TRIFLUOROACETICACIDHYDRAZIDE

Step 2 Step 2: Ethyl trifluoroacetate (1.03 g, 0.865 mL, 7.25 mmol) and hydrazine monohydrate (80percent w/w, 0.498 g, 0.475 mL, 7.97 mmol, 1.1 equiv.) were dissolved in ethanol (1.4 mL) and heated under reflux for 3 h. The solvent was removed under reduced pressure, and the residue was taken up in EtOAc (10 mL) and extracted with water (10 mL). The aqueous phase was extracted with EtOAc (4.x.10 mL), the combined organic phases were washed with water (5 mL), dried over magnesium sulphate and freed from the solvent under reduced pressure. The residue was purified by column chromatography (SiOGeneral procedure: A portion of the catalyst (10% Pd/C(60 mg)) was added to a solution of the CBz-protected carbohydrazide 4b, c (2.0 mmol) in anhydrous THF(~50 ml). Next, the reaction flask was equipped with aseptum, a long syringe, and a balloon filled with hydrogen.Progress of the reaction was monitored by TLC (SiO2, hexane-AcOEt, 1:1), and as soon as the reaction was finished, the solution was filtered through a Celite pad.Next, the appropriate isocyanate 5a-d or isothiocyanate5e-h (2.2 mmol) was added dropwise to the filtrate whilecooling the reaction flask in an ice bath (~0C). Themixture was stirred overnight at room temperature. Afterevaporation of the solvent, the crude products were purifiedby column chromatography (SiO2, hexane, then with increasing amount (40-90%) of AcOEt in hexane). Semicarbazides 6a-f and thiosemicarbazides 6g-j were obtainedas amorphous solids by trituration with Et2O.1, 4-dichlorophthalazine (1.0 g, 5.0 mmol) and 2, 2, 2-trifluoroacetohydrazide (0.64 g, 5.0 mmol) were dissolved in dioxane (10 mL) and heated to reflux for 12 h. The reaction mixture was concentrated, dissolved in CH2C12, washed with a saturated aqueous sodium bicarbonate solution, dried (MgS04) to afford the desired 6-chloro-3-trifluoromethyl- [1, 2, 4] triazolo [3, 4-a] phthalazine. The 6-chloro- 3-trifluoromethyl- [1, 2, 4] triazolo [3, 4-a] phthalazine (300 mg, 1.1 mmol) and [3-({tert- butyldimethyl) silyl] oxy} methyl) phenyl] methanol (Bioorg. Med. Chem. Lett 12, 2002, 137) (280 mg, 1.1 mmol) were dissolved in DMF (10 rnL), cooled to-78 C and treated with a solution of lithium bis (trimethylsilyl) amide (1.1 mL of 1 M in THF). The reaction was allowed to warm to room temperature over 12 h, concentrated, and the crude product was dissolved in THF (5 mL) and treated with TBAF (1.0 mL of 1 M in THF). After stirring the reaction for 2 h at ambient temperature, the reaction was concentrated and purified by flash column chromatography (Si02, 1 to 9% MeOH in CH2C12) to afford [6- (3-trifluoromethyl- [1, 2, 4] triazolo [3, 4-a] phthalazin-6-yloxymethyl)-pyridin-2-yl]- methanol. The alcohol (224 mg, 0.6 mmol) was dissolved in CH2C12 (2 mL) and treated with triethylamine (0.17 mL, 1.2 mmol) and methanesulfonyl chloride (0.07 mL, 0.9 mmol). The reaction was stirred at ambient temperature for 1 h, diluted with CH2C12 (5 mL) and washed with a saturated aqueous sodium bicarbonate solution, dried (MgS04), and concentrated to afford [6- ( { [3- (trifluoromethyl) [1, 2, 4] triazolo [3, 4-a] phthalazin-6-yl] oxy} methyl) pyridin-2-yl] methyl methanesulfonate as a tan solid. The crude mesylate residue was dissolved in methylene chloride (2 mL) and treated with phenethylamine (360 mg, 3.0 mmol) at ambient temperature for 20 h. The reaction was concentrated, and the residue was purified by flash column chromatography (SiOz, 1%-20% MeOH in CH2C12) to afford 2- phenyl-N-[3-({[3-(trifluoromethyl)[1, 2, 4] triazolo [3, 4-a] phthalazin-6-yl] oxy} methyl) benzyl] ethanamine as a colorless oil :'H NMR (500 MHz, CDC13) 8 8.69 (d, 1H), 8. 29 (d, 1H), 8.00 (dt, 1H), 7.86 (dt, 1H), 7.50 (s, 1H), 7.48 (d, 1H), 7.40 (m, 1H), 7.34 (m, 3H), 7.21 (m, 3H), 5.59 (s, 2H), 3.87 (s, 2H), 2.95 (t, 2H), 2.86 (t, 2H); LCMS (ESI) m/z 477 (477 calcd for C26H22F3N5O, M+H).

Molecular Weight:128.05
XLogP3:-0.1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Exact Mass:128.01974721
Monoisotopic Mass:128.01974721
Topological Polar Surface Area:55.1
Heavy Atom Count:8
Complexity:97.9
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes