2,6-dichloro-3,5-dimethoxyaniline

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

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

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

Procedure: Phosgene (20% in toluene, 1 mL, 2.0 mmol, 2.4 equiv) is added to a solution of 2,6-dichloro-3,5-dimethoxyaniline (221 mg, 1.0 mmol, 1.2 equiv) in dioxane (2.5 mL), under an argon atmosphere. The mixture is heated to reflux, stirred for 1 h, allowed to cool to RT, and concentrated in vacuo. The resulting isocyanate is added to a solution of N-methyl-N′-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidine-4,6-diamine (Step 2.1) (259 mg, 0.83 mmol) in toluene (5 mL), at reflux and under an argon atmosphere. The reaction mixture is stirred at reflux for 3 h, allowed to cool to RT, and diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5) affords the title compound as a yellow solid: ESI-MS: 560.0/562.0 [MH]+; tR=3.26 min (purity: 99%, system 1); TLC: Rf=0.37 (DCM/MeOH+1% NH3aq, 9:1). The mixture is heated to reflux concentrated in vacuo at reflux and under an argon atmosphere The reaction mixture is stirred at reflux for 3 h to cool to RT The aqueous layer is separated extracted with DCM The organic phase is washed with brine dried (Na2SO4) filtered concentrated Purification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5)

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

Procedure: To a solution of N-(2,6-dichloro-3,5-dimethoxy-phenyl)-acetamide (34.5 g, 264 mmol) in ethanol (1.3 L), 2M KOH (0.72 L) is added. Then, the reaction mixture is heated to reflux, stirred for 44 h at reflux, then allowed to cool to RT. The resulting suspension is cooled to 0° C. stirred for 1 h, and filtered. The residue is washed with a small portion of cold EtOH/H2O (1:1) and with cold H2O till neutrality, and dried to provide the title compound as a white solid: ESI-MS: 222.0/224.0 [MH]+, TLC: Rf=0.52 (Hex/EtOAc, 1:1). Then, the reaction mixture is heated to reflux at reflux The resulting suspension is cooled to 0° C. stirred for 1 h filtered The residue is washed with a small portion of cold EtOH/H2O (1:1) and with cold H2O till neutrality, and dried

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

Procedure: Phosgene (20% in toluene, 0.8 mL, 1.58 mmol, 2.4 equiv) is added to a solution of 2,6-dichloro-3,5-dimethoxyaniline (175 mg, 0.79 mmol, 1.2 equiv) in dioxane (2.5 mL), under an argon atmosphere. The mixture is heated to reflux, stirred for 1 h, allowed to cool to RT, and concentrated in vacuo. The resulting isocyanate is added to a solution of N-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrimidine-4,6-diamine (208.5 mg, 0.66 mmol) in NMP (2 mL), at 75° C. and under an argon atmosphere. The reaction mixture is stirred at 75° C. for 2 h, allowed to cool to RT, and is then diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 96:4), followed by trituration of the resulting material in MeOH, affords the title compound as a white solid: ESI-MS: 562.9/564.9 [MH]+; tR=2.99 min (purity: 100%, system 1); TLC: Rf=0.36 (DCM/MeOH+1% NH3aq, 93:7). The mixture is heated to reflux concentrated in vacuo The reaction mixture is stirred at 75° C. for 2 h to cool to RT The aqueous layer is separated extracted with DCM The organic phase is washed with brine dried (Na2SO4) filtered concentrated Purification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 96:4)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2,6-dichloro-3,5-dimethoxy-aniline (133 mg, 0.60 mmol; Preparation 2) in 2 ml of dioxane under a nitrogen atmosphere, phosgene (0.54 ml 20% in toluene, 1.0 mmol) is added. The mixture is stirred for 60 min at 100° C., cooled to RT and concentrated in vacuo, yielding 2,6-dichloro-3,5-dimethoxyphenylisocyanate. cooled to RT concentrated in vacuo

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2,6-dichloro-3,5-dimethoxy-aniline (124 mg, 0.56 mmol; Preparation 2) in 2 ml of dioxane under a nitrogene atmosphere, phosgene (0.52 ml 20% in toluene, 0.98 mmol) is added. The mixture is stirred for 70 min at 100° C., cooled to RT and concentrated in vacuo, yielding 2,6-dichloro-3,5-dimethoxyphenylisocyanate. The resulting solid is added portion-wise to a boiling solution of N-methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine (140 mg, 0.47 mmol) in 8 ml of toluene during 20 min. After 3 h, another 2 eq of 2,6-dichloro-3,5-dimethoxyphenylisocyanate are added and stirring is continued for totally 5 h. Then the reaction mixture is diluted with DCM and a saturated aqueous solution of NaHCO3. The aqueous layer is separated and extracted twice with DCM. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; DCM/MeOH/NH3aq, 97:3:0.2) gives the title compound: ESI-MS: 547/549 [MH]+; tR=3.5 min (purity: 100%, gradient J); TLC: Rf=0.40 (DCM/MeOH+1% NH3aq, 95:5). cooled to RT concentrated in vacuo

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

Procedure: To a solution of 2,6-dichloro-3,5-dimethoxyaniline (preparation 2, 74 mg, 0.34 mmol, 1.25 eq.) in dioxane is added 20% phosgene solution in toluene (191 μl, 0.36 mmol, 1.35 eq.) under argon. The reaction mixture is stirred for further 6 h at room temperature under argon. Then, the solvent is evaporated and the colorless crystalline residue is taken up in dry toluene (2.5 ml). After the addition of N-methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine (see example 1, 80 mg, 0.27 mmol, 1.0 eq.) the suspension is stirred at 70° C. for 36 h under argon. After cooling the precipitate is filtered off, washed with toluene, methanol/ether 1:1, and ether to give a beige powder. The crude product is purified by flash chromatography (1% MeOH in DCM to 16% MeOH in DCM within 30 min). The fractions containing the product are pooled, evaporated, and triturated with ether. The precipitate is filtered off, washed (1× cold methanol/ether 1:1, 1× ether), and vacuum dried at 45° C. over night to afford the title compound as colorless powder: m.p. 221° C. (dec.), ESI-MS: 546.1/548.0/550.0 [MH]+. Then, the solvent is evaporated is stirred at 70° C. for 36 h under argon After cooling the precipitate is filtered off washed with toluene, methanol/ether 1:1, and ether to give a beige powder The crude product is purified by flash chromatography (1% MeOH in DCM to 16% MeOH in DCM within 30 min) The fractions containing the product evaporated triturated with ether The precipitate is filtered off washed (1× cold methanol/ether 1:1, 1× ether), and vacuum dried at 45° C. over night

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

Procedure: To a solution of 2,6-dichloro-3,5-dimethoxyaniline (preparation 2, 74 mg, 0.34 mmol, 1.25 eq.) in dioxane is added 20% phosgene solution in toluene (191 μl, 0.36 mmol, 1.35 eq.) under argon. The reaction mixture is stirred for further 6 h at room temperature under argon. Then, the solvent is evaporated and the colorless crystalline residue is taken up in dry toluene (2.5 ml). After the addition of N-methyl-N′-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-4,6-diamine (see example 1, 80 mg, 0.27 mmol, 1.0 eq.) the suspension is stirred at 70° C. for 36 h under argon. After cooling the precipitate is filtered off, washed with toluene, methanol/ether 1:1, and ether to give a beige powder. The crude product is purified by flash chromatography (1% MeOH in DCM to 16% MeOH in DCM within 30 min). The fractions containing the product are pooled, evaporated, and triturated with ether. The precipitate is filtered off, washed (1× cold methanol/ether 1:1, 1× ether), and vacuum dried at 45° C. over night to afford the title compound as colorless powder: m.p. 221° C. (dec.), ESI-MS: 546.1/548.0/550.0 [MH]+. Then, the solvent is evaporated is stirred at 70° C. for 36 h under argon After cooling the precipitate is filtered off washed with toluene, methanol/ether 1:1, and ether to give a beige powder The crude product is purified by flash chromatography (1% MeOH in DCM to 16% MeOH in DCM within 30 min) The fractions containing the product evaporated triturated with ether The precipitate is filtered off washed (1× cold methanol/ether 1:1, 1× ether), and vacuum dried at 45° C. over night

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

Procedure: To a suspension of N-(2,6-dichloro-3,5-dimethoxy-phenyl)-acetamide (f) (6.50 g, 24.61 mmol) in a mixture of EtOH (80 mL) and water (30 mL), KOH (20 g) is added, and the mixture is stirred 2 days at 80° C. After the solvent (EtOH) is removed under vacuum, water (˜15 mL) is added, and a white solid is collected by filtration and washed with water and dried to give final product g: 1H NMR 600 MHz (CDCl3) δ 6.03 (s, 1H), 4.55 (s, 2H), 3.88 (s, 6H); MS m/z 222.00 (M+1). is added After the solvent (EtOH) is removed under vacuum, water (˜15 mL) is added a white solid is collected by filtration washed with water dried

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

Procedure: A suspension of 4-(3-chloro-pyrazin-2-yl)-6-methylsulfanyl-pyrimidine (37) (200 mg, 0.838 mmol), 2,6-dichloro-3,5-dimethoxyaniline (280 mg, 1.26 mmol), DPEphos (90 mg, 0.167 mmol), palladium (II) acetate (19 mg, 0.085 mmol) and cesium carbonate (546 mg, 1.68 mmol) in dioxane (8 mL) is degassed. After purging with Ar, the vial is sealed by the cap and irradiated at 150° C. for 30 minutes in Smith Synthesizer. The reaction mixture is evaporated and purified by silica gel flash chromatography eluting with ethyl acetate in hexanes from 10% to 30% to afford the desired product (2,6-dichloro-3,5-dimethoxy-phenyl)-[3-(6-methylsulfanyl-pyrimidin-4-yl)-pyrazin-2-yl]-amine (38). is degassed After purging with Ar the vial is sealed by the cap irradiated at 150° C. for 30 minutes in Smith Synthesizer The reaction mixture is evaporated purified by silica gel flash chromatography eluting with ethyl acetate in hexanes from 10% to 30%

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

Procedure: A suspension of 4-(3-chloro-pyrazin-2-yl)-6-methylsulfanyl-pyrimidine (37) (200 mg, 0.838 mmol), 2,6-dichloro-3,5-dimethoxyaniline (280 mg, 1.26 mmol), DPEphos (90 mg, 0.167 mmol), palladium (II) acetate (19 mg, 0.085 mmol) and cesium carbonate (546 mg, 1.68 mmol) in dioxane (8 mL) is degassed. After purging with Ar, the vial is sealed by the cap and irradiated at 150° C. for 30 minutes in Smith Synthesizer. The reaction mixture is evaporated and purified by silica gel flash chromatography eluting with ethyl acetate in hexanes from 10% to 30% to afford the desired product (2,6-dichloro-3,5-dimethoxy-phenyl)-[3-(6-methylsulfanyl-pyrimidin-4-yl)-pyrazin-2-yl]-amine (38). is degassed After purging with Ar the vial is sealed by the cap irradiated at 150° C. for 30 minutes in Smith Synthesizer The reaction mixture is evaporated purified by silica gel flash chromatography eluting with ethyl acetate in hexanes from 10% to 30%