1-phenyl-N-(trimethylsilylmethyl)methanamine

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

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

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of chloromethyltrimethylsilane (325g, 370 ml, 2.65 mole) and benzylamine (835 g, 850 ml, 7.78 mole) was heated at 120° C. (oil bath temperature) for 2 h. A white solid began appearing after only 10 minutes and a viscous mixture eventually resulted. The reaction mixture was allowed to cool, then basified with potassium carbonate solution and extracted twice with ether. The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was purified by distillation. The excess benzylamine was removed in the first fractions (b.p. 47°-62° C. at 2 mmHg). The title compound (D10) was obtained as a colourless oil (380 g, 74%) b.p. 75°-80° C. at 2 mmHg. a viscous mixture eventually resulted to cool extracted twice with ether The combined extracts were dried (Na2SO4) concentrated in vacuo to leave a yellow oil, which was purified by distillation The excess benzylamine was removed in the first fractions (b.p. 47°-62° C. at 2 mmHg)

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

Procedure: 900 g of N-Benzyl-N-trimethylsilylmethyl-amine (4654 mmol) were dissolved in 5.6 l THF at 20-25° C. 450 ml of 36% aqueous formaldehyde (5880 mmol, 1.26 equiv.) were added over 15 min, keeping the temperature between 20-25° C. After 15 min, a mixture of 760 ml diethyl fumarate (1 equiv.), 2.25 l THF and 11.2 ml trifluoroacetic acid (0.03 equiv.) was added over 15 min. The reaction mixture was stirred overnight keeping the temperature between 20-30° C. (in process control by GC). 3.5 l of 1N HCl were added, followed by 2.3 l heptane. The aqueous phase was separated and washed with 3.4 l heptane. The heptane phases were washed sequentially with 3.5 l 1N HCl. 4.5 l MTBE were added to the combined aqueous phases. 720 ml of 32% NaOHaq were added (pH 13) under vigorous stirring. The aqueous phase was separated and re-extracted with 4.5 l MTBE. The MTBE phases were washed sequentially with 2.2 l water, combined and concentrated to dryness at 45° C. to give 1.295 kg of crude (rac)-trans-N-benzyl-pyrrolidine-3,4-dicarboxylic acid diethyl ester. If required, the crude cycloadduct can be distilled. between 20-25° C was added over 15 min between 20-30° C. The aqueous phase was separated washed with 3.4 l heptane The heptane phases were washed sequentially with 3.5 l 1N HCl 4.5 l MTBE were added to the combined aqueous phases 720 ml of 32% NaOHaq were added (pH 13) under vigorous stirring The aqueous phase was separated re-extracted with 4.5 l MTBE The MTBE phases were washed sequentially with 2.2 l water concentrated to dryness at 45° C.

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

Procedure: 900 g of N-Benzyl-N-trimethylsilylmethyl-amine (4654 mmol) were dissolved in 5.6 l THF at 20-25° C. 450 ml of 36% aqueous formaldehyde (5880 mmol, 1.26 equiv.) were added over 15 min, keeping the temperature between 20-25° C. After 15 min, a mixture of 760 ml diethyl fumarate (1 equiv.), 2.25 l THF and 11.2 ml trifluoroacetic acid (0.03 equiv.) was added over 15 min. The reaction mixture was stirred overnight keeping the temperature between 20-30° C. (in process control by GC). 3.5 l of 1N HCl were added, followed by 2.3 l heptane. The aqueous phase was separated and washed with 3.4 l heptane. The heptane phases were washed sequentially with 3.5 l 1N HCl. 4.5 l MTBE were added to the combined aqueous phases. 720 ml of 32% NaOHaq were added (pH 13) under vigorous stirring. The aqueous phase was separated and re-extracted with 4.5 l MTBE. The MTBE phases were washed sequentially with 2.2 l water, combined and concentrated to dryness at 45° C. to give 1.295 kg of crude (rac)-trans-N-benzyl-pyrrolidine-3,4-dicarboxylic acid diethyl ester. If required, the crude cycloadduct can be distilled. between 20-25° C was added over 15 min between 20-30° C. The aqueous phase was separated washed with 3.4 l heptane The heptane phases were washed sequentially with 3.5 l 1N HCl 4.5 l MTBE were added to the combined aqueous phases 720 ml of 32% NaOHaq were added (pH 13) under vigorous stirring The aqueous phase was separated re-extracted with 4.5 l MTBE The MTBE phases were washed sequentially with 2.2 l water concentrated to dryness at 45° C.

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 264 mL (2.42 mol) of benzylamine and 97.7 g. (0.796 mol) of chloromethyltrimethylsilane was heated to 200° C. for 2.5 h then cooled to 10° C. A 0.1M sodium hydroxide solution (400 mL) was added and the product was extracted with 3×200 mL of diethyl ether. The combined organic phase was washed with 100 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was distilled at 115°-125° C. and 5 mm of Hg to give 125.4 g (81% yield) of N-trimethylsilylmethyl benzylamine as a clear liquid; 1H NMR (CDCl3) δ:0.0 (s, 9H), 1.1 (br s, 1H), 2.01 (s, 2H), 3.76 (s, 2H), 7.1-7.3 (m, 5H). the product was extracted with 3×200 mL of diethyl ether The combined organic phase was washed with 100 mL of water dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The product was distilled at 115°-125° C.

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 264 mL (2.42 mol) of benzylamine and 97.7 g (0.796 mol) of chloromethyltrimethylsilane was heated to 200° C. for 2.5 h then cooled to 10° C. A 0.1M sodium hydroxide solution (400 mL) was added and the product was extracted with 3×200 mL of diethyl ether. The combined organic phase was washed with 100 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was distilled at 115°-125° C. and 5 mm of Hg to give 125.4 g (81% yield) of N-trimethysilylmethyl benzylamine as a clear liquid. 1H NMR (CDCl3) delta 0.0 (s, 9H), 1.1 (br s, 1H), 2.01 (s, 2H), 3.76 (s, 2H), 7.1-7.3 (m, 5H). then cooled to 10° C the product was extracted with 3×200 mL of diethyl ether The combined organic phase was washed with 100 mL of water dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The product was distilled at 115°-125° C.

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butyllithium (1.6 M solution in hexane, 34.85 mL, 55.76 mmol) was added to N-benzyltrimethylsilylmethylamine (10 g, 55.76 mmol) in dry THF (140 mL) and stirred at −78° C. under nitrogen atmosphere. After 45 minutes, methoxymethyl chloride (4.3 mL, 55.76 mmol) in THF (6 mL) was added and then stirred for another 3 hours. The THF was evaporated, and the residue was dissolved in hexane, washed with water, and dried over sodium sulfate. The solvent was evaporated to give under reduced pressure to give N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (10 g). stirred for another 3 hours The THF was evaporated the residue was dissolved in hexane washed with water dried over sodium sulfate The solvent was evaporated to give under reduced pressure

Conditions: temp:10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 264 mL (2.42 mol) of benzylamine and 97.7 g. (0.796 mol) of chloromethyltrimethylsilane was heated to 200° C. for 2.5 h and then cooled to 10° C. A 0.1M sodium hydroxide solution (400 mL) was added and the product was extracted with 3×200 mL of diethyl ether. The combined organic phase was washed with 100 mL of water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The product was distilled at 115°-125° C. and 5 mm of Hg to afford the title compound as a clear liquid. 1H NMR (CDCl3) δ0.0 (s, 9H), 1.1 (br s, 1H), 2.01 (s, 2H), 3.76 (s, 2H), 7.1-7.3 (m, 5H). the product was extracted with 3×200 mL of diethyl ether The combined organic phase was washed with 100 mL of water dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The product was distilled at 115°-125° C.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a round bottom 3-neck flask equipped with a nitrogen flow and a magnetic stirrer was added formaldehyde (74.000 mmol, 7.4000×10−2 mol) (as a 37% aqueous solution). The flask was cooled to 0° C. and N-benzyl-N-(trimethylsilyl)methylamine (10.000 g, 5.1716790×10−2 mol) was added drowpise with stirring. After stirring for 10 minutes at 0° C., methanol (6.000 mL, 0.14811874 mol) was added in one portion. Potassium carbonate (4.000 g, 2.8942408×10−2 mol) was added to the mixture to absorb the aqueous phase. The mixture was stirred for one hour, then the nonaqueous phase decanted, and then potassium carbonate (2.000 g, 1.4471204×10−2 mol) was added. The mixture was stirred at 25° C. for 12 hours. Ether is added to the mixture and the solution was dried over potassium carbonate, filterd and concentrated under reduced pressure. The residue is distilled at reduced pressure to give the product as a colorless liquid. Into a round bottom 3-neck flask equipped with a nitrogen flow and a magnetic stirrer After stirring for 10 minutes at 0° C. to absorb the aqueous phase The mixture was stirred for one hour the nonaqueous phase decanted The mixture was stirred at 25° C. for 12 hours the solution was dried over potassium carbonate, filterd concentrated under reduced pressure The residue is distilled at reduced pressure

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a round bottom 3-neck flask equipped with a nitrogen flow, a magnetic stirrer, and a friedrichs condenser was added (chloromethyl)trimethylsilane (0.100 mol). To the flask was added benzylamine (0.300 mol), with stirring, and the resulting solution heated at 200° C. for 2.5 hours. Sodium hydroxide aqueous solution (0.1N) was added in order to hydrolyze the white organic salt that had formed. The mixture was extracted with ether and the ether layer was dried over magnesium sulfate and concentrated under reduced pressure through a Vigreux column to give the product at b.p. 68-72° C./0.7-0.8 mm. Into a round bottom 3-neck flask equipped with a nitrogen flow, a magnetic stirrer, and a friedrichs condenser had formed The mixture was extracted with ether the ether layer was dried over magnesium sulfate concentrated under reduced pressure through a Vigreux column to give the product at b.p. 68-72° C./0.7-0.8 mm

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a round bottom 3-neck flask equipped with a nitrogen flow and a magnetic stirrer was added formaldehyde (74.000 mmol, 7.4000×10−2 mol) (as a 37% aqueous solution). The flask was cooled to 0° C. and N-benzyl-N-(trimethylsilyl)methylamine (10.000 g, 5.1716790×10−2 mol) was added dropwise with stirring. After stirring for 10 minutes at 0° C., methanol (6.000 mL, 0.14811874 mol) was added in one portion. Potassium carbonate (4.000 g, 2.8942408×10−2 mol) was added to the mixture to absorb the aqueous phase. The mixture was stirred for one hour, then the nonaqueous phase decanted, and then potassium carbonate (2.000 g, 1.4471204×10−2 mol) was added. The mixture was stirred at 25° C. for 12 hours. Ether is added to the mixture and the solution was dried over potassium carbonate, filterd and concentrated under reduced pressure. The residue is distilled at reduced pressure to give the product as a colorless liquid. Into a round bottom 3-neck flask equipped with a nitrogen flow and a magnetic stirrer After stirring for 10 minutes at 0° C. to absorb the aqueous phase The mixture was stirred for one hour the nonaqueous phase decanted The mixture was stirred at 25° C. for 12 hours the solution was dried over potassium carbonate, filterd concentrated under reduced pressure The residue is distilled at reduced pressure