N,N-dimethylethanamine

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

Procedure: (R)-propyl 2-acetamido-3-chloropropanoate (2.50 g, 12.0 mmol) was dissolved in acetonitrile (25 mL) and 1-pyrrolidino-1-cyclopentene (2.27 mL, 2.14 g, 15.6 mmol) was added. While the reaction was kept at 20° C., dimethylethylamine (1.70 mL, 1.14 g, 15.6 mmol) was added via an addition funnel during 10 min. The homogeneous reaction was stirred at 20° C. for 21 h. Then, water (0.50 mL) was added and the reaction was further stirred for 2.5 h. The solvents were removed in vacuo at 50° C. and the residual oil was purified by silica gel flash chromatography using an EtOAc:petroleum benzene gradient. The product is a yellowish oil. Weight 2.67 g, approx. 87% yield (two diastereomers). 1H NMR: (CDCl3, 300 MHz): δ 6.62 (br d, 0.5H), 6.38 (br d, 0.5H), 4.61-4.49 (m, 1H), 4.05-4.00 (m, 2H), 2.38-1.92 (m, 8H), 1.80-1.47 (m, 6H), 0.90-0.84 (m, 3H). was kept at 20° C. The homogeneous reaction the reaction was further stirred for 2.5 h The solvents were removed in vacuo at 50° C. the residual oil was purified by silica gel flash chromatography

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 47.50 g quantity of ethyldimethylamine (reagent, product of Tokyo Kasei Co., Ltd.) was dissolved in 300 g of dehydrated acetone (reagent, Wako Pure Chemical Ind. Ltd.), followed by replacement with nitrogen. To the solution was added dropwise 52.30 g of chloromethyl methyl ether (reagent, product of Tokyo Kasei Co., Ltd. as purified by distillation) at 5° C. over a period of 1 hour. The mixture was thereafter stirred at a temperature of not higher than 15° C. for 5 hours to terminate the reaction. The reaction mixture was cooled to 5° C., and the resulting solids were filtered off in nitrogen. The filter cake was washed with 150 g of acetone, and thereafter dried in a vacuum, giving 85.90 g of N-ethyl-N-methoxymethyl-N,N-dimethylammonium chloride (white solid). to terminate the reaction The reaction mixture was cooled to 5° C. the resulting solids were filtered off in nitrogen The filter cake was washed with 150 g of acetone dried in a vacuum

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 47.50 g quantity of ethyldimethylamine (reagent, product of Tokyo Kasei Co., Ltd.) was dissolved in 300 g of dehydrated acetone (reagent, Wako Pure Chemical Ind. Ltd.), followed by replacement with nitrogen. To the solution was added dropwise 52.30 g of chloromethyl methyl ether (reagent, product of Tokyo Kasei Co., Ltd. as purified by distillation) at 5° C. over a period of 1 hour. The mixture was thereafter stirred at a temperature of not higher than 15° C. for 5 hours to terminate the reaction. The reaction mixture was cooled to 5° C., and the resulting solids were filtered off in nitrogen. The filter cake was washed with 150 g of acetone, and thereafter dried in a vacuum, giving 85.90 g of N-ethyl-N-methoxymethyl-N,N-dimethylammonium chloride (white solid). to terminate the reaction The reaction mixture was cooled to 5° C. the resulting solids were filtered off in nitrogen The filter cake was washed with 150 g of acetone dried in a vacuum

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

Procedure: Racemic benzyl 2-benzamido-7a-phenyl-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (30 g, 63 mmol) is chirally purified by SFC: (Column: Chiralpak IC 2.1×25 cm; eluent: 40% methanol/acetonitrile (8/2) with 0.2% dimethylethyl amine in CO2; flow: 70 mL/min at UV 284 nm). The second eluting isomer is the title compound (11.1 g, 37%, >98% ee). Chiral analysis of the isolated isomer 2: Chiralpak IC 0.46×10 cm, 5 μm; eluent: 40% methanol/acetonitrile (8/2) with 0.2% dimethyl ethyl amine in CO2; flow: 5 mL/min at UV 215 nm. Rt=3.2 minutes. [α]D20=−88 (C=1.0, methanol), ES/MS (m/e) 372 (M+H)

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

Procedure: Racemic N-[6-Allyl-7a-(4-bromo-2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (2.24 g, 4.84 mmol) is purified by chiral HPLC: (Chiralpak AD 8×40.5 cm; eluent: 100% ethanol with 0.2% dimethylethyl amine); flow: 400 mL/min at UV 270 nm). Analysis conditions: Chiralpak AD-H 0.46×15 cm; eluent: 100% ethanol (0.2% isopropyl amine); flow: 0.6 mL/min at UV 320 nm; Rt=3.03 minutes. The second eluting isomer is isolated to give the title compound (1.08 g, 48%, >99% ee). ES/MS (m/e) (79Br/81Br) 462/464 (M+H). The second eluting isomer is isolated

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: 0.24 g 7-(2,2-dimethyl-propyl)-6-[4-(4-hydroxy-phenyl)-piperazin-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile and 0.128 g dimethylaminoethane.HCl were stirred in 2 ml of acetone in the presence of 0.41 g of potassium carbonate. After 18 hours the mixture was extracted with ethyl acetate/water, dried over Magnesium sulfate and evaporated. The residue was chromatographed on silicagel using CH2Cl2/MeOH yielding 6-{4-[4-(2-dimethylamino-ethoxy)-phenyl]-piperazin-1-ylmethyl}-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile as colorless wax. After 18 hours the mixture was extracted with ethyl acetate/water dried over Magnesium sulfate evaporated The residue was chromatographed on silicagel