Dmso d6

Example 1

General Synthetic Procedure: All commercial reagents were purchased and used as received without further purification. Pd(OAc)₂ was purchased from Pressure Chemical Co. n-Bu₄NBr, CuI, 2-(tributylstannyl)pyridine and 2-picolinic acid were purchased from Sigma Aldrich. Silica gel (40-60 μm) was purchased from Agela Technologies and BDH. DMSO, toluene (low water), and acetic acid were purchased from Alfa Aesar, J. T. Baker, Fluke and BDH respectively.

All reactions were carried out under an inert N₂ atmosphere in oven-dried glassware. External bath temperatures were used to record all reaction temperatures. Flash column chromatography was carried out with silica gel. Proton and carbon NMR spectra (¹H NMR and ¹³C NMR) were recorded in dimethyl sulfoxide-d₆ (DMSO-d₆) on a Varian 400 MHz NMR spectrometer. The solvent residual peak (DMSO-d₆) was calibrated to 2.50 ppm for ¹H NMR and 39.52 ppm for ¹³C NMR. Multiplicities are abbreviated as follows: s=singlet, d=doublet, dd=doublet of doublets, t=triplet, br=broad, m=multiplet.

Example 5

[Figure (not displayed)]

Deacetylcolchicine.TFA (3, 0.18 gm, 0.39 mmol, 1.0 eq.) and N₃—PEG4-Phe-Lys(Trt)-PAB-NPC (0.50 gm, 0.46 mmol, 1.2 eq.) were dissolved in anhydrous DMF (5 mL). TEA (162 μL, 1.16 mmol, 3.0 eq.) and DIPEA (202 μL, 1.16 mmol, 3.0 eq.) were added to the reaction mixture. The yellowish-colored solution was allowed to stir overnight at room temperature under argon atmosphere. The reaction mixture was evaporated to dryness under vacuum at 37° C. The crude product was dissolved in ethyl acetate, purified by a silica gel column on Biotage using ethyl acetate as mobile phase A and methanol as mobile phase B. Elution was monitored at 317 nm. The product-containing fraction was evaporated to near dryness by rotary evaporation, and further dried in vacuum overnight, to give 0.47 gm of yellow colored solid (5, Yield: 79%). Purity 98% (HPLC). NMR of compound 5 (Varian, 10 mg/mL DMSO-d6, δ): 9.992 ppm, s, 1H; 8.112 ppm, m, 2H; 8.020 ppm, d, 1H; 7.566 ppm, d, 2H; 7.381 ppm, d, 6H; 7.226-7.271 ppm, m, 14H; 7.105-7.209 ppm, m, 4H; 7.039 ppm, d, 1H; 6.766 ppm, s, 1H; 4.891 ppm, dd, 2H; 4.557 ppm, t, 1H, ill resolved; 4.080 ppm, m, 1H; 3.870 ppm, s, 3H; 3.828 ppm, s, 3H; 3.784 ppm, s, 3H; 3.527 ppm, m, —CH₂CH₂O—; 3.519 ppm, s, 3H; 2.996 ppm, dd, 1H; 2.742 ppm, 7, 1H; 2.575 ppm, m, 1H; 1.2-2.3 ppm, multiple peaks.

Example 15

This example is directed to a synthesis of (R)-5-methyl-N-(1-(4-morpholinophenyl)ethyl)imidazo[1,2-a]pyridine-2-carboxamide.

[Figure (not displayed)]

To a solution of 5-methylimidazo[1,2-a]pyridine-2-carboxylic acid (100 mg, 0.57 mmol) in DMF (6.0 mL) were added HATU (324 mg, 0.851 mmol) and DIPEA (297 μL, 1.70 mmol). The reaction mixture was stirred at room temperature for 1 hour. After addition of (R)-1-(4-morpholinophenyl)ethanamine hydrochloride (intermediate 4, 207 mg, 0.851 mmol), the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between water and EtOAc and the separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO₂ (Hexane:EtOAc=1:1 to 1:3) to afford the (R)-5-methyl-N-(1-(4-morpholinophenyl)ethyl)imidazo[1,2-a]pyridine-2-carboxamide (90.0 mg, 44%) as a white solid. ¹H-NMR (DMSO-d₆, Varian, 400 MHz): δ 1.49 (3H, d, J=7.2 Hz), 2.63 (3H, s), 3.05 (4H, t, J=5.0 Hz), 3.72 (4H, t, J=4.6 Hz), 5.08-5.16 (1H, m), 6.85 (1H, d, J=6.8 Hz), 6.89 (2H, d, J=8.8 Hz), 7.28-7.34 (3H, m), 7.50 (1H, d, J=9.2 Hz), 8.22 (1H, s), 8.46 (1H, d, J=8.8 Hz). MS: 365.3 [MH⁺].

Example 17

This example is directed to a synthesis of (R)-7-methyl-N-(1-(4-morpholinophenyl)ethyl)imidazo[1,2-a]pyridine-2-carboxamide.

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To a solution of 7-methylimidazo[1,2-a]pyridine-2-carboxylic acid (100 mg, 0.57 mmol) in DMF (6.0 mL) were added HATU (324 mg, 0.851 mmol) and DIPEA (297 μL, 1.70 mmol). The reaction mixture was stirred at room temperature for 1 hours. After addition of (R)-1-(4-morpholinophenyl)ethanamine hydrochloride (intermediate 4, 207 mg, 0.851 mmol), the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partitioned between water and EtOAc and the separated aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by column chromatography on NH—SiO₂ (Hexane:EtOAc=1:1 to 1:3) to afford the (R)-7-methyl-N-(1-(4-morpholinophenyl)ethyl)imidazo[1,2-a]pyridine-2-carboxamide (130 mg, 63%) as a white solid. ¹H-NMR (DMSO-d₆, Varian, 400 MHz): δ 1.47 (3H, d, J=7.2 Hz), 2.36 (3H, s), 3.05 (4H, t, J=4.8 Hz), 3.72 (4H, t, J=4.6 Hz), 5.06-5.10 (1H, m), 6.82 (1H, d, J=6.4 Hz), 6.89 (2H, d, J=8.8 Hz), 7.28 (2H, d, J=8.8 Hz), 7.34 (1H, s), 8.24 (1H, s), 8.38 (1H, d, J=8.4 Hz), 8.45 (1H, d, J=7.2 Hz). MS: 365.3 [MH⁺].