[1-(cyanomethyl)cyclopropyl]methyl methanesulfonate

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:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of [1-(hydroxymethyl)cyclopropyl]acetonitrile (prepared according to the procedure described in WO2005/105749 Example 2/Step 4, incorporated by reference) (1 eq.) in DCM at −40° C. was added triethylamine (3 eq.) and then methanesulfonyl chloride (1.5 eq.). The reaction was warmed to −10° C. over 1 h, and it was diluted with DCM and quenched with saturated aqueous NaHCO3. The aqueous phase was extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 0%→50% EtOAc in Hex) to afford the title compound as an oil. at −40° C. quenched with saturated aqueous NaHCO3 The aqueous phase was extracted with DCM The combined organic extracts were dried over MgSO4 concentrated in vacuo The crude product was purified by flash column chromatography (SiO2, 0%→50% EtOAc in Hex)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.1 M) was added [1-(cyanomethyl)cyclopropyl]methyl methanesulfonate (appendage 4) (2 eq.) and cesium carbonate (2 eq.). The reaction was heated to 80° C. and stirred for 18 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 0%→50% EtOAc in toluene) to afford the title compound as an oil. After cooling to rt The organic extract was washed with water, brine dried over MgSO4 concentrated in vacuo The crude product was purified by flash column chromatography (SiO2, 0%→50% EtOAc in toluene)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of [1-(hydroxymethyl)cyclopropyl]acetonitrile (prepared according to the procedure described in WO2005/105749 Example 2/Step 4) (1 eq.) in DCM at −40° C. was added triethylamine (3 eq.) and then methanesulfonyl chloride (1.5 eq.). The reaction was warmed to −10° C. over 1 h, and it was diluted with DCM and quenched with saturated aqueous NaHCO3. The aqueous phase was extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 0%→50% EtOAc in Hex) to afford the title compound appendage 4 as an oil. at −40° C. quenched with saturated aqueous NaHCO3 The aqueous phase was extracted with DCM The combined organic extracts were dried over MgSO4 concentrated in vacuo The crude product was purified by flash column chromatography (SiO2, 0%→50% EtOAc in Hex)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of [1-(hydroxymethyl)cyclopropyl]acetonitrile (prepared according to the procedure described in WO2005/105749 Example 2/Step 4, incorporated by reference) (1 eq.) in DCM at −40° C. was added triethylamine (3 eq.) and then methanesulfonyl chloride (1.5 eq.). The reaction was warmed to −10° C. over 1 h, and it was diluted with DCM and quenched with saturated aqueous NaHCO3. The aqueous phase was extracted with DCM. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 0%→50% EtOAc in Hex) to afford the title compound as an oil. at −40° C. quenched with saturated aqueous NaHCO3 The aqueous phase was extracted with DCM The combined organic extracts were dried over MgSO4 concentrated in vacuo The crude product was purified by flash column chromatography (SiO2, 0%→50% EtOAc in Hex)