Example 26
Synthesis of 169-A.
A mixture of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (750 mg, 3.54 mmol), 1-methylpiperidin-4-one (800 mg, 7.08 mmol) and acetic acid (2 drops) in DCE (15 mL) was stirred at 50° C. for 2 h. Then Sodium triacetoxyborohydride (1.50 g, 7.08 mmol) was added into above mixture and stirred at 50° C. for another 2 h. After the reaction was completed according to LCMS, the solvent was diluted with water (10 mL) and then extracted by DCM (10 mL×3). The combined organics washed with brine (10 mL×3), dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM:MeOH=100:1˜50:1) to give 169-A (750 mg, 69%) as a yellow oil.
Synthesis of 169-B.
A solution of 169-A (400 mg, 1.29 mmol) in DCM (10 mL) was added TFA (5 mL) and stirred at room temperature for 1 h. when LCMS showed the reaction was finished. The solvent was removed in vacuo to give 169-B as a crude product and used to next step directly.
Synthesis of 169-C.
A mixture of 143-C (306 mg, 0.65 mmol) and 169-B (crude product from last step) in acetonitrile (6 mL) was stirred at 50° C. for 30 min. Then Na2CO3 (624 mg, 6.50 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˜20:1) to give 169-C (230 mg, 76%) as a yellow solid.
Synthesis of 169.
A mixture of 169-C (230 mg, 0.49 mmol) and Pd/C (230 mg) in MeOH (10 mL) was stirred at room temperature for 30 min under H2 atmosphere. Pd/C was then removed by filtration through the Celite. The filtrate was concentrated and the residue was purified by Pre-TLC (DCM:MeOH=10:1) to give 169 (150 mg, 70%) as a white solid.
Compounds 152, 182, 199, 201, 202, 203, 235, 236 and 256 were synthesized in a similar manner using the appropriately substituted aldehyde or ketone variant of 169.
Compound 152.
50 mg, 36%, a light yellow solid.
Compound 182.
70 mg, 38%, a red solid.
Compound 199.
50 mg, 54%, a light yellow solid.
Compound 201.
30 mg, 42%, as a yellow solid.
Compound 202.
30 mg, 42%, a yellow solid.
Compound 203.
30 mg, 18%, a yellow solid.
Compound 235.
170 mg, 87%, a white solid.
Compound 236.
70 mg, 50%, a white solid.
Compound 256.
20 mg, 8%, a light yellow solid.
Compounds 210, 211, 215, 222, 223, 242 and 262 were synthesized in a similar manner using the appropriately substituted amine variant of 169.
Compound 210.
160 mg, 96%, a tan solid.
Compound 211.
70 mg, 40%, a white solid
Compound 215.
70 mg, 75%, a white solid.
Compound 222.
30 mg, 42%, a yellow solid.
Compound 223.
35 mg, 31%, a white solid.
Compound 242.
50 mg, 34%, a white solid.
Compound 262.
38 mg, 43%, a white solid.
