1-FLUORO-4-(PROP-2-YN-1-YL)BENZENE

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: This reaction was carried out as described in Example D1, Step (c) using 1-fluoro-4-prop-2-ynyl-benzene (0.23 g, 1.7 mmol) and {4-[5-(3-bromophenyl) tetrazol-2-ylmethyl]phenoxy}acetic acid tert-butyl ester (0.30 g, 0.67 mmol) in place of 4-[5-(3-bromophenyl)tetrazol-2-ylmethyl]-benzenesulfonic acid, sodium salt. This afforded 0.23 g of the product (68.5% yield).

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 4-[5-(3-bromophenyl)tetrazol-2-ylmethyl]benzenesulfonic acid, sodium salt (0.50 g, 1.27 mmol) in DMF (3 mL) was treated with diisopropylethylamine (0.88 mL, 5.1 mmol), palladium tetrakis(triphenylphosphine) (“Pd(PPh3)4”, 0.29 g, 0.25 mmol), CuI (cat), and 1-fluoro-4-prop-2-ynyl-benzene (0.42 g, 3.1 mmol), and the mixture degassed with nitrogen. The reaction mixture was heated in the microwave for 15 minutes at 100° C., cooled to room temperature, poured into 1N HCl, extracted with EtOAc, washed with brine, dried over MgSO4, and evaporated onto silica gel. The mesh was purified on a 3.5×15 cm silica gel column eluted with ethyl acetate (“EtOAc”)-methanol (“MeOH”) 4:1 with 1% acetic acid (“AcOH”). Evaporation and trituration with ether afforded 0.052 g of orange solid (8.26% yield) NMR (DMSO-d6); 8.03–7.99 (m, 1H), 7.61–7.51 (m, 6H), 7.46–7.42 (dd, 1H), 7.36–7.33 (d, 2H), 7.19–7.15 (t, 2H), 5.98 (s, 2H), 3.90 (s, 2H) the mixture degassed with nitrogen cooled to room temperature poured into 1N HCl extracted with EtOAc washed with brine dried over MgSO4 evaporated onto silica gel The mesh was purified on a 3.5×15 cm silica gel column eluted with ethyl acetate (“EtOAc”)-methanol (“MeOH”) 4:1 with 1% acetic acid (“AcOH”) Evaporation and trituration with ether

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 1.0 g (2.0 mmol) 3-(3,4-Difluoro-benzyl)-6-iodo-1-methyl-1H-quinazoline-2,4-dione from Example 14 Step 1 and 1.0 g (8.4 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis-triphenylphosphine palladium di-chloride (catalytic) followed by CuI (catalytic). 0.44 g (3.3 mmol) 1-fluoro-4-prop-2-ynyl-benzene is added and the mixture is heated to 70° C. for 6 hrs. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filtered and dry under reduced pressure. to cool to room temperature the mixture stirred 30 minutes Filtered dry under reduced pressure

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 0.5 g (1.06 mmol) 3-(3,4-Difluoro-benzyl)-6-iodo-1-methyl-1H-quinazoline-2,4-dione and 0.52 g (4.2 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis-triphenylphosphine palladium di-chloride (catalytic) followed by CuI (catalytic). 0.15 g (1.3 mmol) 1-fluoro-4-prop-2-ynyl-benzene is added and the mixture is heated to 70° C. for 6 hours. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filtered and triturated solid in hot EtOAc and filtered. Purified by flash chromatography (EtOAc/hexane eluent). to cool to room temperature the mixture stirred 30 minutes Filtered triturated solid in hot EtOAc filtered Purified by flash chromatography (EtOAc/hexane eluent)

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To 0.5 g (1.06 mmol) 3-(3,4-Difluoro-benzyl)-6-iodo-1-methyl-1H-quinazoline-2,4-dione and 0.52 g (4.2 mmol) di-isopropyl ethylamine in 15 ml DMF is added bis-triphenylphosphine palladium di-chloride (catalytic) followed by CuI (catalytic). 0.15 g (1.3 mmol) 1-fluoro-4-prop-2-ynyl-benzene is added and the mixture is heated to 70° C. for 6 hours. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filtered and triturated solid in hot EtOAc and filtered. Purified by flash chromatography (EtOAc/hexane eluent). to cool to room temperature the mixture stirred 30 minutes Filtered triturated solid in hot EtOAc filtered Purified by flash chromatography (EtOAc/hexane eluent)

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

实验步骤: Sodium hypochlorite (1.408 mL, 0.912 mmol) was added to a stirred, room temperature mixture of tert-butyl 5-(2-(4-fluorophenyl)-6-((hydroxyimino)methyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (100 mg, 0.228 mmol) and 1-fluoro-4-(prop-2-ynyl)benzene (61.2 mg, 0.456 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for overnight. The reaction was checked with LCMS and starting material was all consumed. The mixture was diluted with dichloromethane (10 mL), washed with aqueous sodium hydrogen carbonate (saturated, 1×8 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/isohexane=50% to give tert-butyl 5-(6-(5-(4-fluorobenzyl)isoxazol-3-yl)-2-(4-fluorophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (102 mg, 0.179 mmol) as a yellow solid. washed with aqueous sodium hydrogen carbonate (saturated, 1×8 mL) dried (MgSO4) filtered the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica gel eluting with EtOAc/isohexane=50%

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

实验步骤: The title compound was prepared using enantiomerically pure propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate from EXAMPLE 6 and 1-fluoro-4-prop-2-yn-1-ylbenzene prepared from 4-fluorobenzyl chloride and ethynyltrimethylsilane described in EXAMPLE 8 EXAMPLE 28.1 and 28.2 were prepared from the chiral azide with the retention time of 10.3 and 11.5 min respectively from EXAMPLE 6. MS (+ESI) m/z: 405.1.

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

实验步骤: The title compound was prepared using enantiomerically pure propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate from EXAMPLE 6 and 1-fluoro-4-prop-2-yn-1-ylbenzene prepared from 4-fluorobenzyl chloride and ethynyltrimethylsilane described in EXAMPLE 8 EXAMPLE 28.1 and 28.2 were prepared from the chiral azide with the retention time of 10.3 and 11.5 min respectively from EXAMPLE 6. MS (+ESI) m/z: 405.1.

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

实验步骤: The title compound was prepared using analogous procedures described in EXAMPLE 3 from propyl (7-azido-4-fluoro-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate (EXAMPLE 7, Step 6) and 1-fluoro-4-prop-2-yn-1-ylbenzene obtained according to the following procedure (Gazz. Chim. Ital. 1990, 120, 783). To a mixture of ethynyltrimethylsilane (1 eq) in THF (0.6M) at room temperature was added ethylmagnesium bromide (1 eq). The mixture was stirred at room temperature for 30 min then copper bromide (I) (0.1 eq) was added. After stirring for 30 min, a 1M solution of 4-fluorobenzyl bromide (1 eq) in THF was added and the mixture was heated to reflux overnight. The reaction mixture was quenched by addition to a cold solution of NH4Cl sat, stirred for 30 min then extracted with Et2O, washed with brine, dried and evaporated. Purification by Combi-flash using a gradient of 0-100% EA/Hex afforded the desired TMS alkyne. The TMS alkyne was directly mixed with potassium fluoride (1.2 eq) in DMF (0.2M containing 1% water). The mixture was stirred at room temperature overnight then quenched by addition of HCl 3N, stirred for 1 h then extracted with pentanes, washed with NaHCO3 sat, brine, dried and evaporated. Crude alkyne compound was used directly for click chemistry described in EXAMPLE 3. The resulting racemic esters were resolved by HPLC using a 4.6×250 mm Chiralpak AS column eluting with 60% EtOH, 39.75% Hexanes and 0.25% Et3N at 0.8 mL/min and 254 nm. The resulting chiral esters (retention times=10.3 and 13.3 min) were hydrolyzed to afford EXAMPLE 8.1 and 8.2 respectively. 11-1 NMR of EXAMPLE 8.1: 1H NMR (400 MHz, DMSO-d6): δ 12.20 (s, 1 H), 7.55 (s, 1 H), 7.33 (dd, 2 H), 7.27 (d, 1 H), 7.17 (t, 2 H), 6.96 (td, 1 H), 6.85 (dd, 1 H), 5.23-5.09 (m, 1 H), 4.58 (dd, 1 H), 4.44 (dd, 1 H), 4.25 (s, 2 H), 3.65-3.52 (m, 2 H), 3.12-3.02 (m, 1 H), 2.89 (ddd, 1 H), 2.32-2.19 (m, 1 H), 2.14-2.02 (m, 1 H). MS (+ESI) m/z: 423.1. obtained After stirring for 30 min the mixture was heated to reflux overnight The reaction mixture was quenched by addition to a cold solution of NH4Cl stirred for 30 min then extracted with Et2O washed with brine dried evaporated Purification by Combi-flash

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

实验步骤: This reaction was carried out as described in Example D1, Step (c) using 1-fluoro-4-prop-2-ynyl-benzene (0.23 g, 1.7 mmol) and {4-[5-(3-bromophenyl) tetrazol-2-ylmethyl]phenoxy}acetic acid tert-butyl ester (0.30 g, 0.67 mmol) in place of 4-[5-(3-bromophenyl)tetrazol-2-ylmethyl]-benzenesulfonic acid, sodium salt. This afforded 0.23 g of the product (68.5% yield).

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

实验步骤: This reaction was carried out as described in Example D1, Step (c) using 1-fluoro-4-prop-2-ynyl-benzene (0.23 g, 1.7 mmol) and {4-[5-(3-bromophenyl) tetrazol-2-ylmethyl]phenoxy}acetic acid tert-butyl ester (0.30 g, 0.67 mmol) in place of 4-[5-(3-bromophenyl)tetrazol-2-ylmethyl]-benzenesulfonic acid, sodium salt. This afforded 0.23 g of the product (68.5% yield).