1-(4-Aminophenyl)-4-(4-hydroxyphenyl)piperazine Chemical Properties

Boiling point:

532.8±50.0 °C(Predicted)

Density 

1.237±0.06 g/cm3(Predicted)

storage temp. 

Keep in dark place,Inert atmosphere,Room temperature

solubility 

DMSO (Slightly), Methanol (Very Slightly, Heated)

form 

Solid:crystalline

pka

12.18±0.30(Predicted)

Appearance

Light brown to brown Solid

InChI

InChI=1S/C16H19N3O/c17-13-1-3-14(4-2-13)18-9-11-19(12-10-18)15-5-7-16(20)8-6-15/h1-8,20H,9-12,17H2

InChIKey

WZIJMPVPOMTRNM-UHFFFAOYSA-N

SMILES

C1(O)=CC=C(N2CCN(C3=CC=C(N)C=C3)CC2)C=C1

CAS DataBase Reference

74853-08-0(CAS DataBase Reference)

1-(4-Aminophenyl)-4-(4-hydroxyphenyl)piperazine Usage And Synthesis

Uses

4-[4-(4-Aminophenyl)-1-piperazinyl]phendiamineol is an intermediate of Posaconazole (P689600), which is orally active antifungal triazole.

Synthesis

Under nitrogen protection, 430 g (1.34 mol) of 4-(4-(4-nitrophenyl)-1-piperazinyl)phenol was suspended in 2.8 liters of methoxyethanol at a controlled temperature of 20°C to 25°C. Subsequently, 52 g of palladium-carbon catalyst (5% palladium loading, 50% water content, Degussa Typ E1049) was added. The suspension is degassed (repeated 3 times) and heated to 70°C to 75°C. A solution of 497 g of sodium hypophosphite monohydrate dissolved in 1.12 liters of water is slowly added dropwise over a period of 2 hours. The temperature is maintained at 75°C to 80°C during the reaction (hydrogen generation is observed starting after approximately 10 ml of solution is added and external heating is required to maintain the temperature if necessary). After dropwise addition, the reaction mixture continues to be stirred at 70°C to 75°C and the progress of the reaction is monitored by thin layer chromatography (TLC, silica gel plate, unfolding agent hexane/ethyl acetate v/v 1:2). When the reaction was complete (about 30-45 min, the color of the reaction solution changed from brownish yellow to grey), the suspension was cooled to 25°C to 30°C and diluted with 2.4 liters of water. Subsequently, about 400 ml of concentrated hydrochloric acid was slowly added at 25°C to 30°C (for about 10 minutes) to adjust the pH to ≤2 and stirring was continued at this temperature for about 15 minutes. The catalyst was removed by filtration and washed with 600 ml of water. The filtrates were combined and heated to 35°C to 40°C, at which temperature about 760 ml of concentrated sodium hydroxide solution was slowly added (note the exothermic reaction) and the pH was adjusted to 7.1 ± 1. The resulting suspension was cooled to 20°C to 25°C and stirred at this temperature for 30 minutes. The product was collected by filtration under nitrogen protection (ca. 40 min) and washed twice with 1.6 liters of water, 400 ml of water/methanol (1:1 v/v) and 800 ml of methanol, in that order. Finally, the product was dried under vacuum (slight nitrogen flow) at 50°C to constant weight. The product 317 g was obtained in 88% yield and analyzed by high performance liquid chromatography (HPLC) with a purity of 99.7% (area percentage).

References

[1] Patent: EP1230231, 2005, B1. Location in patent: Page/Page column 4
[2] Tetrahedron Letters, 1999, vol. 40, # 31, p. 5655 - 5659
[3] Patent: CN108003118, 2018, A. Location in patent: Paragraph 0030

1-(4-Aminophenyl)-4-(4-hydroxyphenyl)piperazine(74853-08-0)Related Product Information

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