tetraethylazanium;fluoride

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (±)-(E)-2-(trimethylsilyl)ethyl 7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-ylcarbamate (16.5 mg, 0.026 mmol) and Et4NF (30 mg) were dissolved in MeCN (3 mL). The solution was heated at 100° C. for 10 min in a microwave. The solution was concentrated and the residue was purified by preparative HPLC to give (±)-(E)-1-(3-amino-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (11 mg, 70%) as its TFA salt. LC-MS Method 1 tR=1.38, min, m/z=479, 481; 1H NMR (CD3OD) 1.53 (m, 1H), 1.67 (m, 1H), 2.08 (m, 1H), 2.55 (m, 1H), 2.9-3.5 (5H), 4.38 (d, 1H), 4.72 (d, 1H), 7.2-8.0 (9H). The solution was concentrated the residue was purified by preparative HPLC

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

実験手順: Tetraethylammonium fluoride (312 mg, 2.18 mmol) was added to a stirred solution of the compound of step (g) (380 mg, 0.55 mmol) in acetonitrile (6 ml) at room temperature under a nitrogen atmosphere. After 12 H the mixture was poured into 1M hydrochloric acid (50 ml) and extracted into ethyl acetate (2×50 ml). The organic fractions were combined, dried (MgSO4) and concentrated in vacuo to give a yellow foam. Flash column chromatography (eluting with 98% dichloromethane/2% methanol) gave the product as a white solid (242 mg). extracted into ethyl acetate (2×50 ml) dried (MgSO4) concentrated in vacuo to give a yellow foam Flash column chromatography (eluting with 98% dichloromethane/2% methanol)

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

実験手順: To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-((triethylsilyl)ethynyl)phenyl)ethyl)-1,3-oxazinan-2-one (184 mg, 0.375 mmol) in acetonitrile (5 mL) was added tetraethylammonium fluoride (112 mg, 2 equiv). The mixture was stirred for 3 h at rt and LC-MS showed the reaction was complete. The mixture was concentrated and purified by chromatography on a 12 g silica cartridge, eluted with a 70-100% EtOAc in hexanes gradient, to afford to afford (S)-3-((S)-1-(4-ethynylphenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (128 mg, 91%) as a white solid. The mixture was concentrated purified by chromatography on a 12 g silica cartridge eluted with a 70-100% EtOAc in hexanes gradient to afford

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

実験手順: A 10 mL flask was charged with methyl 2-((S)-(3-chlorophenyl)((R)-4-((2S,3R)-3-hydroxy-4-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-1-(tetrahydro-2H-pyran-4-yl)butan-2-ylcarbamoyl)morpholin-2-yl)methoxy)ethylcarbamate (30 mg, 0.043 mmol) dissolved in MeCN (4 mL) and Et4NF (14 mg, 0.094 mmol) was added. The mixture was stirred for 0.5 h under reflux. After stirring, it was monitored by HPLC until the reaction ended. The solution was concentrated in vacuo and purified by HPLC to give the target compound (2.97 mg, 12%). 1H NMR (MeOD) 1.27-1.30 (m, 2H), 1.32-1.40 (m, 2H), 1.51-1.62 (m, 2H), 1.65-1.80 (m, 2H), 2.70 (s, 3H), 1.75-1.90 (m, 2H), 1.90-3.10 (m, 4H), 3.65 (s, 3H), 3.80-3.95 (m, 5H), 4.05-4.20 (m, 1H), 4.30 (m, 1H), 7.25-7.40 (m, 4H). under reflux After stirring The solution was concentrated in vacuo purified by HPLC

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

実験手順: A 10 mL flask was charged with methyl 2-((S)-(3-chlorophenyl)((R)-4-((2S,3R)-3-hydroxy-4-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-1-(tetrahydro-2H-pyran-4-yl)butan-2-ylcarbamoyl)morpholin-2-yl)methoxy)ethylcarbamate (30 mg, 0.043 mmol) dissolved in MeCN (4 mL) and Et4NF (14 mg, 0.094 mmol) was added. The mixture was stirred for 0.5 h under reflux. After stirring, it was monitored by HPLC until the reaction ended. The solution was concentrated in vacuo and purified by HPLC to give the target compound (2.97 mg, 12%). 1H NMR (MeOD) 1.27-1.30 (m, 2H), 1.32-1.40 (m, 2H), 1.51-1.62 (m, 2H), 1.65-1.80 (m, 2H), 2.70 (s, 3H), 1.75-1.90 (m, 2H), 1.90-3.10 (m, 4H), 3.65 (s, 3H), 3.80-3.95 (m, 5H), 4.05-4.20 (m, 1H), 4.30 (m, 1H), 7.25-7.40 (m, 4H). under reflux After stirring The solution was concentrated in vacuo purified by HPLC

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

実験手順: In a 1000 mL three neck round bottom flask, a solution of (3aS,6R,6aS)-6-((R)-2, 2-dimethyl-1, 3-dioxolan-4-yl)-2, 2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one (30 g, 116.2 mmol, 1eq) in THF (600 mL) was treated with TMSCF3 (2M in THF, 122 mL, 244 mmol, commercially available from Sigma Aldrich, India) and tetraethylammonium fluoride (TEAF, 2.48 g, 23.24 mmol, Apollo scientific, UK) at rt under a nitrogen atmosphere. The reaction mixture was stirred at rt for 30 minutes and additional TEAF (24.8 g, 232.4 mmol, Apollo scientific, UK) was added to the reaction mixture. The resulting reaction mixture was stirred at rt for 12 h under a nitrogen atmosphere. Upon completion of the reaction (TLC, 30% EtOAc-hexanes, Rf 0.6), the reaction mixture was diluted with water (1000 mL), and it was then extracted with EtOAc (500 mL×2). The combined organic extracts were washed with water (250 mL), brine (250 mL) and dried over anhydrous Na2SO4. The solution was concentrated under reduced pressure. The residue obtained was purified by silica gel (60-120 mesh) column chromatography (gradient elution, 5-10% EtOAc-hexanes) to give (3aS,6R,6aS)-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-4-(trifluoromethyl)tetrahydrofuro[3,4-d][1,3]-dioxol-4-ol, as a yellow semi solid mixture of two isomers (27.3 g, 71.8%): 1H NMR (400 MHz, CDCl3) δ 4.95 (m, 2H), 4.78 (d, J=8 Hz, 1H), 4.61-4.32 (m, 2H), 4.23 (dd, J=8, 4 Hz, 1H), 4.18-4.10 (m, 3H), 4.06 (dd, J=8.0, 4.0 Hz, 2H), 3.98 (m, 1H), 1.52 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H), 1.40 (s, 3H), 1.39 (s, 3H), 1.36 (s, 3H); 19F NMR (376.17 MHz, CDCl3) δ −78.24 & −82.32 ppm. at rt The resulting reaction mixture was stirred at rt for 12 h under a nitrogen atmosphere was then extracted with EtOAc (500 mL×2) The combined organic extracts were washed with water (250 mL), brine (250 mL) dried over anhydrous Na2SO4 The solution was concentrated under reduced pressure The residue obtained was purified by silica gel (60-120 mesh) column chromatography (gradient elution, 5-10% EtOAc-hexanes)

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

実験手順: In a 1000 mL three neck round bottom flask, a solution of (3aS,6R,6aS)-6-((R)-2, 2-dimethyl-1, 3-dioxolan-4-yl)-2, 2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one (30 g, 116.2 mmol, 1eq) in THF (600 mL) was treated with TMSCF3 (2M in THF, 122 mL, 244 mmol, commercially available from Sigma Aldrich, India) and tetraethylammonium fluoride (TEAF, 2.48 g, 23.24 mmol, Apollo scientific, UK) at rt under a nitrogen atmosphere. The reaction mixture was stirred at rt for 30 minutes and additional TEAF (24.8 g, 232.4 mmol, Apollo scientific, UK) was added to the reaction mixture. The resulting reaction mixture was stirred at rt for 12 h under a nitrogen atmosphere. Upon completion of the reaction (TLC, 30% EtOAc-hexanes, Rf 0.6), the reaction mixture was diluted with water (1000 mL), and it was then extracted with EtOAc (500 mL×2). The combined organic extracts were washed with water (250 mL), brine (250 mL) and dried over anhydrous Na2SO4. The solution was concentrated under reduced pressure. The residue obtained was purified by silica gel (60-120 mesh) column chromatography (gradient elution, 5-10% EtOAc-hexanes) to give (3aS,6R,6aS)-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-4-(trifluoromethyl)tetrahydrofuro[3,4-d][1,3]-dioxol-4-ol, as a yellow semi solid mixture of two isomers (27.3 g, 71.8%): 1H NMR (400 MHz, CDCl3) δ 4.95 (m, 2H), 4.78 (d, J=8 Hz, 1H), 4.61-4.32 (m, 2H), 4.23 (dd, J=8, 4 Hz, 1H), 4.18-4.10 (m, 3H), 4.06 (dd, J=8.0, 4.0 Hz, 2H), 3.98 (m, 1H), 1.52 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H), 1.40 (s, 3H), 1.39 (s, 3H), 1.36 (s, 3H); 19F NMR (376.17 MHz, CDCl3) δ −78.24 & −82.32 ppm. at rt The resulting reaction mixture was stirred at rt for 12 h under a nitrogen atmosphere was then extracted with EtOAc (500 mL×2) The combined organic extracts were washed with water (250 mL), brine (250 mL) dried over anhydrous Na2SO4 The solution was concentrated under reduced pressure The residue obtained was purified by silica gel (60-120 mesh) column chromatography (gradient elution, 5-10% EtOAc-hexanes)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of (S)-tert-butyl 1-(2-(trimethylsilyl)ethoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate (6.55 g, 15.4 mmol) in MeCN (100 mL) was added Et4NF (7.5 g, 50 mmol). The mixture was stirred overnight at rt and at 60° C. for 7 h. The mixture was concentrated and the oily residue was taken up in EtOAc (175 mL). The mixture was washed with water (2×50 mL) and brine (50 mL) and dried over Na2SO4. Removal of the solvent afforded (S)-tert-butyl 1-amino-3-cyclohexylpropan-2-ylcarbamate (3.39 g, 80%) as a syrup. The mixture was concentrated The mixture was washed with water (2×50 mL) and brine (50 mL) dried over Na2SO4 Removal of the solvent

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred solution of (S)-tert-butyl 1-(2-(trimethylsilyl)ethoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate (6.55 g, 15.4 mmol) in MeCN (100 mL) was added Et4NF (7.5 g, 50 mmol). The mixture was stirred overnight at rt and at 60° C. for 7 h. The mixture was concentrated and the oily residue was taken up in EtOAc (175 mL). The mixture was washed with water (2×50 mL) and brine (50 mL) and dried over Na2SO4. Removal of the solvent afforded (S)-tert-butyl 1-amino-3-cyclohexylpropan-2-ylcarbamate (3.39 g, 80%) as a syrup. The mixture was concentrated The mixture was washed with water (2×50 mL) and brine (50 mL) dried over Na2SO4 Removal of the solvent

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of (R)-tert-butyl 3-((R)-1-(2-(tert-butyldimethylsilyloxy)ethoxy)-1-(3-chlorophenyl)ethyl)piperidine-1-carboxylate, tetraethylammonium fluoride (7.600 g, 50.9 mmol) in CH3CN was heated at 45° C. for 1 h and then was allowed to stir at rt overnight. The reaction mixture was evaporated under reduced pressure, the residue was dissolved into water and extracted with Et2O (3×), dried over Na2SO4. After the solvent was removed in vacuo, the crude product was purified by reversed-phase HPLC to give 1.000 g (35% in two steps) of (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-hydroxyethoxy)ethyl)piperidine-1-carboxylate. MS ESI +ve m/z 406 (M+Na). The reaction mixture was evaporated under reduced pressure the residue was dissolved into water extracted with Et2O (3×) dried over Na2SO4 After the solvent was removed in vacuo the crude product was purified by reversed-phase HPLC

反応条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of (R)-tert-butyl 3-((R)-1-(2-(tert-butyldimethylsilyloxy)ethoxy)-1-(3-chlorophenyl)ethyl)piperidine-1-carboxylate, tetraethylammonium fluoride (7.600 g, 50.9 mmol) in CH3CN was heated at 45° C. for 1 h and then was allowed to stir at rt overnight. The reaction mixture was evaporated under reduced pressure, the residue was dissolved into water and extracted with Et2O (3×), dried over Na2SO4. After the solvent was removed in vacuo, the crude product was purified by reversed-phase HPLC to give 1.000 g (35% in two steps) of (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-hydroxyethoxy)ethyl)piperidine-1-carboxylate. MS ESI +ve m/z 406 (M+Na). The reaction mixture was evaporated under reduced pressure the residue was dissolved into water extracted with Et2O (3×) dried over Na2SO4 After the solvent was removed in vacuo the crude product was purified by reversed-phase HPLC

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (±)-(E)-2-(trimethylsilyl)ethyl 7-bromo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-ylcarbamate (16.5 mg, 0.026 mmol) and Et4NF (30 mg) were dissolved in MeCN (3 mL). The solution was heated at 100° C. for 10 min in a microwave. The solution was concentrated and the residue was purified by preparative HPLC to give (±)-(E)-1-(3-amino-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one (11 mg, 70%) as its TFA salt. LC-MS Method 1 tR=1.38, min, m/z=479, 481; 1H NMR (CD3OD) 1.53 (m, 1H), 1.67 (m, 1H), 2.08 (m, 1H), 2.55 (m, 1H), 2.9-3.5 (5H), 4.38 (d, 1H), 4.72 (d, 1H), 7.2-8.0 (9H). The solution was concentrated the residue was purified by preparative HPLC