tert-butyl (2S)-2-(aminomethyl)pyrrolidine-1-carboxylate

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

Procedure: DIPEA (1.34 ml, 7.5 mmol) was added to a solution of 1,1-dimethylethyl (2S)-2-(aminomethyl)-1-pyrrolidinecarboxylate (1 g, 5 mmol) in 50 ml of DCM; then chloroacetyl chloride (0.418 ml, 5.25 mmol) was slowly added and the reaction mixture stirred 1 h before being worked up. DCM was added and the organic phase was washed with a saturated solution of ammonium chloride. The crude was purified by flash chromatography eluting with cyclohexane/ethyl acetate 8/2 affording 1.24 g of the target material. the organic phase was washed with a saturated solution of ammonium chloride The crude was purified by flash chromatography eluting with cyclohexane/ethyl acetate 8/2 affording 1.24 g of the target material

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

Procedure: 2-(S)-(3-dimethylaminomethylene-thioureidomethyl)-pyrrolidine-1-carboxylic acid 1,1-dimethylethyl ester was prepared from (S)-2-(aminomethyl)-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester according to the procedure described in Example A (4-(3-dimethylaminomethylene -thioureidomethyl)-piperidine-1-carboxylic acid tert-butyl ester). Purified by column chromatography on silica gel (2:1 to 3:1 ethyl acetate/hexane eluant). Yellow solid. MS: 315.4 (M+H)+ Purified by column chromatography on silica gel (2:1 to 3:1 ethyl acetate/hexane eluant)

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

Procedure: (S)-2-Aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (510 mg, 2.54 mmol) and 2-(1-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-2-oxo-propyl)-6-fluoro-benzoic acid (851 mg, 2.12 mmol) were condensed analogously to the method described for example 4 to give (S)-2-(4-{[(S)-Cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. The Boc-protection group was removed analogously to the method described for example 6 with trifluoroacetic acid in 1,2-dichloroethane to give the title compound. LC-MS (m/z) 466.3 (MH+); tR=0.96. condensed analogously to the method

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

Procedure: The 1-(6-chloroimidazo[1,2-b]pyridazin-3-yl)pyrrolidin-2-one was reacted with (S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate using the amine displacement conditions described in example 5.6.42, Part A to afford the desired product in 73% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38-1.46 (m, 10H) 1.71 (br. s., 1H) 1.80-1.91 (m, 2H) 1.95-2.08 (m, 1H) 2.22 (quin, J=7.55 Hz, 2H) 2.50-2.58 (m, 2H) 3.22-3.41 (m, 4H) 3.90 (q, J=6.69 Hz, 2H) 4.16 (br. s., 1H) 6.40 (d, J=9.70 Hz, 1H) 7.44 (s, 1H) 7.54 (d, J=9.70 Hz, 1H); LRMS (ESI) m/401.0 [(M+H)+, calcd for C20H28N6O3 400.0].

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

Procedure: 2.45 g (10.00 mmol) of potassium phosphate monohydrate was added under argon to a mixture of 1.42 g (5.00 mmol) of 1-bromo-4-iodobenzene, 1.00 g (5.00 mmol) of tert-butyl (S)-2-aminomethylpyrrolidine-1-carboxylate, 48 mg (0.25 mmol) of CuI, and 97 mg (0.50 mmol) of N,N-diethylsalicylamide in 5 mL of DMF and the mixture was stirred for 160 hours at 100° C. The reaction mixture was cooled to RT, combined with 100 mL of 4M aqueous HCl, and stirred for 1 hour at RT. The aqueous phase was washed with MTBE, made basic with concentrated aqueous ammonia, and exhaustively extracted with MTBE. The combined organic extracts were dried over magnesium sulfate, filtered through activated charcoal, and evaporated down in vacuo. The crude product was purified by MPLC (Hyperprep HS C18, 8 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v). The eluates were evaporated down in vacuo and the residue was neutralized with sat. aqueous sodium bicarbonate solution. The aqueous phase was extracted with DCM, dried over magnesium sulfate and evaporated down in vacuo. Yield: 0.20 g (16% of theoretical); C11H15BrN2 (M=255.2); calc.: molpeak (M+H)+: 255/257 (Br); found: molpeak (M+H)+:255/257 (Br); HPLC-MS: 3.90 minutes (method B). The reaction mixture was cooled to RT stirred for 1 hour at RT The aqueous phase was washed with MTBE exhaustively extracted with MTBE The combined organic extracts were dried over magnesium sulfate filtered through activated charcoal evaporated down in vacuo The crude product was purified by MPLC (Hyperprep HS C18, 8 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v) The eluates were evaporated down in vacuo The aqueous phase was extracted with DCM dried over magnesium sulfate evaporated down in vacuo 3.90 minutes (method B)

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

Procedure: 4.90 g (20.00 mmol) of potassium phosphate monohydrate were added under argon to a mixture of 4.16 g (10.00 mmol) of 5-(4-chlorophenyl)-2-(4-iodophenylethynyl)pyridine, 3.10 g (15.00 mmol) of tert-butyl (S)-2-aminomethylpyrrolidine-1-carboxylate, 194 mg (1.00 mmol) of CuI, 0.77 g (4.00 mmol) of N,N-diethylsalicylamide in 10 mL of DMF and the mixture was stirred for 16 hours at 100° C. The reaction mixture was combined with 100 mL of 5% aqueous ammonia, stirred, and the precipitate was filtered off. The precipitate was purified by MPLC (Hyperprep HS C18, 8 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v). 2 fractions were isolated. Fraction 1: yield: 0.48 g (10% of theoretical); C29H30ClN3O2 (M=488.020) molpeak (M+H)+: 488/490 (Cl); found: molpeak (M+H)+: 488/490 (Cl); Rf value: 0.60 (silica gel, PE/EtOAc 1:1). stirred the precipitate was filtered off The precipitate was purified by MPLC (Hyperprep HS C18, 8 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v) 2 fractions were isolated

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

Procedure: 4.90 g (20.00 mmol) of potassium phosphate monohydrate were added under argon to a mixture of 4.16 g (10.00 mmol) of 5-(4-chlorophenyl)-2-(4-iodophenylethynyl)pyridine, 3.10 g (15.00 mmol) of tert-butyl (S)-2-aminomethylpyrrolidine-1-carboxylate, 194 mg (1.00 mmol) of CuI, 0.77 g (4.00 mmol) of N,N-diethylsalicylamide in 10 mL of DMF and the mixture was stirred for 16 hours at 100° C. The reaction mixture was combined with 100 mL of 5% aqueous ammonia, stirred, and the precipitate was filtered off. The precipitate was purified by MPLC (Hyperprep HS C18, 8 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v). 2 fractions were isolated. Fraction 1: yield: 0.48 g (10% of theoretical); C29H30ClN3O2 (M=488.020) molpeak (M+H)+: 488/490 (Cl); found: molpeak (M+H)+: 488/490 (Cl); Rf value: 0.60 (silica gel, PE/EtOAc 1:1). stirred the precipitate was filtered off The precipitate was purified by MPLC (Hyperprep HS C18, 8 μm, gradient 0.15% formic acid in water/acetonitrile 10/90→90/10 v/v) 2 fractions were isolated

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

Procedure: The title compound was prepared by a similar method to preparation 42 from benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preperation 17) and tert-butyl (2S)-2-(aminomethyl)-1-pyrrolidinecarboxylate [JP 63183560 A2], to afford the product as a colourless oil,(100%).

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

Procedure: To a solution of 3,3-dimethylbutanal (130 mg, 1.30 mmol) in acetonitrile (8 mL) was added molecular sieves (4A beads, 8-12 mesh, 0.7 g) and (S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (260 mg, 1.30 mmol). The mixture was stirred for 12 hr at room temperature, filtered, and washed with acetonitrile (5 mL). To this solution was added potassium thiocyanate (168 mg, 1.72 mmol) and the temperature was adjusted at 50° C. The reaction was stirred until all solids were dissolved then iodine (659 mg, 2.6 mmol) was added. The reaction mixture was stirred at 50° C. for another 12 hr, cooled to room temperature, and stirred with 20% sodium metabisulfite for 1 hr. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound. This intermediate was used without further purification. MS (DCI/NH3) m/z 340 (M+H)+. filtered washed with acetonitrile (5 mL) was adjusted at 50° C The reaction was stirred until all solids were dissolved The reaction mixture was stirred at 50° C. for another 12 hr cooled to room temperature The organic layer was separated the aqueous layer was extracted with dichloromethane (3×10 mL) The combined organics were dried over sodium sulfate filtered concentrated under reduced pressure

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

Procedure: DIPEA (1.34 ml, 7.5 mmol) was added to a solution of 1,1-dimethylethyl (2S)-2-(aminomethyl)-1-pyrrolidinecarboxylate (1 g, 5 mmol) in 50 ml of DCM; then chloroacetyl chloride (0.418 ml, 5.25 mmol) was slowly added and the reaction mixture stirred 1 h before being worked up. DCM was added and the organic phase was washed with a saturated solution of ammonium chloride. The crude was purified by flash chromatography eluting with cyclohexane/ethyl acetate 8/2 affording 1.24 g of the target material. the organic phase was washed with a saturated solution of ammonium chloride The crude was purified by flash chromatography eluting with cyclohexane/ethyl acetate 8/2 affording 1.24 g of the target material

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

Procedure: (S)-2-Aminomethylpyrrolidine-1-carboxylic acid tert-butyl ester (0.3 g), 6-chloronicotinonitrile (0.21 g), potassium carbonate (0.41 g) and diisopropylethylamine (0.78 ml) were heated in xylene at 130° C. for 26 h, cooled and the mixture filtered through kieselguhr. The filtrate was evaporated and the residue chromatographed on silica gel, eluting with ethyl acetate-hexane mixtures to afford the title compound (0.2 g). Mass Spectrum (API+): Found 303 (MH+). C16H22N4O2 requires 302. cooled the mixture filtered through kieselguhr The filtrate was evaporated the residue chromatographed on silica gel eluting with ethyl acetate-hexane mixtures

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

Procedure: (S)-2-Aminomethylpyrrolidine-1-carboxylic acid tert-butyl ester (3.38 g), 2,5-dichloropyrimidine (2.50 g), potassium carbonate (4.67 g) and diisopropylethylamine (8.79 ml) were heated in xylene (60 ml) at 100° C. for 3.75 h. The cooled reaction mixture was filtered and the filtrate evaporated to a gum which was chromatographed on silica gel, eluting with ethyl acetate-pentane fractions, to afford the title compound as a pale yellow solid (2.55 g). Mass Spectrum (API+): Found 213 (MH+-tBoc). C14H2135ClN4O2 requires 312. The cooled reaction mixture was filtered the filtrate evaporated to a gum which was chromatographed on silica gel eluting with ethyl acetate-pentane fractions