1-methyl-1-nitrosourea

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:0.00; pressure:0.00; stir:

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

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

Procedure: 7-[5-((1E)(3S)-3-hydroxyoct-1-enyl)(1R,4R,5R)-4-(hydroxy-2-oxocyclopentyl)heptanoic acid (311 mg, 0.877 mmol) was slurried in diethyl ether (10 mL) in a 50 mL erlenmeyer flask and cooled to 0° C. In a separate 50 mL erlenmeyer flask, N-methyl-N-nitrosourea (271 mg, 2.63 mmol, 3 eq) was added to a 1:1 mix of water/diethyl ether (20 mL) and cooled to 0° C. KOH was added to the N-methyl-N-nitrosourea mix at 0° C., generating diazomethane as evidenced by the formation of a yellow color in the diethyl ether layer. After 5 minutes, the yellow ethereal diazomethane solution was slowly added to the prostaglandin solution via a flame polished pipette slowly resulting in the dissolution of the solid material. Once the prostaglandin had gone into solution and a yellow color was maintained in the reaction mixture, addition of the ethereal diazomethane was stopped and both mixtures were allowed to slowly warm to ambient temperature and left until all the yellow color had disappeared. The prostaglandin reaction mixture was dried over sodium sulfate and then the solvent was concentrated in vacuo to give the title compound as a clear colorless oil (99.5%): 1H NMR (300 MHz, CDCl3) δ 5.63 (dd, 1H, J=15.3, 6.8 Hz), 5.49 (dd, 1H, J=15.3, 8.5 Hz), 4.02 (m, 2H), 3.59 (s, 3H), 2.42 (AB part of ABX, 2H, JAB=18.4 Hz, JAX=9.8 Hz, JBX=6.6 Hz, ΔvAB=8.2 Hz), 2.29 (dt, 1H, J=12.0, 8.6 Hz), 2.22 (t, 2H, J=7.4 Hz), 1.94 (m, 1H), 1.80−1.15 (m, 18H), 0.82 (t, 3H, J=6.5 Hz). cooled to 0° C mix at 0° C. slowly resulting in the dissolution of the solid material to slowly warm to ambient temperature left until all the yellow color was dried over sodium sulfate the solvent was concentrated in vacuo

Conditions: temp:-25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-2-BOC-amino-3-(4-methoxy-benzylsulfanyl)-propionic acid (43 g, 132 mmol) prepared in Step B, 1-methylmorpholine (14.5 mL, 132 mmol) and ethylchloroformate (14.1 mL, 132 mmol) were dissolved in tetrahydrofuran (500 mL), and the mixture was stirred for 1 h at −25° C. At the same time, potassium hydroxide (75 g, 1336 mmol) was dissolved in water (75 mL) and diethylether (750 mL), N-methyl-nitrosourea (26 g, 252 mmol) was added in drops thereto over 2 h at 0° C., and the mixture was stirred for 30 min. The two solutions thus obtained were mixed together, and stirred for 3 h at −25° C. to room temperature. After completion of the reaction, water was added to the reaction mixture, which was then washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous ammonium chloride solution in the order. The organic layer was concentrated to give the title compound (46.0 g, Yield 95%). over 2 h at 0° C. the mixture was stirred for 30 min The two solutions thus obtained were mixed together stirred for 3 h at −25° C. to room temperature was added to the reaction mixture, which was then washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous ammonium chloride solution in the order The organic layer was concentrated

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

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

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

Procedure: 7-[5-((1E)(3S)-3-hydroxyoct-1-enyl)(1R,4R,5R)-4-(hydroxy-2-oxocyclopentyl)heptanoic acid (311 mg, 0.877 mmol) was slurried in diethyl ether (10 mL) in a 50 mL erlenmeyer flask and cooled to 0° C. In a separate 50 ml, erlenmeyer flask, N-methyl-N-nitrosourea (271 mg, 2.63 mmol, 3 eq) was added to a 1:1 mix of water/diethyl ether (20 mL) and cooled to 0° C. KOH was added to the N-methyl-N-nitrosourea mix at 0° C., generating diazomethane as evidenced by the formation of a yellow color in the diethyl ether layer. After 5 minutes, the yellow ethereal diazomethane solution was slowly added to the prostaglandin solution via a flame polished pipette slowly resulting in the dissolution of the solid material. Once the prostaglandin had gone into solution and a yellow color was maintained in the reaction mixture, addition of the ethereal diazomethane was stopped and both mixtures were allowed to slowly warm to ambient temperature and left until all the yellow color had disappeared. The prostaglandin reaction mixture was dried over sodium sulfate and then the solvent was concentrated in vacuo to give the title compound as a clear colorless oil (99.5%): 1H NMR (300 MHz, CDCl3) δ 5.63 (dd, 1H, J=15.3, 6.8 Hz), 5.49 (dd, 1H, J=15.3, 8.5 Hz), 4.02 (m, 2H), 3.59 (s, 3H), 2.42 (AB part of ABX, 2H, JAB=18.4 Hz, JAX=9.8 Hz, JBX=6.6 Hz, ΔνAB=8.2 Hz), 2.29 (dt, 1H,J=12.0, 8.6 Hz), 2.22 (t, 2H, J=7.4 Hz), 1.94 (m, 1H), 1.80-1.15 (m, 18H), 0.82 (t, 3H, J=6.5 Hz). cooled to 0° C mix at 0° C. slowly resulting in the dissolution of the solid material to slowly warm to ambient temperature left until all the yellow color was dried over sodium sulfate the solvent was concentrated in vacuo

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

Procedure: 7-[5-((1E)(3S)-3-hydroxyoct-1-enyl)(1R,4R,5R)-4-(hydroxy-2-oxocyclopentyl)heptanoic acid (311 mg, 0.877 mmol) was slurried in diethyl ether (10 mL) in a 50 mL erlenmeyer flask and cooled to 0° C. In a separate 50 ml, erlenmeyer flask, N-methyl-N-nitrosourea (271 mg, 2.63 mmol, 3 eq) was added to a 1:1 mix of water/diethyl ether (20 mL) and cooled to 0° C. KOH was added to the N-methyl-N-nitrosourea mix at 0° C., generating diazomethane as evidenced by the formation of a yellow color in the diethyl ether layer. After 5 minutes, the yellow ethereal diazomethane solution was slowly added to the prostaglandin solution via a flame polished pipette slowly resulting in the dissolution of the solid material. Once the prostaglandin had gone into solution and a yellow color was maintained in the reaction mixture, addition of the ethereal diazomethane was stopped and both mixtures were allowed to slowly warm to ambient temperature and left until all the yellow color had disappeared. The prostaglandin reaction mixture was dried over sodium sulfate and then the solvent was concentrated in vacuo to give the title compound as a clear colorless oil (99.5%): 1H NMR (300 MHz, CDCl3) δ 5.63 (dd, 1H, J=15.3, 6.8 Hz), 5.49 (dd, 1H, J=15.3, 8.5 Hz), 4.02 (m, 2H), 3.59 (s, 3H), 2.42 (AB part of ABX, 2H, JAB=18.4 Hz, JAX=9.8 Hz, JBX=6.6 Hz, ΔνAB=8.2 Hz), 2.29 (dt, 1H,J=12.0, 8.6 Hz), 2.22 (t, 2H, J=7.4 Hz), 1.94 (m, 1H), 1.80-1.15 (m, 18H), 0.82 (t, 3H, J=6.5 Hz). cooled to 0° C mix at 0° C. slowly resulting in the dissolution of the solid material to slowly warm to ambient temperature left until all the yellow color was dried over sodium sulfate the solvent was concentrated in vacuo