound I has a purity of 99.69% and a yield of 92.3%, and can be used for large-scale production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a preparation method of ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate. Background Art

[0002] Sinefungin is a new broad-spectrum imidazole antifungal drug, which is a derivative of ketoconazole, and its structural formula is as follows:

[0003]

[0004] Compared with ketoconazole, sinefungin is suitable for use in the field of personal care products, has been included in the scope of use of European personal care products, and has broad market prospects.

[0005] Ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate (Compound I) is a key intermediate for the synthesis of sinefungin. Studying the preparation process of ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate has important value.

[0006] At present, there are few reported synthetic routes for ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate. Patent DE2804096, 1978 discloses a method for synthesizing ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate using ethyl chloroformate and 4-(1-piperazinyl)phenol dihydrobromide as raw materials in the presence of potassium carbonate. The raw material 4-(1-piperazinyl)phenol dihydrobromide has two active groups, namely the phenolic hydroxyl group and the nitrogen end of piperazine, both of which can react with acylating reagents to form corresponding esters or amides, resulting in poor selectivity and low yield.

[0007] Patent CN101665490B reports the preparation method of ketoconazole derivatives as follows:

[0008]

[0009] Reagents and conditions: (a) dichloroethylamine hydrochloride, 50% NaOH, methanol, yield: 71.9%; (b) ethyl chloroformate, sodium bicarbonate, acetone, 75% ethanol, yield: 58.4%.

[0010] In the above method, the total yield of synthesizing Compound I is only 42%, and the yield is relatively low, which is not suitable for large-scale preparation. Summary of the Invention

[0011] Objective of the Invention: In order to overcome the defects existing in the prior art, the present invention discloses a preparation method of ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate. The present invention uses piperazine (Compound II) as a raw material, reacts with ethoxycarbonylimidazole (Compound III) in an acetic acid / sodium dihydrogen phosphate system for selective mono-ethoxycarbonylation, and then reacts with 4-bromophenol to synthesize ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate (Compound I).

[0012] The preparation method of ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate in the present invention comprises:

[0013]

[0014] Wherein:

[0015] In the step of preparing Compound IV from Compound II and Compound III, first add Solvent 1, acetic acid, and sodium dihydrogen phosphate, start stirring, then add Compound II and Compound III, heat, and raise the temperature to Temperature 1 for reaction; cool, adjust the pH, stir, stand, and separate layers, dry the organic layer, filter by suction, and concentrate the filtrate to obtain the crude product of Compound IV;

[0016] In the step of preparing Compound I from Compound IV, add Solvent 2 and 4-bromophenol to the crude product of Compound IV, stir, then add cesium carbonate and copper(I) iodide, heat, and raise the temperature to Temperature 2 for reaction, and then obtain Compound I after post-treatment and purification.

[0017] In the step of preparing Compound IV from Compound II and Compound III, the molar ratio of Compound II, Compound III, acetic acid to sodium dihydrogen phosphate is 1:1.05 - 1.5:0.5 - 2:0.5 - 2.

[0018] In the step of preparing Compound IV from Compound II and Compound III, the Temperature 1 is 25 - 65 °C.

[0019] In the step of preparing Compound IV from Compound II and Compound III, the Solvent 1 is dichloromethane or methyl tert-butyl ether.

[0020] In the step of preparing Compound I from Compound IV, the molar ratio of Compound IV, 4-bromophenol, cesium carbonate to copper(I) iodide is 1:1 - 1.5:0.75 - 1.25:0.05 - 0.5.

[0021] In the step of preparing Compound I from Compound IV, the Solvent 2 is 1,4-dioxane, 2-methyltetrahydrofuran or tetrahydrofuran.

[0022] In the step of preparing Compound I from Compound IV, the Temperature 2 is 70 - 100 °C.

[0023] In the step of preparing Compound I from Compound IV, the post-treatment step is to recover Solvent 2 by vacuum distillation; add water, cool, filter by suction, add ethanol to the filter cake, heat to dissolve, add activated carbon and sodium dithionite, stir for decolorization, filter while it is hot, cool for crystallization, and dry in vacuum to obtain Compound I.

[0024] Advantages: This method produces less diethoxycarbonyl impurity and does not require purification. It can directly proceed to the next reaction to remove the diethoxycarbonyl impurity; it avoids rectification and purification, has fewer synthesis steps, lower losses, and simple operation; and it avoids the generation of phenol ester impurities. The obtained Compound I has high purity and good color. The purity reaches 99.69% and the yield reaches 92.3%, which can be used for large-scale production. Description of the Drawings

[0025] Figure 1 It is the HPLC purity diagram of ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate for Example 1;

[0026] Figure 2 It is the 1H NMR spectrum diagram of ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate for Example 1. Detailed Description of the Invention

[0027] Example 1:

[0028] Preparation of Compound IV

[0029]

[0030] In a dry reaction kettle equipped with a thermometer, a stirrer, and a reflux condenser, add dichloromethane (345 mL), acetic acid (48 g, 0.8 mol, 2 eq.), sodium dihydrogen phosphate (48 g, 0.4 mol, 1 eq.), start stirring, then add piperazine (Compound II) (34.5 g, 0.4 mol, 1 eq.) and ethoxycarbonylimidazole (Compound III) (67.3 g, 0.48 mol, 1.2 eq.), heat, and react at 45 °C for 4 hours; cool, adjust the pH to greater than 8 with an aqueous sodium carbonate solution, stir, let stand, and separate layers. The organic layer is dried with anhydrous sodium sulfate, filtered by suction, and the filtrate is concentrated to obtain 64.1 g of concentrated liquid Compound IV (i.e., ethyl N-piperazinecarboxylate). The crude product yield is 100%, and it directly proceeds to the next step without purification.

[0031] Preparation of Compound I

[0032]

[0033] In a dry reaction kettle equipped with a thermometer, a stirrer, and a reflux condenser, under nitrogen protection, add 1,4-dioxane (600 mL), ethyl N-piperazinecarboxylate (Compound Ⅳ) (63.3 g, 0.4 mol, 1 eq.), 4-bromophenol (69.2 g, 0.4 mol, 1 eq.). Start stirring, then add cesium carbonate (97.7 g, 0.3 mol, 0.75 eq.), copper(I) iodide (7.6 g, 0.04 mol, 0.1 eq.). Heat to 100 °C and react for 20 hours. Monitor by TLC until the raw materials are completely reacted; recover 1,4-dioxane by vacuum distillation; add water (300 mL), cool, filter by suction. Add ethanol to the filter cake, heat to dissolve, add activated carbon and a small amount of sodium dithionite, stir for decolorization, filter while hot, cool to crystallize, and dry in vacuo to obtain 91.1 g of white crystals with an HPLC purity of 99.69% and a yield of 90.9%. The HPLC purity diagram is as shown in Figure 1 shown; the 1H NMR spectrum diagram is as shown in Figure 2 shown.

[0034] Example 2:

[0035] Preparation of Compound Ⅳ

[0036]

[0037] In a dry reaction kettle equipped with a thermometer, a stirrer, and a reflux condenser, add dichloromethane (345 mL), acetic acid (24 g, 0.4 mol, 1 eq.), sodium dihydrogen phosphate (24 g, 0.2 mol, 0.5 eq.). Start stirring, then add piperazine (34.5 g, 0.4 mol, 1 eq.), ethoxycarbonylimidazole (58.9 g, 0.42 mol, 1.05 eq.). React at 25 °C for 16 hours; cool, adjust the pH to greater than 8 with an aqueous sodium carbonate solution, stir, let stand, and separate the layers. Dry the organic layer with anhydrous sodium sulfate, filter by suction, and concentrate the filtrate to obtain 63.5 g of concentrated solution of Compound Ⅳ (i.e., ethyl N-piperazinecarboxylate) with a yield of 100%. Proceed to the next step without purification.

[0038] Preparation of Compound Ⅰ

[0039]

[0040] In a dry reaction kettle equipped with a thermometer, a stirrer, and a reflux condenser, under nitrogen protection, add 1,4-dioxane (600 mL), ethyl N-piperazinecarboxylate (Compound IV) (63.3 g, 0.4 mol, 1 eq.), 4-bromophenol (76.1 g, 0.44 mol, 1.1 eq.). Start stirring, then add cesium carbonate (97.7 g, 0.3 mol, 0.75 eq.) and copper(I) iodide (3.8 g, 0.02 mol, 0.05 eq.). Heat the mixture to 100 °C and react for 20 hours. Monitor the reaction by TLC until the raw materials are completely reacted. Recover 1,4-dioxane by vacuum distillation. Add water (300 mL), cool the mixture, and filter it by suction. Add ethanol to the filter cake, heat to dissolve, add activated carbon and a small amount of sodium dithionite, stir to decolorize, filter while it is hot, cool to crystallize, and dry under vacuum to obtain 92.4 g of white crystals. The HPLC purity is 99.69%, and the yield is 92.3%.

[0041] Example 3:

[0042] Preparation of Compound IV

[0043]

[0044] In a dry reaction kettle equipped with a thermometer, a stirrer, and a reflux condenser, add methyl tert-butyl ether (500 mL), acetic acid (24 g, 0.4 mol, 1 eq.), and sodium dihydrogen phosphate (72 g, 0.6 mol, 1.5 eq.). Start stirring, then add piperazine (Compound II) (34.5 g, 0.4 mol, 1 eq.) and ethoxycarbonylimidazole (Compound III) (84.1 g, 0.6 mol, 1.5 eq.). Heat the mixture to 65 °C and react for 3 hours. Cool the mixture, adjust the pH to greater than 8 with an aqueous sodium carbonate solution, stir, let it stand, and separate the layers. Dry the organic layer with anhydrous sodium sulfate, filter by suction, and concentrate the filtrate to obtain 63.9 g of concentrated liquid Compound IV (i.e., ethyl N-piperazinecarboxylate). The crude yield is 100%, and it is directly used for the next step without purification.

[0045] Preparation of Compound I

[0046]

[0047] In a dry reaction kettle equipped with a thermometer, a stirrer, and a reflux condenser, under nitrogen protection, add 2-methyltetrahydrofuran (800 mL), ethyl N-piperazinecarboxylate (Compound Ⅳ) (63.3 g, 0.4 mol, 1 eq.), 4-bromophenol (103.8 g, 0.6 mol, 1.5 eq.). Start stirring, then add cesium carbonate (130.3 g, 0.4 mol, 1 eq.) and copper(I) iodide (22.9 g, 0.12 mol, 0.3 eq.). Heat to 80 °C and react for 20 hours. Monitor the reaction by TLC until the raw materials are completely reacted. Recover 2-methyltetrahydrofuran by vacuum distillation. Add water (400 mL), cool, filter by suction. Add ethanol to the filter cake, heat to dissolve, add activated carbon and a small amount of sodium dithionite, stir for decolorization, filter while hot, cool to crystallize, and dry in vacuum to obtain 90.6 g of white crystals, with an HPLC purity of 99.5% and a yield of 90.5%.

[0048] Example 4:

[0049] Preparation of Compound Ⅳ

[0050]

[0051] In a dry reaction kettle equipped with a thermometer, a stirrer, and a reflux condenser, add dichloromethane (500 mL), acetic acid (12 g, 0.2 mol, 0.5 eq.), sodium dihydrogen phosphate (96 g, 0.8 mol, 2 eq.). Start stirring, then add piperazine (Compound Ⅱ) (34.5 g, 0.4 mol, 1 eq.) and ethoxycarbonylimidazole (Compound Ⅲ) (67.3 g, 0.48 mol, 1.2 eq.). Heat to 45 °C and react for 4 hours. Cool, adjust the pH to greater than 8 with aqueous sodium carbonate solution, stir, let stand, and separate the layers. Dry the organic layer with anhydrous sodium sulfate, filter by suction, and concentrate the filtrate to obtain 64.2 g of concentrated liquid of Compound Ⅳ (i.e., ethyl N-piperazinecarboxylate), with a crude yield of 100%. Proceed to the next step without purification.

[0052] Preparation of Compound Ⅰ

[0053]

[0054] In a dry reaction kettle equipped with a thermometer, stirrer, and reflux condenser, under nitrogen protection, add tetrahydrofuran (800 mL), ethyl N-piperazinecarboxylate (Compound IV) (63.3 g, 0.4 mol, 1 eq.), 4-bromophenol (83.0 g, 0.48 mol, 1.2 eq.). Start stirring, then add cesium carbonate (162.9 g, 0.5 mol, 1.25 eq.) and copper(I) iodide (38.1 g, 0.2 mol, 0.5 eq.). Heat to 70 °C and react for 24 hours. Monitor the reaction by TLC until the raw materials are completely reacted. Recover tetrahydrofuran by vacuum distillation. Add water (400 mL), cool, filter by suction. Add ethanol to the filter cake, heat to dissolve, add activated carbon and a small amount of sodium dithionite, stir for decolorization, filter while hot, cool for crystallization, and dry under vacuum to obtain 91.9 g of white crystals. The HPLC purity is 99.5% and the yield is 91.8%.

[0055] The above specific embodiments further elaborate on the purpose, technical solution, and beneficial effects of the present application. It should be understood that the above are only the specific embodiments of the present application and are not used to limit the protection scope of the present application. Any modifications, equivalent replacements, improvements, etc. made on the basis of the technical solution of the present application shall be included in the protection scope of the present application.

Claims

1. A preparation method of ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate, characterized in that, Comprising: Wherein: In the step of preparing Compound IV from Compound II and Compound III, first add Solvent 1, acetic acid, and sodium dihydrogen phosphate, start stirring, then add Compound II and Compound III, heat up to Temperature 1 for reaction; cool down, adjust the pH, stir, stand still, and separate layers. The organic layer is dried, filtered by suction, and the filtrate is concentrated to obtain the crude product of Compound IV; In the step of preparing Compound I from Compound IV, add Solvent 2 and 4-bromophenol to the crude product of Compound IV, stir, then add cesium carbonate and copper iodide, heat up to Temperature 2 for reaction, and after post-treatment and purification, Compound I is obtained; the Temperature 2 is 70 - 100 °C.

2. The preparation method of ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate according to claim 1, characterized in that, In the step of preparing Compound IV from Compound II and Compound III, the molar ratio of Compound II, Compound III, acetic acid to sodium dihydrogen phosphate is 1:1.05 - 1.5:0.5 - 2:0.5 - 2.

3. The preparation method of ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate according to claim 1, characterized in that, In the step of preparing Compound IV from Compound II and Compound III, the Temperature 1 is 25 - 65 °C.

4. The preparation method of ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate according to claim 1, characterized in that, In the step of preparing Compound IV from Compound II and Compound III, the Solvent 1 is dichloromethane or methyl tert-butyl ether.

5. The preparation method of ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate according to claim 1, characterized in that, In the step of preparing Compound I from Compound IV, the molar ratio of Compound IV, 4-bromophenol, cesium carbonate to copper iodide is 1:1 - 1.5:0.75 - 1.25:0.05 - 0.

5.

6. The preparation method of ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate according to claim 1, wherein In the step of preparing Compound I from Compound IV, the Solvent 2 is 1,4-dioxane, 2-methyltetrahydrofuran or tetrahydrofuran.

7. The preparation method of ethyl 4-(4-hydroxyphenyl)-1-piperazinecarboxylate according to claim 1, characterized in that, In the step of preparing Compound I from Compound IV, the post-treatment step is to recover Solvent 2 by vacuum distillation; add water, cool down, filter by suction, add ethanol to the filter cake, heat to dissolve, add activated carbon and sodium dithionite, stir for decolorization, filter while hot, cool for crystallization, and dry in vacuum to obtain Compound I.

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