4,4-difluoropiperidine;hydrochloride

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4,4-difluoropiperidine hydrochloride and isolated as light-yellow gum (10.9 mg, 55%). MS (m/e): 421.4 (MH+).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The titled compound was synthesized by stpes analogous to those described in method AA20 above, but using (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[thiazole-4,9′-xanthen]-2′-ol (prepared as described in Method BB26 and Example 2 but using 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one), 2-fluoropyridin-3-ylboronic acid and 4,4-difluoropiperidine hydrochloride. MS m/z=501.0.0 [M+H]+.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was synthesized by steps analogous to those described in method CC4 above, but using (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (prepared as described in Method BB33), 5-fluoropyridin-3-ylboronic acid and 4,4-difluoropiperidine hydrochloride.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was synthesized by steps analogous to those described in method CC4 above, but using (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (prepared by steps analogous to those described in Method BB33), 2-fluoropyridin-3-ylboronic acid and 4,4-difluoropiperidine hydrochloride. prepared by steps analogous to

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a resealable tube charged with a mixture of (S)-3-chloro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (0.20 g, 0.522 mmol), pd2(dba)3 (0.024 g, 0.026 mmol), 2-(dicyclohexylphosphino)-2′-(n,n-dimethylamino)biphenyl (0.031 g, 0.078 mmol) and 4,4-difluoropiperidine HCl (0.247 g, 1.567 mmol) was added 1.0 M lithium bis(trimethylsilyl)amide (3.13 mL, 3.13 mmol) in THF and the resulting mixture was heated at 90° C. for 24 h. The mixture was concentrated and purified on silica gel using 0-6% MeOH/DCM to afford (S)-3-(4,4-difluoropiperidin-1-yl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine. The mixture was concentrated purified on silica gel using 0-6% MeOH/DCM

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 4,4-difluoropiperidine hydrochloride (1 M in DMF) instead of methylamine, to the title compound (131 mg, 98%) which was obtained as a light yellow gum. MS: m/e=414.4 [M+H]+.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 4,4-difluoropiperidine hydrochloride (1 M in DMF) instead of methylamine, to the title compound (131 mg, 98%) which was obtained as a light yellow gum. MS: m/e=414.4 [M+H]+.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (260 mg, 0.82 mmol), 4,4-difluoropiperidine hydrochloride (323 mg, 2.05 mmol), absolute ethanol (11 mL), activated 4 Å molecular sieves, titanium (IV) isopropoxide (1.209 mL, 4.09 mmol) and STAB (1.475 g, 6.96 mmol) were reacted in accordance with the general procedure D. The isolated waxy solid was purified by reverse phase preparative HPLC on a Xterra column eluting with a gradient of MeCN:H2O:Et3N (from 29.9:70:0.1 to 94.9:5:0.1 in 13 min) to give the title compound (26 mg, 6%). 1H NMR (400 MHz, CDCl3) δ 7.21 (d, 2H), 6.88 (d, 2H), 4.02 (t, 2H), 3.77-3.73 (m, 2H), 3.53-3.47 (t, 2H), 2.64 (t, 2H), 2.54 (m, 4H), 2.39 (s, 2H), 2.30-2.24 (m, 6H), 2.13 (d, 2H), 2.02 (m, 2H), 1.90-1.71 (m, 6H). The isolated waxy solid was purified by reverse phase preparative HPLC on a Xterra column eluting with a gradient of MeCN

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (260 mg, 0.82 mmol), 4,4-difluoropiperidine hydrochloride (323 mg, 2.05 mmol), absolute ethanol (11 mL), activated 4 Å molecular sieves, titanium (IV) isopropoxide (1.209 mL, 4.09 mmol) and STAB (1.475 g, 6.96 mmol) were reacted in accordance with the general procedure D. The isolated waxy solid was purified by reverse phase preparative HPLC on a Xterra column eluting with a gradient of MeCN:H2O:Et3N (from 29.9:70:0.1 to 94.9:5:0.1 in 13 min) to give the title compound (26 mg, 6%). 1H NMR (400 MHz, CDCl3) δ 7.21 (d, 2H), 6.88 (d, 2H), 4.02 (t, 2H), 3.77-3.73 (m, 2H), 3.53-3.47 (t, 2H), 2.64 (t, 2H), 2.54 (m, 4H), 2.39 (s, 2H), 2.30-2.24 (m, 6H), 2.13 (d, 2H), 2.02 (m, 2H), 1.90-1.71 (m, 6H). The isolated waxy solid was purified by reverse phase preparative HPLC on a Xterra column eluting with a gradient of MeCN

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4,4-difluoropiperidine hydrochloride (2.0 g) in water (32 mL) was added an aqueous 2N sodium hydroxide solution (7.6 mL) and the mixture was stirred at room temperature for 1 hours. To the reaction mixture was added sodium nitrite (1.75 g) and thereto was added acetic acid (1.27 mL) under ice-cooling. The mixture was stirred at room temperature for 2 hours. To the reaction mixture was added an aqueous sodium hydrogencarbonate solution and the mixture was stirred and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=4/1) to obtain 4,4-difluoro-1-nitrosopiperidine (1.89 g, yield: 99%) as a pale yellow solid. cooling The mixture was stirred at room temperature for 2 hours the mixture was stirred extracted with chloroform The extract was dried over magnesium sulfate filtered The filtrate was concentrated in vacuo the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=4/1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4,4-difluoropiperidine hydrochloride (2.0 g) in water (32 mL) was added an aqueous 2N sodium hydroxide solution (7.6 mL) and the mixture was stirred at room temperature for 1 hours. To the reaction mixture was added sodium nitrite (1.75 g) and thereto was added acetic acid (1.27 mL) under ice-cooling. The mixture was stirred at room temperature for 2 hours. To the reaction mixture was added an aqueous sodium hydrogencarbonate solution and the mixture was stirred and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=4/1) to obtain 4,4-difluoro-1-nitrosopiperidine (1.89 g, yield: 99%) as a pale yellow solid. cooling The mixture was stirred at room temperature for 2 hours the mixture was stirred extracted with chloroform The extract was dried over magnesium sulfate filtered The filtrate was concentrated in vacuo the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=4/1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4,4-Difluoropiperidine hydrochloride (249 mg, 1.58 mmol) was dissolved in 1N NaOH (5 ml) and extracted with CH2Cl2 (2×5 ml). Organic phase was dried over Na2SO4, filtered and evaporated. The residue was dissolved in THF (2 ml) and this solution was added to a solution of 1 (185 mg, 0.79 mmol) in THF (2 ml); the mixture was stirred at room temperature for 48 hours. The solvent was evaporated, the crude solid washed with EtOH and dried under vacuum, affording 8 (245 mg, 95%) as yellow-brown solid. extracted with CH2Cl2 (2×5 ml) Organic phase was dried over Na2SO4 filtered evaporated The residue was dissolved in THF (2 ml) The solvent was evaporated the crude solid washed with EtOH dried under vacuum