benzyl N-(2-aminoethyl)carbamate;hydrochloride

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

Procedure: Prepared from benzyl 2-aminoethylcarbamate hydrochloride and N-[2-1-piperidinyl)ethyl]-1H-imidazole-1-carboxamide (Preparation 18) by a similar procedure to Preparation 50. The title compound was obtained as a yellow oil. to Preparation 50

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

Procedure: A solution of benzyl 2-aminoethylcarbamate hydrochloride (4.33 g, 18.8 mmol), N-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (Preparation 19) (3.73 g, 15.64 mmol) and triethylamine (2.62 ml, 18.8 mmol) in dichloromethane (100 ml) was heated under reflux for 14 hours. The solution was allowed to cool to room temperature and then washed with water (20 ml). The aqueous layer was separated and extracted with more dichloromethane (20 ml). The combined organic layers were dried over anhydrous magnesium sulfate and solvent evaporated under reduced pressure to give the title compound as a yellow oil (6.25 g). under reflux for 14 hours washed with water (20 ml) The aqueous layer was separated extracted with more dichloromethane (20 ml) The combined organic layers were dried over anhydrous magnesium sulfate and solvent evaporated under reduced pressure

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

Procedure: Preparation takes place in analogy to Example 79A from 300 mg (0.82 mmol) of N5-[(benzyloxy)carbonyl]-N-(tert-butoxycarbonyl)-L-ornithine and 246 mg (1.06 mmol) of benzyl (2-aminoethyl)carbamate hydrochloride in 6 ml of dimethylformamide with the addition of 204 mg (1.06 mmol) of EDC, 33 mg (0.25 mmol) of HOBt and 148 mg (1.15 mmol) of N,N-diisopropylethylamine. Preparation

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

Procedure: Preparation takes place in analogy to Example 79A from 300 mg (0.82 mmol) of N5-[(benzyloxy)carbonyl]-N-(tert-butoxycarbonyl)-L-ornithine and 246 mg (1.06 mmol) of benzyl (2-aminoethyl)carbamate hydrochloride in 6 ml of dimethylformamide with the addition of 204 mg (1.06 mmol) of EDC, 33 mg (0.25 mmol) of HOBt and 148 mg (1.15 mmol) of N,N-diisopropylethylamine. Preparation

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

Procedure: 549.7 mg (1.446 mmol) of HATU and 339.7 mg (2.629 mmol) of N,N-diisopropylethylamine are added to a solution of 500 mg (1.31 mmol) of (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl)amino]hexanoic acid in 25 ml of anhydrous DMF. After stirring at RT for 15 min, 333.5 mg (1.446 mmol) of benzyl (2-aminoethyl)carbamate hydrochloride are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC. The reaction mixture is stirred at RT for 15 h The solvent is then evaporated The organic phase is washed with water dried over magnesium sulfate concentrated The crude product is purified by preparative HPLC

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

Procedure: 549.7 mg (1.446 mmol) of HATU and 339.7 mg (2.629 mmol) of N,N-diisopropylethylamine are added to a solution of 500 mg (1.31 mmol) of (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[(tert-butoxycarbonyl)amino]hexanoic acid in 25 ml of anhydrous DMF. After stirring at RT for 15 min, 333.5 mg (1.446 mmol) of benzyl (2-aminoethyl)carbamate hydrochloride are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC. The reaction mixture is stirred at RT for 15 h The solvent is then evaporated The organic phase is washed with water dried over magnesium sulfate concentrated The crude product is purified by preparative HPLC

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

Procedure: 419.3 mg (1.1 mmol) of HATU and 258.5 mg (2 mmol) of N,N-diisopropylethylamine are added to a solution of 408.4 mg (1 mmol) of N5-[{[(benzyloxy)carbonyl]amino}(imino)methyl]-N2-(tert-butoxycarbonyl)-L-ornithine in 15 ml of anhydrous DMF. After stirring at RT for 15 min, 253.76 mg (1.1 mmol) of benzyl (2-aminoethyl)carbamate hydrochloride are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC. The reaction mixture is stirred at RT for 15 h The solvent is then evaporated The organic phase is washed with water dried over magnesium sulfate concentrated The crude product is purified by preparative HPLC

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

Procedure: 419.3 mg (1.1 mmol) of HATU and 258.5 mg (2 mmol) of N,N-diisopropylethylamine are added to a solution of 408.4 mg (1 mmol) of N5-[{[(benzyloxy)carbonyl]amino}(imino)methyl]-N2-(tert-butoxycarbonyl)-L-ornithine in 15 ml of anhydrous DMF. After stirring at RT for 15 min, 253.76 mg (1.1 mmol) of benzyl (2-aminoethyl)carbamate hydrochloride are added. The reaction mixture is stirred at RT for 15 h. The solvent is then evaporated and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over magnesium sulfate and concentrated. The crude product is purified by preparative HPLC. The reaction mixture is stirred at RT for 15 h The solvent is then evaporated The organic phase is washed with water dried over magnesium sulfate concentrated The crude product is purified by preparative HPLC

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 10.0 g (0.043 mol) of (1f) and 10.3 g (0.036 mol) of N-BOC-L-alanine, N-hydroxysuccinimide ester in anhydrous N,N-dimethylformamide (50 ml) was cooled with an ice bath. To this was added 7.6 ml (0.054 mol) of triethylamine in anhydrous N,N-dimethylformamide (20 ml) over a period of 30 minutes. The reaction was stirred at ca. 5° C. for 1 hour, then at room temperature for 1 hour. The N,N-dimethylformamide was removed in vacuo and the resulting residue was dissolved in 300 ml of ethyl acetate. The solution was washed with 1M HCl (3×100 ml), water (100 ml), saturated sodium bicarbonate solution (3×100 ml) and finally, with brine (100 ml). After drying over anhydrous magnesium sulfate, the solution was filtered and concentrated in vacuo to give 12.4 g (94% yield) of N-BOC-L-alanine, 2-(benzyloxycarbonylamino)ethyl amide (1g) as a white solid. TLC: Rf 0.67 (chloroform-isopropanol 9:1); 1H NMR(CDCl3) δ 1.27(d, 3H), 1.40(s, 9H), 3.32(m, 4H), 4.15(m, 1H), 5.06(s, 2H), 5.51(d, 1H), 5.90(m, 1H), 7.19(m, 1H), 7.31(bs, 5H); 13C NMR (CDCl3) δ 18.5, 28.2, 39.6, 40.5, 50.1, 66.5, 79.8, 127.9, 128.3, 136.3, 155.4, 156.9, 173.7. at room temperature for 1 hour The N,N-dimethylformamide was removed in vacuo the resulting residue was dissolved in 300 ml of ethyl acetate The solution was washed with 1M HCl (3×100 ml), water (100 ml), saturated sodium bicarbonate solution (3×100 ml) After drying over anhydrous magnesium sulfate the solution was filtered concentrated in vacuo

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

Procedure: Under an atmosphere of dry argon, 24.3 g (0.128 mol) of N-CBZ-aminoacetonitrile (1e) was dissolved in anhydrous tetrahydrofuran (32 ml). The solution was stirred and 64 ml of borane-methylsulfide complex (2M in tetrahydrofuran) was added via syringe. The mixture was heated to reflux and stirred overnight. The mixture was cooled with an ice bath as 5 ml of water was added slowly, with vigorous stirring. The stirring was continued for ca. 5 minutes, then 75 ml of 6M HCl was slowly added. The mixture was stirred for 1 hour, then the excess tetrahydrofuran and dimethyl sulfide was removed in vacuo . The aqueous residue was extracted with ether (2×50 ml). The ether extracts were then discarded. The pH of the aqueous residue was raised to 11 by adding concentrated NH4OH. The resulting aqueous solution was extracted with ethyl acetate (3×100 ml) and the ethyl acetate extracts were combined and washed with brine (50 ml). After drying over anhydrous magnesium sulfate, the solution was filtered and concentrated in vacuo. The resulting oil was dissolved in 30 ml of anhydrous methanol, treated with cold methanolic HCl and concentrated in vacuo to produce a solid. The solid was triturated with ether and collected by filtration to give 15.1 g (51% yield) of N-CBZ-ethylenediamine hydrochloride (1f) as a white powder. 1H NMR(D2O) δ 3.15(m, 2H), 3.46(m, 2H), 5.14(s, 2H), 7.46(bs, 5H); 13C NMR (D2O) δ 41.1, 42.6, 70.4, 131.0, 131.3, 131.7, 132.0, 139.4, 161.7. The mixture was heated to reflux stirred overnight was added slowly, with vigorous stirring The mixture was stirred for 1 hour the excess tetrahydrofuran and dimethyl sulfide was removed in vacuo The aqueous residue was extracted with ether (2×50 ml) The pH of the aqueous residue was raised to 11 by adding concentrated NH4OH The resulting aqueous solution was extracted with ethyl acetate (3×100 ml) washed with brine (50 ml) After drying over anhydrous magnesium sulfate the solution was filtered concentrated in vacuo The resulting oil was dissolved in 30 ml of anhydrous methanol treated with cold methanolic HCl concentrated in vacuo to produce a solid The solid was triturated with ether collected by filtration

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

Procedure: Benzyl 2-aminoethylcarbamate hydrochloride (2 g, 8.65 mmol) was dissolved in dichloromethane (50 ml) and 3-pentanone (3.7 ml, 35 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature. Sodium triacetoxy borohydride (5.5 g, 26 mmol) was added and the reaction mixture was then stirred for 16 hours at room temperature. The solution was washed with saturated aqueous sodium hydrogen carbonate solution (40 ml). The dichloromethane phase was dried over anhydrous magnesium sulphate and the solvent was removed. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 by volume). This gave the title compound as an oil (1.8 g). the reaction mixture was then stirred for 16 hours at room temperature The solution was washed with saturated aqueous sodium hydrogen carbonate solution (40 ml) The dichloromethane phase was dried over anhydrous magnesium sulphate the solvent was removed The residue was purified by column chromatography on silica gel eluting with dichloromethane

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

Procedure: Benzyl 2-aminoethylcarbamate hydrochloride (2 g, 8.65 mmol) was dissolved in dichloromethane (50 ml) and 3-pentanone (3.7 ml, 35 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature. Sodium triacetoxy borohydride (5.5 g, 26 mmol) was added and the reaction mixture was then stirred for 16 hours at room temperature. The solution was washed with saturated aqueous sodium hydrogen carbonate solution (40 ml). The dichloromethane phase was dried over anhydrous magnesium sulphate and the solvent was removed. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 by volume). This gave the title compound as an oil (1.8 g). the reaction mixture was then stirred for 16 hours at room temperature The solution was washed with saturated aqueous sodium hydrogen carbonate solution (40 ml) The dichloromethane phase was dried over anhydrous magnesium sulphate the solvent was removed The residue was purified by column chromatography on silica gel eluting with dichloromethane