methyl 3-amino-4-fluorobenzoate

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: A solution of methyl 3-amino-4-fluorobenzoate (5 g, 29.6 mmol) in pyridine (200 ml) was treated with imidazo[1,2-a]pyridine-3-carbonyl chloride.HCl (step 1) (6.43 g, 29.6 mmol) and the mixture was stirred at RT for 2 days. The mixture was poured into water (30 ml) and a small exotherm was observed. After cooling to RT, the resulting precipitate was filtered and dried in a vacuum oven to afford the title compound; the resulting precipitate was filtered dried in a vacuum oven

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

Procedure: A mixture comprising 2-(2,6-cis-dimethylpiperidin-1-yl)ethanaminium chloride (4 g, 20.75 mmol) and methyl 3-amino-4-fluorobenzoate (3.51 g, 20.75 mmol) in THF (50 ml) was treated with TBD (2.89 g, 20.75 mmol) and stirred at 80° C. for 16 hrs. A further portion of methyl 3-amino-4-fluoro benzoate (1 g) and TBD (0.5 g) were added and heating continued for 24 hrs. The resulting mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The mixture was extracted once with ethyl acetate and once with chloroform. The combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Purification of the residue by chromatography on silica eluting with 0-20% MeOH in DCM afforded the title compound; heating continued for 24 hrs The resulting mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate The mixture was extracted once with ethyl acetate and once with chloroform The combined organic layers were dried (MgSO4) filtered evaporated to dryness Purification of the residue by chromatography on silica eluting with 0-20% MeOH in DCM

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

Procedure: The title compound was prepared from methyl 3-amino-4-fluorobenzoate, benzylamine and 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine analogously to 3-amino-4-methyl-N-(2-(4-methylpiperazin-1-yl)benzyl)benzamide (Intermediate 4A, step 1);

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

Procedure: A mixture comprising methyl 3-amino-4-fluorobenzoate (2 g, 11.82 mmol), (3,4-difluorophenyl)methanamine (2.54 g, 17.74 mmol) and TBD (1.646 g, 11.82 mmol) in THF (39.4 ml) was heated at 80° C. overnight. After cooling to RT, the mixture was purified by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/DCM to afford the title compound. the mixture was purified by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/DCM

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

Procedure: A mixture comprising 2-tert-butoxyethanamine (1.2 g, 5.12 mmol, 50% w/w) and methyl 3-amino-4-fluorobenzoate (0.866 g, 5.12 mmol) in THF (10 ml) was treated with TBD (0.713 g, 5.12 mmol) and heated at 90° C. for 16 hrs. After cooling to RT, the solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The organic portion was separated and washed with 10% aq citric acid (×2), NaHCO3 (sat. aq), brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-100% EtOAc in iso-hexane afforded the title compound as a clear oil; After cooling to RT the solvent was removed in vacuo the residue was partitioned between water and EtOAc The organic portion was separated washed with 10% aq citric acid (×2), NaHCO3 (sat. aq), brine dried (MgSO4) concentrated in vacuo Purification of the crude product by chromatography on silica eluting with 0-100% EtOAc in iso-hexane

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

Procedure: A mixture comprising 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (step 3) (1.8 g, approximately 7.47 mmol) and thionyl chloride (10 ml, 137 mmol) under N2 was heated at reflux for 1.5 hrs. The reaction mixture was concentrated in vacuo and azeotroped with toluene. Methyl 3-amino-4-fluorobenzoate (1.263 g, 7.47 mmol) (pre-dried at 45° C.) was added followed by pyridine and the mixture was stirred at room temperature under N2 overnight. The reaction mixture was diluted with EtOAc and washed with H2O. The resulting solid was collected by filtration. The filtrate was dried (MgSO4) and concentrated in vacuo and triturated with ether to afford cream solid. The solids were combined and dried at 45° C. to afford the title compound; at reflux for 1.5 hrs The reaction mixture was concentrated in vacuo azeotroped with toluene washed with H2O The resulting solid was collected by filtration The filtrate was dried (MgSO4) concentrated in vacuo triturated with ether to afford cream solid dried at 45° C.

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the solution of compound 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate A step 3) (1.26 Kg, 5.23 mol) in DMAC (15 L) was added dropwise SOCl2 (1.86 kg, 15.6 mol) at 10° C. in 30 min. To the resulting mixture warmed to 20° C. was added compound methyl 3-amino-4-fluorobenzoate (884 g, 5.23 mol) in DMAC (3.0 L) over 30 min. After addition, the reaction temperature went up to 30° C. HPLC showed the reaction went to completion within 5 min. To the reaction mixture was added water (20 L) over 20 min. The mixture was filtered and dried under vacuum to afford the title compound as a white solid; After addition went up to 30° C The mixture was filtered dried under vacuum

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: To a solution of methyl 3-amino-4-fluorobenzoate (109 g, 644 mmol) in THF (2000 mL), saturated NaHCO3 (68 g, 805 mmol) was added. Then 2-propen-1-yl chloridocarbonate (93 g, 773 mmol) was added dropwise at 0° C. The mixture was stirred at rt for 2 h. The solution was extracted with EtOAc (500 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product (160 g, 98%), which was used in the next step directly. 1H NMR (400 MHz, CDCl3) δ ppm 8.72-8.81 (m, 1H), 7.71-7.79 (m, 1H), 7.09-7.16 (m, 1H), 6.87-6.94 (br, 1H), 5.91-6.03 (m, 1H), 5.41 (d, J=17.1 Hz, 1H), 5.28 (d, J=10.5, 1H), 4.70 (d, J=10.5 Hz, 1H), 4.70 (d, J=5.5 Hz, 2H), 3.90 (s, 3H). Then 2-propen-1-yl chloridocarbonate (93 g, 773 mmol) was added dropwise at 0° C The solution was extracted with EtOAc (500 mL×3) The combined organic layers were washed with water and brine successively dried over Na2SO4 filtered concentrated under reduced pressure