Synthesis method of 1-(4-aminophenyl)-4-(4-hydroxyphenyl) piperazine

Abstract

The invention relates to the field of organic synthesis, in particular to a synthesis method of 1-(4-aminophenyl)-4-(4-hydroxyphenyl) piperazine. The preparation method comprises the following steps: taking a compound 1 and piperazine as raw materials, and carrying out Buchwald-Harwig coupling reaction, selectable protection group removal, reaction with ammonium acetate and hydrolysis steps to finally prepare the product disclosed by the invention. The invention provides a new synthesis route, the raw materials are easy to obtain, the operation steps are conventional chemical reactions, the method is simple, the operability is strong, the yield and the 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, in particular to a synthesis method of 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine. Background technique

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

[0003]

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

[0005] There are many known synthesis methods of posaconazole at present, and basically all adopt the convergent synthesis method. According to the structure of posaconazole, it can ...

Examples

Embodiment 1

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

[0048]

[0049] 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 D, and 19.549g of cesium carbonate in a 100ml reaction bottle (60mmol), after the addition, the temperature was raised to reflux for 1 hour. After cooling down to room temperature, it was filtered, and the filtrate was concentrated to dryness and passed through a column to obtain 4.487 g of off-white solid (purity 98%, yield 83%). The experimental data of the hydrogen spectrum spectrum obtained by the nuclear magnetic hydrogen spectrum experiment are: 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 20ml of acetic acid, 2.703g (10mmol) of 4,4'-(piperazine-1,4-bis)phenol, 7.708g (100mmol) of ammonium ace...

Embodiment 2

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

[0058]

[0059] Prepare a 100ml reaction bottle, pretreatment to keep dry and nitrogen blanketing, add ethylene glycol dimethyl ether 40ml, catalyst [Pd(IPr)Cl 2 ] 2 0.056g, 1.8g of potassium tert-amylate, 0.431g (5mmol) of piperazine, and 3.085g (12mmol) of p-bromophenoxytetrahydropyran, after the addition, the temperature was raised to 80°C for 1 hour to react. Then cool down to room temperature, add dropwise 5% ammonium chloride aqueous solution 80g below 20°C under temperature control, extract the reaction solution with 200g of dichloromethane, then concentrate to dryness, pass through the column to obtain 2.036g of off-white solid (purity 99%, yield 96%) ). The experimental data of the hydrogen spectrum spectrum obtained by the nuclear magnetic hydrogen spectrum experiment are: 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,...

Embodiment 3

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

[0068]

[0069] Prepare a 100ml reaction bottle, pretreatment to keep dry and nitrogen blanketing, add toluene 40ml, catalyst palladium acetate 0.025g, potassium tert-amylate 1.8g, piperazine 0.431g (5mmol), p-methoxybromobenzene 2.244g (12mmol), heated up to 110°C for 1 hour after addition. Then cool down to room temperature, add dropwise 5% ammonium chloride aqueous solution 80g below 20°C under temperature control, extract the reaction solution with 200g of dichloromethane, then concentrate to dryness, pass through the column to obtain 1.343g of off-white solid (purity 99%, yield 90%) ). The experimental data of the hydrogen spectrum spectrum obtained by the nuclear magnetic hydrogen spectrum experiment are: 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 reactio...

technical field

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

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

[0003]

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

[0005] There are many known synthesis methods of posaconazole at present, and basically all adopt the convergent synthesis method. According to the structure of posaconazole, it can ...

Examples

Embodiment 1

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

[0048]

[0049] 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 D, and 19.549g of cesium carbonate in a 100ml reaction bottle (60mmol), after the addition, the temperature was raised to reflux for 1 hour. After cooling down to room temperature, it was filtered, and the filtrate was concentrated to dryness and passed through a column to obtain 4.487 g of off-white solid (purity 98%, yield 83%). The experimental data of the hydrogen spectrum spectrum obtained by the nuclear magnetic hydrogen spectrum experiment are: 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 20ml of acetic acid, 2.703g (10mmol) of 4,4'-(piperazine-1,4-bis)phenol, 7.708g (100mmol) of ammonium ace...

Embodiment 2

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

[0058]

[0059] Prepare a 100ml reaction bottle, pretreatment to keep dry and nitrogen blanketing, add ethylene glycol dimethyl ether 40ml, catalyst [Pd(IPr)Cl 2 ] 2 0.056g, 1.8g of potassium tert-amylate, 0.431g (5mmol) of piperazine, and 3.085g (12mmol) of p-bromophenoxytetrahydropyran, after the addition, the temperature was raised to 80°C for 1 hour to react. Then cool down to room temperature, add dropwise 5% ammonium chloride aqueous solution 80g below 20°C under temperature control, extract the reaction solution with 200g of dichloromethane, then concentrate to dryness, pass through the column to obtain 2.036g of off-white solid (purity 99%, yield 96%) ). The experimental data of the hydrogen spectrum spectrum obtained by the nuclear magnetic hydrogen spectrum experiment are: 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,...

Embodiment 3

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

[0068]

[0069] Prepare a 100ml reaction bottle, pretreatment to keep dry and nitrogen blanketing, add toluene 40ml, catalyst palladium acetate 0.025g, potassium tert-amylate 1.8g, piperazine 0.431g (5mmol), p-methoxybromobenzene 2.244g (12mmol), heated up to 110°C for 1 hour after addition. Then cool down to room temperature, add dropwise 5% ammonium chloride aqueous solution 80g below 20°C under temperature control, extract the reaction solution with 200g of dichloromethane, then concentrate to dryness, pass through the column to obtain 1.343g of off-white solid (purity 99%, yield 90%) ). The experimental data of the hydrogen spectrum spectrum obtained by the nuclear magnetic hydrogen spectrum experiment are: 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 reactio...

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