N-(2,2-dimethoxyethyl)-N-(4-fluorobenzyl)amine

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

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

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: 20 g of (2,2-dimethoxy-ethyl)-(4-fluoro-benzyl)-amine (1) were dissolved in 120 ml of dichloromethane. 20 mL of pyridine were added. At 0° C. a solution of 23.8 g p-toluenesulfonic acid chloride in dichloromethane was added dropwise. The reaction was allowed to warm to room temperature and stirring was continued until conversion was completed. For workup, the reaction mixture was washed twice with 2M hydrochloric acid, twice with sodium bicarbonate solution and once with brine. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product was purified by silica gel chromatography to yield 22.95 g of compound 2 as an orange oil. Rt=1.71 min (Method C). Detected mass: 336.1 (M-OMe−). For workup, the reaction mixture was washed twice with 2M hydrochloric acid, twice with sodium bicarbonate solution and once with brine The organic layer was dried over magnesium sulfate evaporated to dryness the obtained crude product was purified by silica gel chromatography

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

Procedure: 12.4 g of 4-fluorobenzaldehyde were dissolved in 100 mL of toluene and reacted with 10.5 g of 2-aminoacetaldehyde dimethylacetal and 1.90 g of p-toluenesulfonic acid monohydrate for two hours at a Dean Stark apparatus. The solution was allowed to cool down, extracted with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated to dryness. The crude product was dissolved in 100 mL of ethanol. 1.89 g of sodium borohydride were added portionwise. Stirring was continued overnight. For workup, acetic acid was added until no gas evolution could be observed. Then the solution was evaporated to dryness, taken up in dichloromethane and washed twice with water. The organic layer was extracted with brine, dried over magnesium sulfate and evaporated to dryness. The obtained crude product (20 g) was used for further reactions without purification. Rt=0.86 min (Method B). Detected mass: 182.1 (M-OMe−), 214.2 (M+H+). to cool down extracted with saturated sodium bicarbonate solution, water and brine dried over magnesium sulfate evaporated to dryness The crude product was dissolved in 100 mL of ethanol 1.89 g of sodium borohydride were added portionwise For workup, acetic acid was added until no gas evolution Then the solution was evaporated to dryness washed twice with water The organic layer was extracted with brine dried over magnesium sulfate evaporated to dryness

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: 20 g (2,2-Dimethoxy-ethyl)-(4-fluoro-benzyl)-amine (21) were dissolved in 120 ml of dichloromethane. 20 mL of pyridine are added. At 0° C. a solution of 23.8 g p-toluenesulfonic acid chloride in dichloromethane was added dropwise. The reaction was allowed to warm to room temperature and stirring is continued until conversion was completed. For workup, the reaction mixture was extracted twice with 2M hydrochloric acid, twice with sodium bicarbonate and once with brine. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product was purified by silica gel chromatography to yield 22.95 g of compound 22 as an orange oil. Rt=1.71 min (Method #4). Detected mass: 336.1 (M-OMe−). For workup, the reaction mixture was extracted twice with 2M hydrochloric acid, twice with sodium bicarbonate and once with brine The organic layer was dried over magnesium sulfate evaporated to dryness the obtained crude product was purified by silica gel chromatography

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

Procedure: 12.4 g of 4-Fluorobenzaldehyde were dissolved in 100 mL of toluene and reacted with 10.5 g 2-Aminoacetaldehyde dimethylacetal and 1.90 g (10 mmol) p-toluenesulfonic acid monohydrate for two hours at a Dean Stark apparatus. The solution was allowed to cool down, extracted with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate and evaporated to dryness. The crude product was dissolved in 100 mL of ethanol. 1.89 g of sodium borohydride were added portionwise. Stirring was continued overnight. For workup, acetic acid was added until no gas evolution could be observed. Then the solution was evaporated to dryness, taken up in dichloromethane and washed twice with water. The organic layer was extracted with brine, dried over magnesium sulfate and evaporated to dryness. The obtained crude product (20 g) was used for further reactions without purification. Rt=0.86 min (Method #1). Detected mass: 182.1 (M-OMe−), 214.2 (M+H+). to cool down extracted with saturated sodium bicarbonate, water and brine dried over magnesium sulfate evaporated to dryness The crude product was dissolved in 100 mL of ethanol 1.89 g of sodium borohydride were added portionwise For workup, acetic acid was added until no gas evolution Then the solution was evaporated to dryness washed twice with water The organic layer was extracted with brine dried over magnesium sulfate evaporated to dryness

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

Procedure: To a solution of 2-amino-N-benzyl-4-methylthiazole-5-carboxamide (0.31 g, 1.25 mmol) in tetrahydrofuran (20 mL) was added 1,1′-carbonyldiimidazole (0.24 g, 1.50 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 6 hours, and N-(4-fluorobenzyl)-2,2-dimethoxyethanamine (0.35 g, 1.65 mmol) was added. The reaction mixture was stirred at ambient temperature for 17 hour. The solvent was removed in vacuo, and the residue was purified by column chromatography to afford the title compound in 77% yield (0.47 g): MS (ES+) m/z 487.4 (M+1). The resulting reaction mixture The reaction mixture was stirred at ambient temperature for 17 hour The solvent was removed in vacuo the residue was purified by column chromatography

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

Procedure: To a solution of 4-fluorobenzylamine (2.00 mL, 17.6 mmol) and dimethoxyacetaldehyde (60% solution in water, 3.00 mL, 19.9 mmol) in tetrahydrofuran (100 mL) was added sodium triacetoxyborohydride (5.90 g, 26.4 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 5 hours, followed by the addition of saturated sodium bicarbonate (50 mL) and extraction with ethyl acetate (3×100 mL). The combined organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by column chromatography to afford N-(4-fluorobenzyl)-2,2-dimethoxyethanamine (2.70 g, 71%): 1H NMR (300 MHz, CDCl3) δ 7.24-7.19 (m, 2H), 6.97-6.89 (m, 2H), 4.43-4.39 (m, 1H), 3.70 (s, 2H), 3.30 (s, 6H), 2.67 (dd, J=5.4, 1.5 Hz, 2H); MS (ES+) m/z 214.3 (M+1). The resulting reaction mixture The combined organic solution was dried over anhydrous sodium sulfate filtered The filtrate was concentrated the residue was purified by column chromatography