4-(3-CHLORO-PROPYL)-PIPERAZINE-1-CARBOXYLIC ACID TERT-BUTYL ESTER

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (200 mg, 0.99 mmol), 4-(3-chloro-propyl)-piperazine-1-carboxylic acid tert-butyl ester (203 mg, 0.76 mmol), DMF (4 ml) and K2CO3 (553 g, 4.00 mmol) was heated to 70° C. and work up according to general procedure E. The organic phase was washed with 2M NaOH (3.×20 ml), water (2×20 ml), dried over MgSO4, fitered and concentrate in vacuo at 35° C. to provided the title compound (272 mg, 64%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.11-4.04 (m, 2H), 4.03 (t, 2H), 3.89 (td, 2H), 3.50-3.37 (m, 4H), 2.53 (t, 2H), 2.45-2.34 (m, 4H), 2.15-2.00 (m, 4H), 1.97 (p, 2H), 1.46 (s, 9H). The organic phase was washed with 2M NaOH (3.×20 ml), water (2×20 ml) dried over MgSO4 fitered and concentrate in vacuo at 35° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (200 mg, 0.99 mmol), 4-(3-chloro-propyl)-piperazine-1-carboxylic acid tert-butyl ester (203 mg, 0.76 mmol), DMF (4 ml) and K2CO3 (553 g, 4.00 mmol) was heated to 70° C. and work up according to general procedure E. The organic phase was washed with 2M NaOH (3.×20 ml), water (2×20 ml), dried over MgSO4, fitered and concentrate in vacuo at 35° C. to provided the title compound (272 mg, 64%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.11-4.04 (m, 2H), 4.03 (t, 2H), 3.89 (td, 2H), 3.50-3.37 (m, 4H), 2.53 (t, 2H), 2.45-2.34 (m, 4H), 2.15-2.00 (m, 4H), 1.97 (p, 2H), 1.46 (s, 9H). The organic phase was washed with 2M NaOH (3.×20 ml), water (2×20 ml) dried over MgSO4 fitered and concentrate in vacuo at 35° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (200 mg, 0.99 mmol), 4-(3-chloro-propyl)-piperazine-1-carboxylic acid tert-butyl ester (203 mg, 0.76 mmol), DMF (4 ml) and K2CO3 (553 g, 4.00 mmol) was heated to 70° C. and work up according to general procedure E. The organic phase was washed with 2M NaOH (3.×20 ml), water (2×20 ml), dried over MgSO4, fitered and concentrate in vacuo at 35° C. to provided the title compound (272 mg, 64%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.11-4.04 (m, 2H), 4.03 (t, 2H), 3.89 (td, 2H), 3.50-3.37 (m, 4H), 2.53 (t, 2H), 2.45-2.34 (m, 4H), 2.15-2.00 (m, 4H), 1.97 (p, 2H), 1.46 (s, 9H). The organic phase was washed with 2M NaOH (3.×20 ml), water (2×20 ml) dried over MgSO4 fitered and concentrate in vacuo at 35° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (200 mg, 0.99 mmol), 4-(3-chloro-propyl)-piperazine-1-carboxylic acid tert-butyl ester (203 mg, 0.76 mmol), DMF (4 ml) and K2CO3 (553 g, 4.00 mmol) was heated to 70° C. and work up according to general procedure E. The organic phase was washed with 2M NaOH (3.×20 ml), water (2×20 ml), dried over MgSO4, fitered and concentrate in vacuo at 35° C. to provided the title compound (272 mg, 64%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.11-4.04 (m, 2H), 4.03 (t, 2H), 3.89 (td, 2H), 3.50-3.37 (m, 4H), 2.53 (t, 2H), 2.45-2.34 (m, 4H), 2.15-2.00 (m, 4H), 1.97 (p, 2H), 1.46 (s, 9H). The organic phase was washed with 2M NaOH (3.×20 ml), water (2×20 ml) dried over MgSO4 fitered and concentrate in vacuo at 35° C.

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2S,4R)-N-(4-Chloro-phenyl)-N-{2-methyl-1-[4-(3-piperazin-1-yl-propoxy)-benzoyl]-1,2,3,4-tetrahydro-quinolin-4-yl}-acetamide was prepared from (2S,4R)-4-[3-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester. (2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.40 g, 0.92 mmol) was dissolved in DMF at room temperature and K2CO3 (0.127 g, 0.921 mmol) was added. 4-(3-Chloro-propyl)-piperazine-1-carboxylic acid tert-butyl ester (0.242 g, 0.921 mmol) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography to afford the product as colorless oil in 50% yield. (2S,4R)-4-[3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester (246 mg) was dissolved in 4M HCl in dioxane (2 mL). The mixture was stirred for 2 h at room temperature. After concentration, the white solid was washed with EtOAc to provide the title compound in 100% yield. The reaction mixture was concentrated in vacuo The residue was partitioned between ethyl acetate and water extracted three times with ethyl acetate dried over MgSO4 filtered concentrated down The crude residue was purified by silica gel chromatography

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tert-Butyl-4-(3-Chloropropyl)-1-piperazine carboxylate and sodium-azide were dissolved (suspended) in 8 ml DMSO dry and heated to 90° C. for 15 h. The reaction mixture was allowed to cool to room temperature and pored into 50 ml of water. The product was extracted with DCM and the combined organic phases dried over MgSO4. The product was purified by flash column chromatography (n-heptane/ethylacetate 1:1, RF=0.34). Yield: 3.5 g. dry to cool to room temperature The product was extracted with DCM the combined organic phases dried over MgSO4 The product was purified by flash column chromatography (n-heptane/ethylacetate 1:1, RF=0.34)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4.94 g tert-Butyl-1-piperazine-carboxylate and 12.66 g 1-Bromo-3-chloropropane in 15 ml DMF (dry) was added 4.08 g K2CO3 and the reaction heated to 50° C. for one minute and stirred at room temperature for additional 3 h. The reaction mixture is pored into 200 ml of water and extracted with DCM. The combined organic phases were washed with water and dried over MgSO4 and evaporated in vacuo. The product was purified by flash column chromatography (n-heptane/ethylacetate 1:1, RF=0.3) Yield 3.9 g. extracted with DCM The combined organic phases were washed with water dried over MgSO4 evaporated in vacuo The product was purified by flash column chromatography (n-heptane/ethylacetate 1:1, RF=0.3) Yield 3.9 g

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: T1 was prepared from 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol and tert-butyl 4-(3-chloropropyl)piperazine-1-carboxylate following the general procedure reported in Preparative Example 54 Step 1-2. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.38 (s, 9H), 1.96 (m, 2H), 2.23 (m, 4H), 2.47 (m, 2H), 3.30 (m, 4H), 3.92 (s, 3H), 4.17 (t, J=6.3 Hz, 2H), 5.46 (br s, 2H), 6.37 (d, J=5.2 Hz, 1H), 6.45 (dd, J=8.9 Hz, J=1.8 Hz, 1H), 6.54 (dd, J=13.1 Hz, J=2.4 Hz, 1H), 7.05 (t, J=8.9 Hz, 1H), 7.35 (s, 1H), 7.49 (s, 1H), 8.42 (d, J=5.2 Hz, 1H). MS (ES) C29H35FN4O5 requires: 526. Found: 527 (M+H)+.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (200 mg, 0.99 mmol), 4-(3-chloro-propyl)-piperazine-1-carboxylic acid tert-butyl ester (203 mg, 0.76 mmol), DMF (4 ml) and K2CO3 (553 g, 4.00 mmol) was heated to 70° C. and work up according to general procedure E. The organic phase was washed with 2M NaOH (3.×20 ml), water (2×20 ml), dried over MgSO4, fitered and concentrate in vacuo at 35° C. to provided the title compound (272 mg, 64%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.93 (d, 2H), 4.11-4.04 (m, 2H), 4.03 (t, 2H), 3.89 (td, 2H), 3.50-3.37 (m, 4H), 2.53 (t, 2H), 2.45-2.34 (m, 4H), 2.15-2.00 (m, 4H), 1.97 (p, 2H), 1.46 (s, 9H). The organic phase was washed with 2M NaOH (3.×20 ml), water (2×20 ml) dried over MgSO4 fitered and concentrate in vacuo at 35° C.