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With sodium tetrahydroborate |
11
Certain intermediates are synthesized as illustrated in the scheme below. In the scheme below, Ref 1 refers to WO 2005/040120 and Ref 2 refers to WO 2008/121687, which are incorporated by reference in their entireties |
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With methanol; sodium tetrahydroborate at 0℃; for 0.25h; Inert atmosphere; |
1 -Benzyl-3,3-difluoropiperidin-4-ol:In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 1 -benzyl-3,3-difluoropiperidine-4,4-diol (WO2008/121687 and WO2005/040120) (2.88 g, 1 1 .85 mmol) in dry MeOH (58 mL) was added NaBH4 (672 mg, 17.76 mmol) portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 15 min. Aq. 0.1 M NaHC03 (5 mL) was then added and the mixture further stirred for 5 min, dried (MgS04), filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 2:1 -> 1 :1 ) and the title compound obtained as a beige oil. LC- MS-conditions 08: tR = 0.42 min; [M+H]+ = 228.32. |
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With sodium tetrahydroborate In methanol at 0℃; Inert atmosphere; |
1-Benzyl-3,3-difluoropiperidin-4-ol
1-Benzyl-3,3-difluoropiperidin-4-ol In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 1-benzyl-3,3-difluoropiperidine-4,4-diol (WO2008/121687 and WO2005/040120) (2.88 g, 11.85 mmol) in dry MeOH (58 mL) was added NaBH4 (672 mg, 17.76 mmol) portionwise at 0° C. The reaction mixture was stirred at 0° C. for 15 min. Aq. 0.1M NaHCO3 (5 mL) was then added and the mixture further stirred for 5 min, dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 2:1->1:1) and the title compound obtained as a beige oil. LC-MS-conditions 08: tR=0.42 min; [M+H]+=228.32. |
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With sodium tetrahydroborate In methanol at 0℃; for 0.25h; Inert atmosphere; |
1 -Benzyl-3,3-difluoropiperidin-4-ol:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 1 -benzyl-3,3-difluoropiperidine-4,4-diol (WO2008/121687 and WO2005/040120) (2.88 g, 1 1.85 mmol) in dry MeOH (58 mL) was added NaBH4 (672 mg, 17.76 mmol) portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 15 min. Aq. 0.1 M NaHC03 (5 mL) was then added and the mixture further stirred for 5 min, dried (MgS04), filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept/EA, 2:1 -> 1 :1 ) and the title compound obtained as a beige oil. LC- MS-conditions 08: tR = 0.42 min; [M+H]+ = 228.32. |
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With methanol; sodium tetrahydroborate at 0℃; for 2h; |
1.1.5 1.1.5 Preparation of Compound 8
10247] To a solution of compound 7 (5.3 g, 21.4 mmol) in MeOH (80 mE) was added NaI3H4 (1.2 g, 32.1 mmol) at 00 C. and the solution was stirred for 2 h, the solution was washed with water and extracted by EtOAc (180 mE), the organic layer was dried over Na2SO4 and concentrated in vacuo to give the crude product compound 8 (4.8 g, yield 96%) as colorless liquid. LCMS: 228 [M+1]. ‘H NMR (400 MHz, CDC13) ö 7.34 (s, 5H), 3.92-3.78 (m, 1H), 3.63 (s, 2H), 2.97-2.82 (m, 1H), 2.75-2.5 1 (m, 2H), 2.47-2.29 (m, 2H),2.06-1.97 (m, 1H), 1.89-1.82 (m, 1H). |
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