A method for synthesizing 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine

Abstract

The present invention relates to the field of organic synthesis, and in particular to a method for synthesizing 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine. The present invention uses compound 1 and piperazine as raw materials, and undergoes Buchwald-Hartwig coupling reaction, optional deprotection group, reaction with ammonium acetate and hydrolysis steps to finally prepare the product of the present invention. The present invention provides a new synthetic route, the raw materials are easily available, the operating steps are all conventional chemical reactions, the process is simple, the operability is strong, the yield and purity are high, and the final product is easier to industrialize.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for synthesizing 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine. Background Art

[0002] Chemical name of posaconazole: 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-1yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one; molecular formula C37H42F2N8O4; relative molecular mass M=700.33; low solubility in water and acidic media.

[0003]

[0004] Posaconazole is a third-generation antifungal drug developed by Schering-Plough Pharmaceuticals Ltd. It was first launched in Germany in December 2005, in the UK in March 2006, and was approved by the FDA in the United States in September 2006.

[0005] There are many known methods for synthesizing posaconazole, and most of them adopt convergent synthesis methods. According to the structure of posaconazole, it is easy to conclude that it is mainly divided into the following three fragments. The existing synthesis methods all start from these three fragments and use a certain order and method to obtain the final product.

[0006]

[0007] These three fragments correspond to the three intermediate structures of posaconazole, and according to fragment 2, 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine is an important intermediate of posaconazole.

[0008] This patent focuses on the synthesis method of 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine. After comprehensive reference, it is found that the synthesis method of 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine mainly includes the following routes:

[0009] The product is prepared by reacting p-methoxyaniline with bis(2-chloroethyl)amine hydrochloride in an organic solvent, and then reacting the product with p-chloronitrobenzene, followed by demethylation, and finally reducing it with palladium on carbon.

[0010]

[0011] The product is prepared by the reaction of p-hydroxyphenylpiperazine with p-chloronitrobenzene and palladium-carbon catalytic reduction.

[0012]

[0013] p-Anisidine and N,N-bis(2-chloroethyl)-4-nitroaniline are used as raw materials, and condensation cyclization, demethylation, and finally catalytic reduction are carried out to obtain the product.

[0014]

[0015] The above technical solutions for preparing 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine process all have the following problems:

[0016] 1. The raw materials used, such as p-hydroxyphenylpiperazine, N,N-bis(2-chloroethyl)-4-nitroaniline and palladium on carbon, are either difficult to purchase or are relatively expensive, which greatly increases the cost of preparing the product.

[0017] 2. The reaction requires the use of hydrobromic acid or hydrogen bromide gas and palladium carbon hydrogenation reduction, which places high demands on the reaction equipment and personnel operation.

[0018] 3. The overall preparation process has a low yield, which greatly increases the production cost and is not conducive to industrial application. Summary of the invention

[0019] In order to solve the above problems, the present invention aims to provide a new synthetic route, the raw materials are easily available, the operation steps are all conventional chemical reactions, it is simple, has strong operability, high yield and purity, and the final product is easier to industrialize.

[0020] In order to achieve the above object, the present invention specifically adopts the following technical solutions:

[0021] A method for synthesizing 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine comprises the following steps:

[0022] (a) using compound 1 and piperazine as raw materials to carry out Buchwald-Hartwig coupling reaction to generate compound 2;

[0023] (b) Compound 2 undergoes a corresponding dehydroxylation reaction to obtain Compound 3;

[0024] (c) Compound 3 is reacted in the presence of ammonium acetate to prepare the corresponding compound 4;

[0025] (d) Compound 4 is hydrolyzed to obtain the final product Compound 5;

[0026]

[0027] wherein X is selected from a halogen group;

[0028] R is selected from hydrogen, C1-C8 branched or straight chain alkyl; 3-8 membered heterocyclic hydrocarbon; aryl; heteroaryl; Ar(CH2) n - group, Ar represents an aryl or heteroaryl group, n = 1-6;

[0029] When R is hydrogen or a 3-8 membered heterocyclic hydrocarbon group, step (b) is omitted.

[0030] The heteroatom in the 3-8 membered heterocyclic hydrocarbon group is selected from O or N.

[0031] Preferably, R is selected from hydrogen, tetrahydropyranyl, and methyl.

[0032] Preferably, the reaction in step (a) is carried out in an organic solvent, and the organic solvent is selected from toluene, xylene, dioxane, ethanol, ethylene glycol, ethylene glycol dimethyl ether or tert-butyl ether.

[0033] Preferably, the specific steps of step (a) are: compound 1 and piperazine are refluxed under the action of a catalyst and an acid binding agent, wherein the catalyst is selected from cuprous iodide, palladium acetate or a palladium complex; and the acid binding agent is selected from cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium tert-amylate or sodium tert-amylate.

[0034] Preferably, the specific reaction steps of step (b) are: when R is a 3-8 membered heterocyclic hydrocarbon group, an organic acid is added to the reaction system of step (b) to control the temperature and remove the protecting group; when R is a C1-C8 branched or straight chain alkyl, aryl, heteroaryl or Ar(CH2) n -group, the protecting group is removed by using boron tribromide at low temperature in step (b).

[0035] Preferably, the organic solvent in step (c) is selected from acetic acid, the organic solvent in step (b) is selected from dichloromethane, and the organic solvent in step (d) is selected from ethylene glycol or methanol.

[0036] Preferably, the specific reaction steps of step (c) are: under the condition of acetic acid as solvent, compound 3 and ammonium acetate are added to the reaction system, and the temperature is raised to 200-220° C. in a sealed manner for reaction.

[0037] Further preferably, the specific reaction steps of step (d) are: compound 4 is subjected to an aminolysis reaction in the presence of an organic solvent and an acid or an organic solvent, an acid and ammonia; or compound 4 is hydrolyzed in the presence of acidic or alkaline water to obtain a product.

[0038] Beneficial effects:

[0039] The present invention provides a new synthetic route, with more readily available raw materials and lower costs;

[0040] The operation steps of the present invention are all conventional chemical reactions, which are simple, convenient and highly operable;

[0041] The product of the invention has high yield and high purity, and the final product is easier to industrialize. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 The hydrogen spectrum of the final product of Example 1 DETAILED DESCRIPTION

[0043] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. The following description of at least one exemplary embodiment is actually only illustrative and is by no means intended to limit the present invention and its application or use. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0044] The present invention is described in detail below with reference to the accompanying drawings to facilitate those skilled in the art to understand the present invention.

[0045] The compounds used in the following examples were purchased from the market.

[0046] Example 1

[0047] Step 1: Preparation of 4,4'-(piperazine-1,4-bis)phenol

[0048]

[0049] In a 100ml reaction bottle, add 50ml of ethanol, 1.723g (20mmol) of piperazine, 12.00g (60mmol) of p-iodophenol, 0.381g (2mmol) of cuprous iodide, 0.687g (4mmol) of metformin D6, and 19.549g (60mmol) of cesium carbonate, and heat to reflux for 1 hour after addition. Then cool to room temperature, filter, concentrate the filtrate to dryness, and pass through a column to obtain 4.487g of off-white solid (purity 98%, yield 83%). The hydrogen spectrum experimental data obtained by nuclear magnetic hydrogen spectrum experiment is: 1 H NMR (400MHz, DMSO) δ6.85–6.73(m,4H),6.59–6.49(m,4H),3.66(s,2H),3.07(s,8H).

[0050] Step 2: Preparation of 1-(4-acetylaminophenyl)-4-(4-hydroxyphenyl)piperazine

[0051]

[0052] Add 20 ml of acetic acid, 2.703 g (10 mmol) of 4,4'-(piperazine-1,4-bis)phenol, and 7.708 g (100 mmol) of ammonium acetate into a 50 ml pressure reactor, close the valve after adding, heat to 220°C and keep warm for 18 hours, cool to 5°C, filter, add 40 ml of toluene to dissolve the filter cake, wash the dissolved organic phase with water, and concentrate to obtain 2.678 g of off-white solid (purity 96%, yield 86%). The experimental data of its hydrogen spectrum obtained by nuclear magnetic hydrogen spectrum experiment is: 1 H NMR (400MHz, DMSO) δ7.66–7.58(m,2H),6.90–6.48(m,6H),5.31(s,1H),3.78(s,1H),3.15–2.96(m,8H),2.08(s,3H).

[0053] Step 3: Preparation of 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine

[0054]

[0055] In a 50ml reaction bottle, add 10ml of methanol and 1.557g (5mmol) of 1-(4-acetylaminophenyl)-4-(4-hydroxyphenyl)piperazine. Add 1.785g (15mmol) of thionyl chloride dropwise at a temperature below 20°C. After adding, heat to reflux for 6 hours. Cool to 0°C, filter, add the filter cake to a 20ml toluene reaction bottle, add 10% dropwise at room temperature to adjust the pH to above 12, stand for phase separation, wash the organic phase with a small amount of water and concentrate to dryness to obtain 1.306g of off-white solid (purity 99%, yield 97%). The hydrogen spectrum of the product is as follows: Figure 1 shown.

[0056] Example 2

[0057] Step 1: Preparation of 1,4-bis(4-((tetrahydropyran-2-yl)oxy)phenyl)piperazine

[0058]

[0059] Prepare a 100ml reaction bottle, keep it dry and nitrogen-sealed in pretreatment, add 40ml of ethylene glycol dimethyl ether, catalyst [Pd(IPr)Cl2]2 0.056g, 1.8g of potassium tert-amyl alcohol, 0.431g (5mmol) of piperazine, and 3.085g (12mmol) of p-bromophenoxytetrahydropyran to the bottle under a nitrogen atmosphere, and heat to 80°C for 1 hour. Then cool to room temperature, add 80g of 5% ammonium chloride aqueous solution at a temperature below 20°C, extract the reaction solution with 200g of dichloromethane, and then concentrate to dryness. Pass the column to obtain 2.036g of off-white solid (purity 99%, yield 96%). The hydrogen spectrum experimental data obtained by nuclear magnetic hydrogen spectrum experiment are as follows:1 H NMR (400MHz, DMSO) δ6.85–6.75(m,4H),6.70–6.60(m,4H),5.82(t,2H),3.20–2.96(m,12H),2.20–1.52(m,12H).

[0060] Step 2: Preparation of 1-(4-acetylaminophenyl)-4-(4-hydroxyphenyl)piperazine

[0061]

[0062] Add 10g of acetic acid, 2.00g (4.7mmol) of 1,4-bis(4-((tetrahydropyran-2-yl)oxy)phenyl)piperazine, and 3.623g (47mmol) of ammonium acetate into a 50ml pressure reactor, close the valve after adding, heat to 200℃ and keep warm for 20 hours, cool to 5℃, filter, add 40ml of toluene to dissolve the filter cake, wash the dissolved organic phase with water, and concentrate to obtain 1.083g of off-white solid (purity 95%, yield 74%). The experimental data of its hydrogen spectrum obtained by nuclear magnetic hydrogen spectrum experiment is: 1 H NMR (400MHz, DMSO) δ7.66–7.56(m,2H),6.95–6.46(m,6H),5.26(s,1H),3.76(s,1H),3.15–2.95(m,8H),2.08(s,3H).

[0063] Step 3: Preparation of 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine

[0064]

[0065] 8 ml of ethylene glycol, 0.934 g (3.0 mmol) of 1-(4-acetylaminophenyl)-4-(4-hydroxyphenyl)piperazine, and 0.147 g (1.5 mmol) of phosphoric acid were added to a 50 ml pressure reactor. 0.409 g (24.0 mmol) of ammonia was added to the reactor at room temperature. The valve was closed and the temperature was raised to 145°C for reaction for 15 hours. The temperature was then lowered to room temperature. 10% was added dropwise at room temperature to adjust the pH to above 12. 50 ml of toluene was then added to the reaction system for extraction. The organic phase was washed with a small amount of water and concentrated to dryness to obtain 0.767 g of an off-white solid (purity 99%, yield 95%). The hydrogen spectrum experimental data obtained by nuclear magnetic hydrogen spectrum experimental analysis are as follows: 1 H NMR (400MHz, DMSO) δ6.97–6.46(m,8H),4.58(s,2H),3.75(s,1H),3.18–2.98(m,8H).

[0066] Example 3

[0067] Step 1: Preparation of 1,4-bis(p-methoxyphenyl)piperazine

[0068]

[0069] Prepare a 100ml reaction bottle, keep it dry and nitrogen-sealed in pretreatment, add 40ml of toluene, 0.025g of catalyst palladium acetate, 1.8g of potassium tert-amyl alcohol, 0.431g (5mmol) of piperazine, and 2.244g (12mmol) of p-methoxybromobenzene to the bottle under a nitrogen atmosphere, and heat to 110°C for 1 hour. Then cool to room temperature, add 80g of 5% ammonium chloride aqueous solution at a temperature below 20°C, extract the reaction solution with 200g of dichloromethane, and then concentrate to dryness. Pass the column to obtain 1.343g of off-white solid (purity 99%, yield 90%). The hydrogen spectrum experimental data obtained by nuclear magnetic hydrogen spectrum experiment are as follows: 1 H NMR (400MHz, DMSO) δ6.85–6.75(m,4H),6.70–6.60(m,4H),3.33(s,6H),3.07(s,8H).

[0070] Step 2: Preparation of 1,4-bis(p-hydroxyphenyl)piperazine

[0071]

[0072] Prepare a 50ml reaction bottle, add 10ml of dichloromethane, 1,4-bis(p-methoxyphenyl)piperazine 1.00g (3.35mmol), cool to -40℃, add dichloromethane solution of boron tribromide (6.7mmol), keep warm at -40℃ for 2 hours, slowly raise the temperature to 20℃, add 10ml of water to quench, stand for phase separation, wash the organic phase with water, and concentrate to dryness to obtain 0.906g of off-white solid (purity 95%, yield 74%). The hydrogen spectrum experimental data obtained by nuclear magnetic hydrogen spectrum experiment is: 1 H NMR (400MHz, DMSO) δ6.85–6.75(m,4H),6.59–6.48(m,4H),3.62(s,2H),3.07(s,8H).

[0073] Step 3: Preparation of 1-(4-acetylaminophenyl)-4-(4-hydroxyphenyl)piperazine

[0074]

[0075] Add 10g of acetic acid, 0.900g (3.33mmol) of 1,4-bis(p-hydroxyphenyl)piperazine, and 2.567g (33.3mmol) of ammonium acetate into a 50ml pressure reactor, close the valve after adding, heat to 200℃ and keep warm for 20 hours, cool to 5℃, filter, add 40ml of toluene to dissolve the filter cake, wash the dissolved organic phase with water, and concentrate to obtain 0.902g of off-white solid (purity 93%, yield 87%). The experimental data of its hydrogen spectrum obtained by nuclear magnetic hydrogen spectrum experiment is: 1 H NMR (400MHz, DMSO) δ7.66–7.56(m,2H),6.96–6.45(m,6H),5.20(s,1H),3.72(s,1H),3.15–2.95(m,8H),2.08(s,3H).

[0076] Step 4: Preparation of 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine

[0077]

[0078] 8 ml of ethylene glycol, 0.900 g (2.89 mmol) of 1-(4-acetylaminophenyl)-4-(4-hydroxyphenyl)piperazine, and 0.147 g (1.5 mmol) of phosphoric acid were added to a 50 ml pressure reactor. 0.409 g (24.0 mmol) of ammonia was added to the reactor at room temperature. The valve was closed, and the temperature was raised to 145°C for reaction for 15 hours. The temperature was then lowered to room temperature. 10% of the reaction mixture was added dropwise at room temperature to adjust the pH to above 12. 50 ml of toluene was then added to the reaction system for extraction. The organic phase was washed with a small amount of water and concentrated to dryness to obtain 0.739 g of an off-white solid (purity 99%, yield 95%). The product was analyzed by hydrogen spectrum, and the experimental data obtained were: 1 H NMR (400MHz, DMSO) δ6.98–6.88(m,2H),6.88–6.79(m,2H),6.79–6.69(m,2H),6.56–6.46(m,2H),4.56(s,2H),3.75(s,1H),3.17–2.98(m,8H).

[0079] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A method for synthesizing 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine, characterized in that: The steps include: (a) using compound 1 and piperazine as raw materials to carry out Buchwald-Hartwig coupling reaction to generate compound 2; (b) Compound 2 undergoes a corresponding dehydroxylation reaction to obtain Compound 3; (c) Compound 3 is reacted in the presence of ammonium acetate to prepare the corresponding compound 4; (d) Compound 4 is hydrolyzed to obtain the final product Compound 5; wherein X is selected from a halogen group; The R is selected from hydrogen, tetrahydropyranyl, methyl, wherein when R is hydrogen, step (b) is omitted; The step (a) is reacted in an organic solvent, wherein the organic solvent is selected from toluene, xylene, dioxane, ethanol, ethylene glycol, ethylene glycol dimethyl ether or tert-butyl ether; The specific steps of step (a) are as follows: Compound 1 and piperazine are subjected to reflux reaction under the action of a catalyst and an acid-binding agent, wherein the catalyst is selected from cuprous iodide, palladium acetate or a palladium complex; and the acid-binding agent is selected from cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium tert-amylate or sodium tert-amylate; The organic solvent in step (c) is selected from acetic acid, the organic solvent in step (b) is selected from dichloromethane, and the organic solvent in step (d) is selected from ethylene glycol or methanol; The specific reaction steps of step (c) are: under the condition of acetic acid as a solvent, compound 3 and ammonium acetate are added into the reaction system, and the temperature is raised to 200-220° C. for reaction in a sealed manner; The specific reaction steps of step (d) are: compound 4 is subjected to an aminolysis reaction in the presence of an organic solvent and an acid or an organic solvent, an acid and ammonia; or compound 4 is hydrolyzed in the presence of acidic or alkaline water to obtain a product.

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