2-chloroethylurea

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

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

Procedure: Following General Procedure A, B, the title compound was prepared from 2-Amino-4-chloro-benzenethiol, (2-chloro-ethyl)-urea and 1-benzofuran-2-sulfonyl chloride.

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

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

Procedure: Chloroethylisocyanate (Compound 5, Aldrich, 346 mg, 3.3 mmol) was added to a stirred solution of 2,3-dimethylaniline (Aldrich, 400 mg, 3.3 mmol) in tetrahydrofuran (5 ml) at room temperature. After 30 minutes a white precipitate formed. The solid chloroethylurea was collected by vacuum filtration yield: 477 mg (64%): mp 145°-146° C. HNMR (300 MHz, CDCl3) σ 7.00 (m, 3H); 6.72 (br, 1H); 5.19 (br, 1H), 3.59 (m, 2H); 3.49 (m, 2H); 2.30 (s, 3H); 2.18 (s, 3H); Mass spectrum m/e 226.0872 (C1H15C1N2O requires 226.0872). The chlorethylurea (199 mg, 0.88 mmol) was suspended in H2O (4 ml) and CH3OH (4 ml) and heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with 1N NaOH (to pH 13). The organic layer was dried over Na2CO3 and concentrated in vacuo to yield 140 mg (84%) of the title compound as a white crystalline solid: mp 112°-113.5° C.; 1H NMR (300 MHz, CDCl3) σ 7.19 (m, 1H); 7.09 (m, 1H), 6.91 (m, 1H); 5.00 (br, s, 1H); 4.40 (t, 2H); 3.70 (t, 2H); 2.30 (s, 3H); 2.15 (s, 3H); Mass spectrum m/e 190.1104 (C11H14N2O requires 190.1106). After 30 minutes a white precipitate formed The solid chloroethylurea was collected by vacuum filtration yield: 477 mg (64%) to reflux for 1 hour concentrated in vacuo The residue was dissolved in CH2Cl2 washed with 1N NaOH (to pH 13) The organic layer was dried over Na2CO3 concentrated in vacuo

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

Procedure: Chloroethylisocyanate (Compound 5 210 mg, 2.05 mmol) was added to a stirred solution at 5,6,7,8-tetrahydro-1-naphthylamine (302 mg, 2.05 mmol) in tetrahydrofuran (2 ml). After 30 minutes the resulting chloroethylurea was collected by vacuum filtration. Yield: 302 mg (58%) of fine white crystals: mp 101°-103°; H NMR (300 MHz, CDCl3) σ 6.98-7.30 (m, 3H); 6.08 (brs, 1H); 5.19 (br, s, 1H); 3.68 (m, 2H); 3.55 (m, 2H); 2.79 (m, 2H); 2.61 (m, 2H); 1.80 (m, 4H); Mass spectrum m/e 252.1034 (C13H17ClN2O requires 252.1029). The chloroethyl urea (237 mg, 0.94 mmol) was suspended in H2O (3 ml) and CH3OH (3 ml) and heated to reflux for 18 hours. The reaction mixture was cooled to room temperature and worked up as above to yield after recrystallization (hexane/CHCl3) 187.6 mg (87%) of the title compound: mp 160°-162° C.; 1H NMR (300 MHz, CDCl3) σ 7.23 (m, 1H); 7.08 (m, 1H; 6.75 (m, 1H); 5.55 (br, 1H); 4.35 (t, 2H); 3.70 (t, 2H); 2.70 (m, 2H); 2.58 (m, 2H); 1.80 (m, 4H); Mass spectrum m/e 216.1257 (C13H16N2O requires 216.1262). After 30 minutes the resulting chloroethylurea was collected by vacuum filtration to reflux for 18 hours to yield after recrystallization (hexane/CHCl3) 187.6 mg (87%) of the title compound

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

Procedure: Chloroethylisocyanate (Compound 5, Aldrich, 346 mg, 3.3 mmol) was added to a stirred solution of 2,3-dimethylaniline (Aldrich, 400 mg, 3.3 mmol) in tetrahydrofuran (5 ml) at room temperature. After 30 minutes a white precipitate formed. The solid chloroethylurea was collected by vacuum filtration yield: 477 mg (64%): mp 145°-146° C. HNMR (300 MHz, CDCl3) σ 7.00 (m, 3H); 6.72 (br, 1H); 5.19 (br, 1H), 3.59 (m, 2H); 3.49 (m, 2H); 2.30 (s, 3H); 2.18 (s, 3H); Mass spectrum m/e 226.0872 (C1H15ClN2O requires 226.0872). The chlorethylurea (199 mg, 0.88 mmol) was suspended in H2O (4 ml) and CH3OH (4 ml) and heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with 1N NaOH (to pH 13). The organic layer was dried over Na2CO3 and concentrated in vacuo to yield 140 mg (84%) of the title compound as a white crystalline solid: mp 112°-113.5° C.; 1H NMR (300 MHz, CDCl3) σ 7.19 (m, 1H); 7.09 (m, 1H), 6.91 (m, 1H); 5.00 (br, s, 1H); 4.40 (t, 2H); 3.70 (t, 2H); 2.30 (s, 3H); 2.15 (s, 3H); Mass spectrum m/e 190.1104 (C11H14N2O requires 190.1106). After 30 minutes a white precipitate formed The solid chloroethylurea was collected by vacuum filtration yield: 477 mg (64%) to reflux for 1 hour concentrated in vacuo The residue was dissolved in CH2Cl2 washed with 1N NaOH (to pH 13) The organic layer was dried over Na2CO3 concentrated in vacuo

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

Procedure: Following General Procedure A, B, the title compound was prepared from 2-Amino-4-chloro-benzenethiol, (2-chloro-ethyl)-urea and 1-benzofuran-2-sulfonyl chloride.

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

Procedure: Following General Procedure A, B, the title compound was prepared from 2-Amino-4-chloro-benzenethiol, (2-chloro-ethyl)-urea and 1-benzofuran-2-sulfonyl chloride.

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

Procedure: Following General Procedure A, B, the title compound was prepared from 2-Amino-4-chloro-benzenethiol, (2-chloro-ethyl)-urea and 1-benzofuran-2-sulfonyl chloride.

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

Procedure: Sodium hydrogen sulfide (1.07 g) was dissolved in N,N-dimethylformamide (25 ml). To the mixture was added 4N hydrogen chloride in ethylacetate (13.3 ml) at room temperature. After stirring for approximately 30 minutes at the same temperature, to the resulting mixture were added 4-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-6-methanesulfinyl-pyrimidin-2-ylamine (1.20 g) obtained in Step 5 of Example 314 and N,N-diisopropylethylamine (2.9 ml) successively. The mixture was stirred at 80° C. for four hours, and then the mixture was allowed to cool to room temperature. To the mixture were added to 2-chloro-ethylurea (3.20 g), N,N-diisopropylethylamine (5.8 ml) and N,N-dimethylformamide (15 ml) successively. The reaction mixture was stirred at 80° C. for 14 hours and then allowed to cool to room temperature. The reaction was quenched by adding water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine subsequently, dried over anhydrous sodium sulfate. After removal of inorganic salts, the solution was concentrated by evaporation. The resulting residue was purified by HPLC (column; ODS, mobile phase; 0.05% TFA in water: 0.05% TFA in acetonitrile=65:35) to give {2-[2-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-pyrimidin-4-ylsulfanyl]-ethyl}-urea (0.93 g). The mixture was stirred at 80° C. for four hours The reaction mixture was stirred at 80° C. for 14 hours to cool to room temperature The reaction was quenched by adding water extracted with ethyl acetate The organic layer was separated washed with water and brine subsequently dried over anhydrous sodium sulfate After removal of inorganic salts the solution was concentrated by evaporation The resulting residue was purified by HPLC (column; ODS, mobile phase; 0.05% TFA in water: 0.05% TFA in acetonitrile=65:35)

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

Procedure: Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and 2-chloroethylurea. Under the same conditions as the method for synthesizing Compound A7-17

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

Procedure: Sodium hydrogen sulfide (1.07 g) was dissolved in N,N-dimethylformamide (25 ml). To the mixture was added 4N hydrogen chloride in ethylacetate (13.3 ml) at room temperature. After stirring for approximately 30 minutes at the same temperature, to the resulting mixture were added 4-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-6-methanesulfinyl-pyrimidin-2-ylamine (1.20 g) obtained in Step 5 of Example 314 and N,N-diisopropylethylamine (2.9 ml) successively. The mixture was stirred at 80° C. for four hours, and then the mixture was allowed to cool to room temperature. To the mixture were added to 2-chloro-ethylurea (3.20 g), N,N-diisopropylethylamine (5.8 ml) and N,N-dimethylformamide (15 ml) successively. The reaction mixture was stirred at 80° C. for 14 hours and then allowed to cool to room temperature. The reaction was quenched by adding water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine subsequently, dried over anhydrous sodium sulfate. After removal of inorganic salts, the solution was concentrated by evaporation. The resulting residue was purified by HPLC (column; ODS, mobile phase; 0.05% TFA in water: 0.05% TFA in acetonitrile=65:35) to give {2-[2-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-pyrimidin-4-ylsulfanyl]-ethyl}-urea (0.93 g). The mixture was stirred at 80° C. for four hours The reaction mixture was stirred at 80° C. for 14 hours to cool to room temperature The reaction was quenched by adding water extracted with ethyl acetate The organic layer was separated washed with water and brine subsequently dried over anhydrous sodium sulfate After removal of inorganic salts the solution was concentrated by evaporation The resulting residue was purified by HPLC (column; ODS, mobile phase; 0.05% TFA in water: 0.05% TFA in acetonitrile=65:35)