Preparation method of 4-[4-[4-(4-hydroxyphenyl) piperazine-1-yl] phenyl] phenyl carbamate

Abstract

The invention discloses a preparation method of 4-[4-[4-(4-hydroxyphenyl) piperazine-1-yl] phenyl] phenyl carbamate, which comprises the following steps: by taking 4-hydroxyaniline as a raw material, carrying out ring closing on the 4-hydroxyaniline and dichloroethylamine hydrochloride to synthesize 1-(4-hydroxyphenyl) piperazine with the purity of 95A% and the correction yield of 80%; 4-nitrochlorobenzene and the prepared 1-(4-hydroxyphenyl) piperazine are coupled to synthesize 4-(4-(4-nitrophenyl)-1-piperazinyl) phenol, the purity is 93 A%, and the correction yield is 88%; then carrying out nitro reduction to synthesize 1-(4-aminophenyl)-4-(4-hydroxyphenyl) piperazine with the purity of 98A% and the correction yield of 77%; and finally, synthesizing 4-[4-[4-(4-hydroxyphenyl) piperazine-1-yl] phenyl] phenyl carbamate with the purity of 98.7%, the content of 98.5 wt% and the correction yield of 83% by using phenyl chloroformate to protect phenolic hydroxyl groups. According to the invention, the high-purity target product 4-[4-[4-(4-hydroxyphenyl) piperazine-1-yl] phenyl] phenyl carbamate can be obtained through easily available raw materials and simple process steps.

Description

technical field

[0001] The invention relates to a preparation method of phenyl 4-[4-[4-(4-hydroxyphenyl)piperazin-1-yl]phenyl]carbamate, which belongs to the technical field of pharmaceutical intermediate synthesis. Background technique

[0002] Posaconazole is suitable for fungemia caused by fungi of the genus Candida and Cryptococcus, respiratory, gastrointestinal, urinary tract mycosis, peritonitis, meningitis, etc. It is also clinically used for the treatment of aspergillosis, zygomycosis, fusarium disease, and some Candida infections. Studies have shown that posaconazole can widely and effectively treat phaeohyphomycosis and improve the survival rate of patients infected with exophthias dermatitis. As a second-line drug, the effective rate for invasive aspergillosis resistant to amphotericin B or itraconazole is 44% to 78%, and the effective rate for zygomycete infection is 71%.

[0003] While the new crown epidemic is becoming more and more serious in India, mucormyc...

Examples

preparation example Construction

[0060] The preparation method of 4-[4-[4-(4-hydroxyphenyl) piperazin-1-yl] phenyl] phenyl carbamate of the present invention comprises the following steps:

[0061] S1 prepares 1-(4-hydroxyphenyl) piperazine;

[0062] S2 prepares 4-(4-(4-nitrophenyl)-1-piperazinyl)phenol;

[0063] S3 prepares 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine;

[0064] S4 prepares 4-[4-[4-(4-hydroxyphenyl) piperazin-1-yl] phenyl] phenyl carbamate;

[0065] The reaction formula of S1~S4 process is as follows:

[0066]

[0067] Among them, 1 is 4-hydroxyaniline, 2 is 1-(4-hydroxyphenyl) piperazine, 3 is 4-(4-(4-nitrophenyl)-1-piperazinyl) phenol, 4 is 1 -(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine, 5 is 4-[4-[4-(4-hydroxyphenyl)piperazin-1-yl]phenyl]carbamic acid phenyl esters.

Embodiment 1

[0069] The present embodiment provides a preparation method of 4-[4-[4-(4-hydroxyphenyl)piperazin-1-yl]phenyl]phenyl carbamate, specifically as follows:

[0070] S1 prepares 1-(4-hydroxyphenyl) piperazine

[0071] In reactor, add 4-hydroxyaniline (30kg, 27.5mol, 1eq.), dichloroethylamine hydrochloride (99kg, 55mol, 2eq.) and water (300L, 10vol); Then add sodium hydroxide (11kg, 27.5mol, 1eq.). Heat the reaction solution I to 50-60°C, and continue to react for 6h at a temperature of 50-60°C; then take a sample of the liquid phase control (210nm), of which 92% is the target product and 4% is the raw material; the reaction solution is cooled to After 10-20°C, adjust the pH of the reaction solution to 7-8 with 5% aqueous sodium hydroxide solution. After a large amount of solids are precipitated, remove the filtrate by filtration, rinse the filter cake I with acetone (60L, 2v), and dry the rinsed Filter cake I yielded 64 kg of 1-(4-hydroxyphenyl)piperazine.

[0072] The obtained...

Embodiment 2

[0087] S1 prepares 1-(4-hydroxyphenyl) piperazine

[0088] Add 4-hydroxyaniline (30g, 275mmol, 1eq.), dibromoethylamine hydrochloride (147g, 550mmol, 2eq.) and water (300mL, 10vol) into the reaction kettle; Then add sodium hydroxide (11g, 27.5 mol, 1 eq.). Heat the reaction solution I to 50-60°C, and continue to react for 6h at a temperature of 50-60°C; then take a sample of the liquid phase control (210nm), of which 85% is the target product and 5% is the raw material; the reaction solution is cooled to After 10-20°C, adjust the pH of the reaction solution to 7-8 with 5% aqueous sodium hydroxide solution. After a large amount of solids are precipitated, remove the filtrate by filtration, rinse the filter cake I with acetone (60mL, 2v), and dry the rinsed Filter cake I yielded 50 g of 1-(4-hydroxyphenyl)piperazine.

[0089] S2 prepares 4-(4-(4-nitrophenyl)-1-piperazinyl)phenol

[0090] Add the prepared 1-(4-hydroxyphenyl)piperazine (10g, 46.6mmol, 1.0eq.), p-nitrobromobenze...

technical field

[0001] The invention relates to a preparation method of phenyl 4-[4-[4-(4-hydroxyphenyl)piperazin-1-yl]phenyl]carbamate, which belongs to the technical field of pharmaceutical intermediate synthesis. Background technique

[0002] Posaconazole is suitable for fungemia caused by fungi of the genus Candida and Cryptococcus, respiratory, gastrointestinal, urinary tract mycosis, peritonitis, meningitis, etc. It is also clinically used for the treatment of aspergillosis, zygomycosis, fusarium disease, and some Candida infections. Studies have shown that posaconazole can widely and effectively treat phaeohyphomycosis and improve the survival rate of patients infected with exophthias dermatitis. As a second-line drug, the effective rate for invasive aspergillosis resistant to amphotericin B or itraconazole is 44% to 78%, and the effective rate for zygomycete infection is 71%.

[0003] While the new crown epidemic is becoming more and more serious in India, mucormyc...

Examples

preparation example Construction

[0060] The preparation method of 4-[4-[4-(4-hydroxyphenyl) piperazin-1-yl] phenyl] phenyl carbamate of the present invention comprises the following steps:

[0061] S1 prepares 1-(4-hydroxyphenyl) piperazine;

[0062] S2 prepares 4-(4-(4-nitrophenyl)-1-piperazinyl)phenol;

[0063] S3 prepares 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine;

[0064] S4 prepares 4-[4-[4-(4-hydroxyphenyl) piperazin-1-yl] phenyl] phenyl carbamate;

[0065] The reaction formula of S1~S4 process is as follows:

[0066]

[0067] Among them, 1 is 4-hydroxyaniline, 2 is 1-(4-hydroxyphenyl) piperazine, 3 is 4-(4-(4-nitrophenyl)-1-piperazinyl) phenol, 4 is 1 -(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine, 5 is 4-[4-[4-(4-hydroxyphenyl)piperazin-1-yl]phenyl]carbamic acid phenyl esters.

Embodiment 1

[0069] The present embodiment provides a preparation method of 4-[4-[4-(4-hydroxyphenyl)piperazin-1-yl]phenyl]phenyl carbamate, specifically as follows:

[0070] S1 prepares 1-(4-hydroxyphenyl) piperazine

[0071] In reactor, add 4-hydroxyaniline (30kg, 27.5mol, 1eq.), dichloroethylamine hydrochloride (99kg, 55mol, 2eq.) and water (300L, 10vol); Then add sodium hydroxide (11kg, 27.5mol, 1eq.). Heat the reaction solution I to 50-60°C, and continue to react for 6h at a temperature of 50-60°C; then take a sample of the liquid phase control (210nm), of which 92% is the target product and 4% is the raw material; the reaction solution is cooled to After 10-20°C, adjust the pH of the reaction solution to 7-8 with 5% aqueous sodium hydroxide solution. After a large amount of solids are precipitated, remove the filtrate by filtration, rinse the filter cake I with acetone (60L, 2v), and dry the rinsed Filter cake I yielded 64 kg of 1-(4-hydroxyphenyl)piperazine.

[0072] The obtained...

Embodiment 2

[0087] S1 prepares 1-(4-hydroxyphenyl) piperazine

[0088] Add 4-hydroxyaniline (30g, 275mmol, 1eq.), dibromoethylamine hydrochloride (147g, 550mmol, 2eq.) and water (300mL, 10vol) into the reaction kettle; Then add sodium hydroxide (11g, 27.5 mol, 1 eq.). Heat the reaction solution I to 50-60°C, and continue to react for 6h at a temperature of 50-60°C; then take a sample of the liquid phase control (210nm), of which 85% is the target product and 5% is the raw material; the reaction solution is cooled to After 10-20°C, adjust the pH of the reaction solution to 7-8 with 5% aqueous sodium hydroxide solution. After a large amount of solids are precipitated, remove the filtrate by filtration, rinse the filter cake I with acetone (60mL, 2v), and dry the rinsed Filter cake I yielded 50 g of 1-(4-hydroxyphenyl)piperazine.

[0089] S2 prepares 4-(4-(4-nitrophenyl)-1-piperazinyl)phenol

[0090] Add the prepared 1-(4-hydroxyphenyl)piperazine (10g, 46.6mmol, 1.0eq.), p-nitrobromobenze...

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