(4-methoxyphenyl)methyl 2-bromoacetate

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

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

Procedure: Cesium carbonate (1.58 g) was added to a stirred solution of (3S,4S)-4-t-butyldimethylsilyloxymethyl-3-tritylaminoazetidin-2-one (1.45 g) (IV) (H. Mastalerz et al., J. Med. Chem., 1988, 31, 1190-1196) in a mixture of acetonitrile (44 ml) and dimethylformamide (35 ml). 4-Methoxybenzyl bromoacetate (1.44 g) was then added and the mixture stirred at room temperature for 48 h. The mixture was then partitioned between ethyl acetate and water, the organic phase was washed four times with water, and then with brine. The solution was dried over magnesium sulphate and evaporated. The title compound (2.29 g) was isolated by column chromatography of the residue (Silica gel, 3:1 hexane:ethyl acetate as eluent). [α]D21 -9.0°; νmax (CHCl3) 3352, and 1755 cm-1 ; δ(CDCl3) -0.04 (3H, s), 0.00 (3H, s), 0.88 (9H, s), 1.69 (1H, br s), 2.54 (1H, dd, J 3.33 and 11.68 Hz), 3.19 (1H, dd, J 2.05 and 11.68 Hz), 3.38 (1H, m), 3.51 (1H, d, J 17.98 Hz), 3.90 (3H, s), 4.46 (1H, d, J 17.98 Hz), 4.54 (1H, m), 5.06 (1H, d, J 11.79 Hz), 5.15 (1H, d, J 11.81 Hz), 6.94 (2H, d, J 8.68 Hz), 7.2-7.65 (17H, m). The mixture was then partitioned between ethyl acetate and water the organic phase was washed four times with water The solution was dried over magnesium sulphate evaporated

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

Procedure: (3S,4S)-4-t-Butyldimethylsilyloxymethyl-3-tritylaminoazetidinone (IV), (1.67 g) [H. Mastalerz et al., J. Med. Chem., 1988, 31, 1190] as a suspension in acetonitrile (40 ml) was treated with DMF (20 ml) to obtain a clear solution. Cesium carbonate (1.29 g) followed by 4 -methoxybenzyl bromoacetate (1.19 g) were added and the mixture vigorously stirred overnight. T.l.c. analysis showed no starting material, the solution was diluted with ethyl acetate and washed with water (4×), brine and then dried. Removal of solvent in vacuo and purification by flash chromatography afforded the title compound as a pale yellow foam, (1.744 g, 76%), νmax (CH2Cl2) 1760 and 1744 cm-1 ; δH (CDCl3) -0.06 and -0.13 (6H, 2s), 0.81 (9H, s), 1.60 (1H, brs), 2.44 (1H, dd, J 3.3, 11.7 Hz), 3.10 (1H, dd, 2.2, 11.7 Hz), 3.29 (1H, m), 3.41 (1H, d, J 18.0 Hz), 3.80 (3H, s), 4.36 (1H, d, J 18.0 Hz), 4.45 (1H, m), 4.97 and 5.05 (2H, ABq, J 11.8 Hz), 6.85 (2H, d, J 8.7 Hz), 7.16-7.30 (15H, m) and 7.52 (2H, d, J 8.7 Hz); [mass spectrum: MH+ (651)]. to obtain a clear solution were added the mixture vigorously stirred overnight washed with water (4×), brine dried Removal of solvent in vacuo and purification by flash chromatography

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

Procedure: (3S,4S)-4-t-Butyldimethylsilyloxymethyl-3-tritylaminoazetidinone (IV), (1.67 g) [H. Mastalerz et al., J. Med. Chem., 1988, 31, 1190] as a suspension in acetonitrile (40 ml) was treated with DMF (20 ml) to obtain a clear solution. Cesium carbonate (1.29 g) followed by 4 -methoxybenzyl bromoacetate (1.19 g) were added and the mixture vigorously stirred overnight. T.l.c. analysis showed no starting material, the solution was diluted with ethyl acetate and washed with water (4×), brine and then dried. Removal of solvent in vacuo and purification by flash chromatography afforded the title compound as a pale yellow foam, (1.744 g, 76%), νmax (CH2Cl2) 1760 and 1744 cm-1 ; δH (CDCl3) -0.06 and -0.13 (6H, 2s), 0.81 (9H, s), 1.60 (1H, brs), 2.44 (1H, dd, J 3.3, 11.7 Hz), 3.10 (1H, dd, 2.2, 11.7 Hz), 3.29 (1H, m), 3.41 (1H, d, J 18.0 Hz), 3.80 (3H, s), 4.36 (1H, d, J 18.0 Hz), 4.45 (1H, m), 4.97 and 5.05 (2H, ABq, J 11.8 Hz), 6.85 (2H, d, J 8.7 Hz), 7.16-7.30 (15H, m) and 7.52 (2H, d, J 8.7 Hz); [mass spectrum: MH+ (651)]. to obtain a clear solution were added the mixture vigorously stirred overnight washed with water (4×), brine dried Removal of solvent in vacuo and purification by flash chromatography

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

Procedure: To a cold (0°-5° C.) solution of 3-(t-butyloxycarbonylamino)-1-propylamine (4.00 g, 23 mmol) and triethylamine (2.8 mL, 20 mmol) in anhydrous CH2Cl2 (15 mL) was added slowly a solution of p-methoxybenzyl bromoacetate (5.18 g, 20 mmol) in anhydrous CH2Cl2 (10 mL) over a period of 2.5 h. The mixture was stirred at 0°-5° C. for 2 h, at which time TLC indicated that the reaction was complete. The mixture was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a dark residue. The crude material was purified by column chromatography on silica gel (elution with 50% ethyl acetate/hexane) to afford 2.81 g (40% yield) of p-methoxybenzyl [3-(t-butyloxycarbonylamino)-1-propylamino]acetate as an amber oil. 1H NMR (300 MHz, CDCl3) δ1.41 (s, 9H), 1.61 (quint, J=7 Hz, 2H), 2.63 (t, J=7 Hz, 2H), 3.17 (q, J=6 Hz, 2H), 3.38 (s, 2H), 3.78 (s, 3H), 5.07 (s, 2H), 6.86 (m, 2H), and 7.26 (m, 2H); IR (film), 1736, 1708 cm-1 ; MS (isobutane-DCI) MH+ =353. Anal. Calcd. for C18H28N2O5 : C, 61.35; H, 8.01; N, 7.95. Found: C, 60.87; H, 8.30; N, 7.89. The mixture was washed with water and saturated sodium chloride solution dried over anhydrous sodium sulfate filtered concentrated in vacuo to give a dark residue The crude material was purified by column chromatography on silica gel (elution with 50% ethyl acetate/hexane)

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

Procedure: To a -78° C. solution of p-methoxybenzyl alcohol (6.91 g, 50 mmol) and triethylamine (6.95 mL, 50 mmol) in anhydrous CH2Cl2 (50 mL) was added a solution of bromoacetyl bromide (10.1 g, 50 mmol) in CH2Cl2 at -78° C. under nitrogen, over a period of 10 min. The cooling bath was removed, and the reaction mixture was stirred for 2 h. The mixture was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to provide 12 g (93% yield) of p-methoxybenzyl bromoacetate as a dark colored oil which was used in the next reaction without purification. A portion was purified by column chromatography on silica gel (elution with 20% ethyl acetate/hexanes) to give a clear, colorless oil. 1H NMR (300 MHz, CDCl3) δ3.79 (s, 3H), 3.83 (s, 2H), 5.12 (s, 2H), 6.87 (m, 2H), and 7.30 (m, 2H); IR (film) 1738 cm-1 ; MS (ESI/NH4OAc) M+NH4+ =276. The cooling bath was removed The mixture was washed with water and saturated sodium chloride solution dried over anhydrous sodium sulfate filtered concentrated

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

Procedure: To a cold (0°-5° C.) solution of 3-(t-butyloxycarbonylamino)-1-propylamine (4.00 g, 23 mmol) and triethylamine (2.8 mL, 20 mmol) in anhydrous CH2Cl2 (15 mL) was added slowly a solution of p-methoxybenzyl bromoacetate (5.18 g, 20 mmol) in anhydrous CH2Cl2 (10 mL) over a period of 2.5 h. The mixture was stirred at 0°-5° C. for 2 h, at which time TLC indicated that the reaction was complete. The mixture was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a dark residue. The crude material was purified by column chromatography on silica gel (elution with 50% ethyl acetate/hexane) to afford 2.81 g (40% yield) of p-methoxybenzyl [3-(t-butyloxycarbonylamino)-1-propylamino]acetate as an amber oil. 1H NMR (300 MHz, CDCl3) δ1.41 (s, 9H), 1.61 (quint, J=7 Hz, 2H), 2.63 (t, J=7 Hz, 2H), 3.17 (q, J=6 Hz, 2H), 3.38 (s, 2H), 3.78 (s, 3H), 5.07 (s, 2H), 6.86 (m, 2H), and 7.26 (m, 2H); IR (film), 1736, 1708 cm-1 ; MS (isobutane-DCI) MH+ =353. Anal. Calcd. for C18H28N2O5 : C, 61.35; H, 8.01; N, 7.95. Found: C, 60.87; H, 8.30; N, 7.89. The mixture was washed with water and saturated sodium chloride solution dried over anhydrous sodium sulfate filtered concentrated in vacuo to give a dark residue The crude material was purified by column chromatography on silica gel (elution with 50% ethyl acetate/hexane)

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

Procedure: To a -78° C. solution of p-methoxybenzyl alcohol (6.91 g, 50 mmol) and triethylamine (6.95 mL, 50 mmol) in anhydrous CH2Cl2 (50 mL) was added a solution of bromoacetyl bromide (10.1 g, 50 mmol) in CH2Cl2 at -78° C. under nitrogen, over a period of 10 min. The cooling bath was removed, and the reaction mixture was stirred for 2 h. The mixture was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to provide 12 g (93% yield) of p-methoxybenzyl bromoacetate as a dark colored oil which was used in the next reaction without purification. A portion was purified by column chromatography on silica gel (elution with 20% ethyl acetate/hexanes) to give a clear, colorless oil. 1H NMR (300 MHz, CDCl3) δ3.79 (s, 3H), 3.83 (s, 2H), 5.12 (s, 2H), 6.87 (m, 2H), and 7.30 (m, 2H); IR (film) 1738 cm-1 ; MS (ESI/NH4OAc) M+NH4+ =276. The cooling bath was removed The mixture was washed with water and saturated sodium chloride solution dried over anhydrous sodium sulfate filtered concentrated

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

Procedure: 20.2 g (0.1 mol) of bromoacetyl bromide are dissolved in 100 ml of toluene, this solution is cooled to -10° C. (CaCl2 tube) and 8.7 g (0.11 mol) of pyridine are added dropwise at -10° C. Thereafter, 13.8 g (0.1 mol) of 4-methoxybenzyl alcohol, dissolved in 20 ml of toluene are added dropwise to this mixture in the course of 20 minutes at -10° C., and the mixture is allowed to react for 1 hour at this temperature. are added dropwise at -10° C are added dropwise to this mixture in the course of 20 minutes at -10° C. to react for 1 hour at this temperature

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

Procedure: D-cysteine is S-alkyl substituted with p-methoxybenzyl bromoacetate in presence of sodium carbonate in a THF-water medium. The S-benzyloxycarbonylmethylcysteine thus obtained is N-acylated with (R)-3-tetradecanoyloxytetradecanoic acid chloride, and the S-alkyl-N-acyl-D-cysteine derivative is then with (2R)-5-amino-2-[(R)-3-hydroxytetradecanoylamino]pentan-1-ol amine {obtained by hydrogenolysis of the (2R)-5-amino-2-[(R)-3-benzyloxy-tetradecanoyl-amino]pentan-1-ol, see 4.1.1.} in presence of IIDQ. The thus obtained product is selectively O-acylated in its primary position with the ester derived from reacting HOBt with 7-(p-methoxybenzyloxy-carbonylamino)heptanoic acid. The two p-methoxybenzyl groups are then removed by treating the ester with aqueous trifluoroacetic acid. C59H112N4O10S. MM 1069.64.

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

Procedure: Cesium carbonate (1.58 g) was added to a stirred solution of (3S,4S)-4-t-butyldimethylsilyloxymethyl-3-tritylaminoazetidin-2-one (1.45 g) (IV) (H. Mastalerz et al., J. Med. Chem., 1988, 31, 1190-1196) in a mixture of acetonitrile (44 ml) and dimethylformamide (35 ml). 4-Methoxybenzyl bromoacetate (1.44 g) was then added and the mixture stirred at room temperature for 48 h. The mixture was then partitioned between ethyl acetate and water, the organic phase was washed four times with water, and then with brine. The solution was dried over magnesium sulphate and evaporated. The title compound (2.29 g) was isolated by column chromatography of the residue (Silica gel, 3:1 hexane:ethyl acetate as eluent). [α]D21 -9.0°; νmax (CHCl3) 3352, and 1755 cm-1 ; δ(CDCl3) -0.04 (3H, s), 0.00 (3H, s), 0.88 (9H, s), 1.69 (1H, br s), 2.54 (1H, dd, J 3.33 and 11.68 Hz), 3.19 (1H, dd, J 2.05 and 11.68 Hz), 3.38 (1H, m), 3.51 (1H, d, J 17.98 Hz), 3.90 (3H, s), 4.46 (1H, d, J 17.98 Hz), 4.54 (1H, m), 5.06 (1H, d, J 11.79 Hz), 5.15 (1H, d, J 11.81 Hz), 6.94 (2H, d, J 8.68 Hz), 7.2-7.65 (17H, m). The mixture was then partitioned between ethyl acetate and water the organic phase was washed four times with water The solution was dried over magnesium sulphate evaporated

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

Procedure: (3S,4S)-4-t-Butyldimethylsilyloxymethyl-3-tritylaminoazetidinone (IV), (1.67 g) [H. Mastalerz et al., J. Med. Chem., 1988, 31, 1190] as a suspension in acetonitrile (40 ml) was treated with DMF (20 ml) to obtain a clear solution. Cesium carbonate (1.29 g) followed by 4-methoxybenzyl bromoacetate (1.19 g) were added and the mixture vigorously stirred overnight. T.l.c. analysis showed no starting material, the solution was diluted with ethyl acetate and washed with water (4×), brine and then dried. Removal of solvent in vacuo and purification by flash chromatography afforded the title compound as a pale yellow foam, (1.744 g, 76%), νmax (CH2Cl2) 1760 and 1744 cm-1 ; δH (CDCl3) -0.06 and -0.13 (6H, 2s), 0.81 (9H, s), 1.60 (1H, brs), 2.44 (1H, dd, J 3.3, 11.7 Hz), 3.1 (1H, dd, 2.2, 11.7Hz), 3.29 (1H, m), 3.41 (1H, d, J 18.0 Hz), 3.80 (3H, s), 4.36 (1H, d, J 18.0 Hz), 4.45 (1H, m), 4.97 and 5.05 (2H, ABq, J 11.8 Hz), 6.85 (2H, d, J 8.7 Hz), 7.16-7.30 (15H, m) and 7.52 (2H, d, J 8.7 Hz); [mass spectrum: MH+ (651)]. to obtain a clear solution were added the mixture vigorously stirred overnight washed with water (4×), brine dried Removal of solvent in vacuo and purification by flash chromatography