Synthesis of 155-A and Derivatives

Example 22

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Synthesis of 155-A.

A mixture of potassium (bromomethyl)trifluoroborate (1.00 g, 4.98 mmol) and pyrrolidine (371 mg, 5.23 mmol) in THF (10 mL) was stirred at 80° C. for 4 h. The solvent was removed in vacuo. The residue was dissolved in acetone and the solution filtered to remove KCl. The filtrate was concentrated in vacuo, dissolved in a minimal amount of hot acetone (10 mL), and precipitated by the dropwise addition of Et₂O (5 mL). Additional Et₂O (150 mL) was added to facilitate filtering to give 155-A (750 mg, 98%) as a white solid.

Synthesis of 155-B.

A mixture of 155-A (750 mg, 4.90 mmol), SM-A (500 mg, 4.67 mmol), Cs₂CO₃ (4.56 g, 14.0 mmol), Pd(OAc)₂ (52 mg, 0.23 mmol) and XPhos (224 mg, 0.47 mmol) in THF/H₂O (20 mL/2 mL) was stirred 80° C. for 12 h under Ar. The mixture was cooled to room temperature and diluted with H₂O (50 mL). The mixture was extracted with EtOAc (20 mL×3). The combined organics washed with brine (20 mL×3), dried over anhydrous Na₂SO₄ and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE:EtOAc=8:1˜3:1) to give 155-B (700 mg, 47%) as a yellow solid.

Synthesis of 155-C.

To a solution of 155-B (350 mg, 1.15 mmol) in DCM (8 mL) was added TFA (4 mL) and stirred at room temperature for 1 h. when LCMS showed the reaction was finished. The solvent was removed in vacuo to give 155-C as a crude product and used to next step directly.

Synthesis of 155-D.

A mixture of 143-C (200 mg, 0.42 mmol) and 155-C (crude product from last step) in acetonitrile (5 mL) was stirred at 50° C. for 30 min. Then Na₂CO₃ (356 mg, 3.36 mmol) was added into above mixture and stirred at 50° C. for 3 h. After the reaction was completed according to LCMS, the mixture was cooled to room temperature. The Na₂CO₃ was removed by filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM:MeOH=100:1˜50:1) to give 155-D (180 mg, 93%) as a yellow solid.

Synthesis of 155.

A mixture of 155-D (180 mg, 0.39 mmol) and Pd/C (180 mg) in MeOH (5 mL) was stirred at room temperature for 1 h under H₂ atmosphere. Pd/C was removed by filtration through the Celite. The filtrate was concentrated and the residue was purified by Pre-TLC (DCM:MeOH=8:1) to give 155 (125 mg, 74%) as a yellow solid

Compound 144 was synthesized in a similar manner using thiophen-2-ylboronic acid variant of 155. Compound 144. 80 mg, 60%, a yellow solid.