索利那新EP杂质E

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1.63 g (13 mmol) of the 3-quinuclidinone (I), 1.1 mg (1.3 μmol) of {[(5)-(6,6′-dimethyl-1,1′-biphenyl-2,2′-diyl)-bis(di-p-tolylphosphine)]ruthenium (II) dichloride (DMF)n} complex, 12.7 ml of 2-propanol and 31 μl (1.55 μmol) of a 0.05 M 2-propanol solution of (2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine were added to an autoclave in which the inside had been replaced with argon followed by carrying out a degassing procedure and stirring for 30 minutes at room temperature. 0.26 mL (0.26 mmol) of a 2-propanol solution of potassium tert-butoxide (1.0 M) were added thereto followed by stirring for 16 hours at 20 to 25° C. at a hydrogen pressure of 2.0 MPa to obtain (R)-3-quinuclidinol (3-R). S/C, conversion rate and enantiomeric excess are indicated below.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1.63 g (13 mmol) of the 3-quinuclidinone (I), 1.1 mg (1.3 μmol) of {[(S)-(6,6′-dimethyl-1,1′-biphenyl-2,2′-diyl)-bis(diphenylphosphine)]ruthenium (II) dichloride (DMF)n} complex, 12.7 ml of 2-propanol and 31 μl (1.55 μmol) of a 0.05 M 2-propanol solution of (2R,3R,4R,5R)-3,4-O-isopropylidenehexane-2,5-diamine were added to an autoclave in which the inside had been replaced with argon followed by carrying out a degassing procedure and stirring for 30 minutes at room temperature. 0.26 mL (0.26 mmol) of a 2-propanol solution of potassium tert-butoxide (1.0 M) were added thereto followed by stirring for 16 hours at 20 to 25° C. at a hydrogen pressure of 2.0 MPa to obtain (R)-3-quinuclidinol (3-R). S/C, conversion rate and enantiomeric excess are indicated below.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 2-(piperidin-1-yl)-2-(thiophen-3-yl)acetic acid 21c (250 mg, 1.11 mmol), DCC (458 mg, 2.22 mmol), HOBT (340 mg, 2.22 mmol) and (R)-quinuclidin-3-ol (282 mg, 2.22 mmol) in dry THF (11.1 ml) and dry DMF (5.5 ml) was stirred at room temperature under nitrogen for 48 hours. The solvent was evaporated and the crude was purified by flash chromatography (DCM/MeOH=97/3+0.3% NH4OH). The product was triturated with THF (10 ml) to obtain the title compound (217 mg, 58.5% yield) as a colorless oil. The solvent was evaporated the crude was purified by flash chromatography (DCM/MeOH=97/3+0.3% NH4OH) The product was triturated with THF (10 ml)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 2-(piperidin-1-yl)-2-(thiophen-2-yl)acetic acid (250 mg, 1.11 mmol), DCC (458 mg, 2.22 mmol), HOBT (300 mg, 2.22 mmol) and (R)-quinuclidin-3-ol (282 mg, 2.22 mmol) in dry THF (11.1 ml) was stirred at room temperature under nitrogen atmosphere for 24 hours. The pale pink suspension was filtered washing with THF (5 ml) and the pale pink solution was evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5+0.4% NH4OH) to obtain the title compound (132 mg, 35.6% yield) as a colorless oil. The pale pink suspension was filtered washing with THF (5 ml) the pale pink solution was evaporated The crude was purified by flash chromatography (DCM/MeOH=95/5+0.4% NH4OH)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-(2,4-Difluorophenyl)-2-(piperidin-1-yl)acetic acid (304 mg, 1.19 mmol), DCC (491 mg, 2.38 mmol), and HOBT (365 mg, 2.38 mmol) were dissolved in dry THF (12 ml). (R)-quinuclidin-3-ol (454 mg, 3.57 mmol) was added and the mixture was stirred at room temperature for 16 hours. THF was evaporated and the residue was taken up with EtOAc and washed with sat. NaHCO3. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=9/1+0.1% NH4OH) to obtain the title product as colorless oil (280 mg, 64.5% yield). THF was evaporated washed with sat. NaHCO3 The organic phase was dried over Na2SO4 filtered evaporated to dryness The crude was purified by flash chromatography (DCM/MeOH=9/1+0.1% NH4OH)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-(4-Fluorophenyl)-2-(piperidin-1-yl)acetic acid hydrochloride (255 mg, 0.93 mmol) was dissolved in dry THF (10 ml) and (R)-quinuclidin-3-ol (355 mg, 2.79 mmol), DCC (384 mg, 1.86 mmol), HOBt (285 mg, 1.86 mmol) were added. The mixture was stirred at room temperature for 16 hours. THF was evaporated and the residue was taken up with EtOAc and washed with sat. NaHCO3, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH/NH4OH=98/2/0.2) to obtain (R)-quinuclidin-3-yl 2-(4-fluorophenyl)-2-(piperidin-1-yl)acetate (126 mg, 39.0% yield) as a white solid. THF was evaporated washed with sat. NaHCO3, water and brine The organic phase was dried over Na2SO4 filtered evaporated The crude was purified by flash chromatography (DCM/MeOH/NH4OH=98/2/0.2)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-(4-Chlorophenyl)-2-(piperidin-1-yl)acetic acid (190 mg, 0.75 mmol), DCC (309 mg, 1.50 mmol), and HOBT (229 mg, 1.50 mmol) were dissolved in dry THF (8 ml). (R)-quinuclidin-3-ol (286 mg, 2.25 mmol) was added and the reaction was stirred at room temperature for 16 hours. THF was evaporated and the residue was dissolved in EtOAc and washed with 1M NaHCO3, water and brine. The organic layer was separated, dried over Na2SO4, filtered and evaporated. The crude compound was purified by flash chromatography (DCM/MeOH/NH4OH=9 5/5/0.1) to obtain (R)-quinuclidin-3-yl 2-(4-chlorophenyl)-2-(piperidin-1-yl)acetate (167 mg, 61.5% yield) as a colorless oil. THF was evaporated the residue was dissolved in EtOAc washed with 1M NaHCO3, water and brine The organic layer was separated dried over Na2SO4 filtered evaporated The crude compound was purified by flash chromatography (DCM/MeOH/NH4OH=9 5/5/0.1)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Lithium 2-(4-methoxyphenyl)-2-(piperidin-1-yl)acetate (384 mg, 1.50 mmol), DCC (621 mg, 3.01 mmol), and HOBT (461 mg, 3.01 mmol) were dissolved in dry THF (16 ml). (R)-quinuclidin-3-ol (574 mg, 4.51 mmol) was added and the mixture was stirred at room temperature for 16 hours. THF was evaporated and the crude was dissolved in EtOAc, washed with sat. NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH/NH4OH=9/1/0.02) to obtain (R)-quinuclidin-3-yl 2-(4-methoxyphenyl)-2-(piperidin-1-yl)acetate (207 mg, 38.4% yield) as a colourless oil. THF was evaporated the crude was dissolved in EtOAc washed with sat. NaHCO3, water and brine The organic layer was dried over Na2SO4 filtered evaporated The crude was purified by flash chromatography (DCM/MeOH/NH4OH=9/1/0.02)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-(Piperidin-1-yl)-2-p-tolylacetic acid hydrochloride (242 mg, 0.90 mmol), DCC (370 mg, 1.79 mmol) and HOBT (275 mg, 1.79 mmol) were dissolved in dry THF (10 ml). (R)-quinuclidin-3-ol (342 mg, 2.69 mmol) was added and the mixture was stirred at room temperature for 16 hours. THF was evaporated and the residue was taken up with EtOAc and washed with sat. NaHCO3, water and brine. The organic layer was recovered, dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(piperidin-1-yl)-2-p-tolylacetate (169 mg, 55% yield) as a colourless oil. THF was evaporated washed with sat. NaHCO3, water and brine The organic layer was recovered dried over Na2SO4 filtered evaporated The crude was purified by flash chromatography (DCM/MeOH=9/1)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-(3-Fluorophenyl)-2-(piperidin-1-yl)acetic acid hydrochloride (225 mg, 0.82 mmol), DCC (339 mg, 1.64 mmol), and HOBT (252 mg, 1.64 mmol) were dissolved in dry THF (9 ml). (R)-quinuclidin-3-ol (314 mg, 2.47 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. THF was evaporated, the residue was taken up with EtOAc and washed with sat. NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(3-fluorophenyl)-2-(piperidin-1-yl)acetate (166 mg, 58.3 yield). THF was evaporated washed with sat. NaHCO3, water and brine The organic layer was dried over Na2SO4 filtered evaporated to dryness The crude was purified by flash chromatography (DCM/MeOH=9/1)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 2-(2-oxopyrrolidin-1-yl)-2-phenylacetic acid (345 mg, 1.57 mmol), DCC (649 mg, 3.15 mmol), HOBT (425 mg, 3.15 mmol) and (R)-quinuclidin-3-ol (400 mg, 3.15 mmol) in dry THF (15.7 ml) was stirred at room temperature for 24 hours. The yellow suspension was filtered washing the white solid with THF. The yellow solution was evaporated and the crude was purified by flash chromatography (DCM/MeOH=96/4+0.4% NH4OH) to collect the title compound (482 mg, 93% yield) as a pale yellow oil. The yellow suspension was filtered washing the white solid with THF The yellow solution was evaporated the crude was purified by flash chromatography (DCM/MeOH=96/4+0.4% NH4OH)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of (R)-2-((R)-2-methylpyrrolidin-1-yl)-2-phenylacetic acid 22c (150 mg, 0.68 mmol) in dry THF (6.8 ml), were added DCC (282 mg, 1.37 mmol), HOBT (185 mg, 1.37 mmol) and (R)-quinuclidin-3-ol (174 mg, 1.37 mmol). The mixture was stirred at room temperature under nitrogen for 24 hours. The pale yellow suspension was filtered washing with THF (5 ml) and the yellow solution was evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5 to 9/1 and then with DCM/MeOH/NH4OH=95/5/0.2) to collect the title compound (48 mg, 21.4% yield) as a colorless oil. The pale yellow suspension was filtered washing with THF (5 ml) the yellow solution was evaporated The crude was purified by flash chromatography (DCM/MeOH=95/5 to 9/1