N-(cyclohexylmethyl)-N-methylcarbamoyl chloride

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

Procedure: The title compound is prepared analogously as described for cyclohexylmethyl-methylcarbamoyl chloride. TLC, Rf (CH2Cl2/MeOH 95:5)=0.9. MS (LC-MS): [M+H]+=210.2. tR (HPLC, Waters Symmetry C18 column, 20-100% CH3CN/H2O/5 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 4.67 min. 4.67 min.

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

Procedure: To a solution of triphosgene (77 mg, 0.259 mmol) in CH2Cl2 (1 mL) at −78° C. is added dropwise pyridine (63 μl, 0.786 mmol) followed by a solution of cyclohexylmethyl-methylamine (100 mg, 0.786 mmol) in CH2Cl2 (1 mL). The yellow mixture is allowed to reach RT and stirred overnight. The solvent is concentrated, and the residue taken up in AcOEt. An aqueous saturated solution of NaHCO3 is added, the layers are separated and the aqueous one is extracted twice with AcOEt. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated to afford the title compound as a yellow oil. TLC, Rf (CH2Cl2/MeOH 95:5)=0.95. MS (LC-MS): 189.1 [M+H]+. to reach RT The solvent is concentrated An aqueous saturated solution of NaHCO3 is added the layers are separated the aqueous one is extracted twice with AcOEt The combined organic extracts are washed with brine dried over Na2SO4 filtered concentrated

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

Procedure: To a stirred suspension of NaH (60% oily dispersion, 17 mg, 0.42 mmol) in THF (2 mL) is added at 0° C. (3S,4R)-3-hydroxymethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (160 mg, 0.303 mmol) in THF (3 mL). The resulting solution is stirred 30 min before the addition of a solution of cyclohexylmethyl-methyl-carbamoyl chloride (80 mg, 0.421 mmol) in THF (3 mL). The mixture is further stirred overnight at RT and poured into an aqueous solution of NH4Cl. AcOEt is added, the layers are separated and the aqueous one extracted twice with AcOEt. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 95:5). TLC, Rf (CH2Cl2/MeOH 95:5)=0.25. MS (LC-MS): 648 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 6.83 min. the layers are separated the aqueous one extracted twice with AcOEt The combined organic extracts are dried over Na2SO4 filtered concentrated The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 95:5) tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min) 6.83 min.