(Z)-3-(3-(3,5-bis(trifluoroMethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(3,3- Chemical Properties

Boiling point:

477.2±55.0 °C(Predicted)

Density 

1.56±0.1 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

insoluble in EtOH; insoluble in H2O; ≥19.85 mg/mL in DMSO

form 

solid

pka

0.59±0.50(Predicted)

color 

White to off-white

InChI

InChI=1S/C16H10F8N4O/c17-14(18)6-27(7-14)12(29)1-2-28-8-25-13(26-28)9-3-10(15(19,20)21)5-11(4-9)16(22,23)24/h1-5,8H,6-7H2/b2-1-

InChIKey

JCHAWRDHMUSLMM-UPHRSURJSA-N

SMILES

C(N1CC(F)(F)C1)(=O)/C=C\N1C=NC(C2=CC(C(F)(F)F)=CC(C(F)(F)F)=C2)=N1

(Z)-3-(3-(3,5-bis(trifluoroMethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(3,3- Usage And Synthesis

Description

KPT-276 is an orally bioavailable inhibitor of Exportin 1 (XPO1/CRM1) with anticancer activity. In vivo, KPT-276 (150 mg/kg) increases survival and reduces spleen weight and white blood cell count in an MV4-11 acute myeloid leukemia (AML) mouse xenograft model. It also reduces tumor volume and increases survival in a BT 145 glioblastoma mouse xenograft model when administered at a dose of 75 mg/kg.

Uses

PKT-276, an analogue of PKT-185, is an oral bioavailable and selective inhibitor of nuclear output (SINE). PKT-276 is also a CRM1 antagonist that irreversibly binds to and blocks the function of CRM1[1].

Synthesis

General synthesis of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazole and compound (CAS:1421920-40-2) as raw material for (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(3,3-difluoroazetidin-1-yl)prop-2-en-1-one Procedure: to a 50 mL three-necked round-bottomed flask fitted with a nitrogen inlet under nitrogen protection was added 3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazole (0.18 g, 1.0 eq.) dissolved in DMF (5.0 mL, 27.0 V), followed by the addition of DABCO (0.143 g, 2.0 eq.) and (Z)-1-(3, 3-difluoroazetidin-1-yl)-3-iodo-2-en-1-one (0.192 g, 1.1 eq.). The reaction mixture was stirred at room temperature for 2-3 hours. The reaction progress was monitored by TLC using 80% ethyl acetate-hexane as the mobile phase with an Rf value of 0.60 for the feedstock and 0.4 for the product.Upon completion of the reaction, the mixture was poured into ice water (50 mL) and extracted with EtOAc (3 x 25 mL). The organic layers were combined, washed with brine solution (3 × 25 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation (25 °C, 20 mmHg) to give 0.3 g of crude product. The crude product was purified by silica gel column chromatography (60/120 mesh) using ethyl acetate:hexane as mobile phase. The silica gel column (5 × 10 cm) was packed with hexane and then eluted with ethyl acetate in a gradient manner, starting from 40% ethyl acetate/hexane and gradually increasing to 45% ethyl acetate/hexane, and 50 mL of gradient was collected. The target compound was eluted starting from 40% ethyl acetate/hexane. The TLC distribution grade fractions containing the target compound were combined, resulting in 70 mg of pure product in 25.64% yield.

References

[1]. ranganathan p, yu x, na c, et al. preclinical activity of a novel crm1 inhibitor in acute myeloid leukemia. blood, 2012, 120(9): 1765-1773.
[2]. schmidt j, braggio e, kortuem km, et al. genome-wide studies in multiple myeloma identify xpo1/crm1 as a critical target validated using the selective nuclear export inhibitor kpt-276. leukemia, 2013, 27(12): 2357-2365.

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