| 75% |
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 24h; |
99.1 Example 99: 8-(l-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-a zabicyclo[3.2.1]octane-3-carboxylic acid -bromo-6-((cis-4-methylcvclohexyl)oxy)naphthalene
Example 99: 8-(l-(5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-a zabicyclo[3.2.1]octane-3-carboxylic acid -bromo-6-((cis-4-methylcvclohexyl)oxy)naphthalene To a mixture of trans-4-methylcyclohexan-l-ol (20.5 g, 179.6 mmol, 1.2 eq) and 6-bromonaphthalen-2-ol (33.1 g, 149.8 mmol)in THF (300 mL) was added PPh3 (62.8 g, 239.5 mmol, 1.6 eq), followed by DIAD (48.4 g, 239.5 mmol, 1.6 eq) dropwise. The mixture was stirred at rt for 24 h and concentrated. The residue was diluted with EtOAc (300 mL), washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2S04 and evaporated. The residue was purified by column chromatography on silica gel (Petroleum ether/EtOAc = 20/1) to give 2-bromo-6-((cis-4-methylcyclohexyl)oxy)naphthalene as a white solid (35.5 g, yield: 75%). -bromo-2-((cis-4-methylcyclohexyl)oxy)-l-naphthaldehyde To a solution of 2-bromo-6-((cis-4-methylcyclohexyl)oxy)naphthalene (35.5 g, 111.6 mmol) in CH2CI2 (350 mL) was added a solution of TiCl4 (31.5 g, 167.5 mmol, 1.5 eq) and dichloro(methoxy)methane (14.0 g, 122.8 mmol, 1.1 eq) in CH2CI2 (700 mL) at 0 °C. After addition, the mixture was stirred at rt for 12 h. IN HC1 (200 mL) was added and the mixture was extracted with CH2CI2 (500 mLx2). The organic layers were dried over Na2S04, filtered and concentrated to give 6-bromo-2-((cis-4-methylcyclohexyl)oxy)-l-naphthaldehyde as a light yellow solid (38.0 g, yield: 98%), which was used to the next step without further purification. -bromo- 1 -(difluoromethyl)-2-((cis-4-methylcvclohexyl)oxy)naphthalene To a solution of 6-bromo-2-((cis-4-methylcyclohexyl)oxy)-l-naphthaldehyde (38.0 g, 109.83 mmol) in DCE (200 mL) was added DAST (106.1 g, 658.98 mmol, 6.0 eq) at rt. The mixture was stirred at 80 °C for 24 h and cooled down. Water (300 mL) was added and the mixture was extracted with CH2CI2 (200 mLx2). The combined organic layers were washed with sat. aq. NaHC03 (200 mL), dried over Na2S04, filtered and concentrated. The residue was washed with heptane to give 6-bromo- l-(difluoromethyl)-2-((cis-4-methylcyclohexyl)oxy)naphthalene as a white solid (38.0 g, yield: 95%). 1H NMR (400 MHz, CDC13) δ 8.24 (d, /= 9.2 Hz, 1H), 7.93 (d, / = 2.0 Hz , 1H), 7.77 (d, / = 9.2 Hz, 1H), 7.58 (dd, / = 2.0 Hz, 9.2 Hz, 1H), 7.56 (t, / = 54.8 Hz, 1H), 7.24 (d, / = 9.2 Hz, 1H), 4.72-4.70 (m, 1H), 2.04-2.00 (m, 2H), 1.63-1.54 (m, 5H), 1.35 (m, 2H), 0.96 (d, / = 6.4 Hz, 3H). -(difluoromethyl)-6-((cis-4-methylcvclohexyl)oxy)-2-naphthaldehyde To a solution of 6-bromo-l-(difluoromethyl)-2-((cis-4-methylcyclohexyl)oxy)naphthalene (17 g, 46.19 mmol) in THF (130 mL) was added nBuLi (33 mL, 1.6 M, 55.43 mmol, 1.2 eq) dropwise at -78 °C. After addition, the mixture was stirred at -78 °C for 30 min. DMF (6.74 g, 92.38 mmol, 2.0 eq) was added to the mixture and stirring continued for 2 hours -78 °C and the reaction was quenched with water (200 mL) and extracted with CH2CI2 (200 mLx2). The combined organic layers were washed with water (200 mLx2), brine (200 mLx2) and concentrated. The residue was washed with heptane to give 5-(difluoromethyl)-6-((cis-4-methylcyclohexyl)oxy)-2-naphthaldehyde as a white solid (12.5 g, yield: 85%). 1H NMR (400 MHz, CDC13) δ 10.12 (s, 1H), 8.46 (d, / = 8.8 Hz, 1H), 8.27 (d, J = 1.6 Hz, 1H), 8.03 (d, / = 9.2 Hz, 1H), 7.99 (dd, / = 2.0 Hz, 8.8 Hz, 1H), 7.59 (t, / = 54.8 Hz, 1H), 7.32 (d, / = 8.8 Hz, 1H), 4.80-4.78 (m, 1H), 2.07-2.03 (m, 2H), 1.67-1.55 (m, 5H) 1.37-1.33 (m, 2H) 0.97 (d, / = 6.4 Hz, 3H). ESI-MS (M+H) +: 319.1. Step 5: Methyl 8-(l-(5-(difluoromethyl)-6-((c 5,-4-methylcyclohexyl)oxy)naphthalene-2-yl)propyl)-8-aza bicyclor3.2.11octane-3-carboxylate To a mixture of potassium carbonate (62 mg, 0.45 mmol) and 8-aza-bicyclo[3.2.1]octane-3-carboxylic acid methyl ester HC1 salt (80 mg, 0.39 mmol) was added a solution of 6-(l-bromopropyl)-l-(difluoromethyl)-2-((c 5'-4-methylcyclohexyl)oxy)naphthalene in DMF (3 mL, 0.3 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered, and purified by HPLC (TFA method) to collect the desired ester as a white powder after lyophilization (81 mg, yield 44%). LCMS m/z 500.1 [M+H]+ Step 6: 8-(l-(5-(Difluoromethyl)-6-((c 5,-4-methylcyclohexyl)oxy)naphthalen-2-yl)propyl)-8-azab icvclor -3-carboxylic acid To the above ester in THF (0.6 mL) and MeOH (0.6 mL) was added 3 M of NaOH in water (0.200 mL, 0.600 mmol). The reaction mixture was heated at 55 °C (hot plate) for lh. Neutralized with 2N HC1, diluted with MeOH, and purified by HPLC (TFA method) to collect TFA salt of the the desired acid as a white powder after lyophilization (67 mg, yield 84%). 1H NMR (400 MHz, METHANOL-d4) δ 8.45 (d, / = 8.78 Hz, 1H), 8.05 (d, / = 9.29 Hz, 1H), 7.99 (s, 1H), 7.40 - 7.78 (m, 3H), 4.89 (br. S., 1H), 4.51 - 4.65 (m, 1H), 4.07 (dd, 7 = 3.26, 11.55 Hz, 1H), 3.37 - 3.50 (m, 1H), 2.86 - 3.05 (m, 1H), 2.49 - 2.64 (m, 1H), 2.35 - 2.48 (m, 1H), 1.86 - 2.33 (m, 10H), 1.65 - 1.80 (m, 2H), 1.46 - 1.63 (m, 3H), 1.27 - 1.42 (m, 2H), 0.98 (d, / = 6.27 Hz, 3H), 0.79 (t, / = 7.28 Hz, 3H); LCMS m/z 486.1 [M+H]+ |
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