methyl 2-[1-(methylsulfonyloxymethyl)cyclopropyl]acetate

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:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (962 mg, 4.16 mmol), anhydrous powdered potassium carbonate (574 mg, 4.16 mmol), and lithium iodide (557 mg, 4.16 mmol), was added DMF (18 mL) at room temperature. After stirring for 30 min, crude (1-methanesulfonyloxymethyl-cyclopropyl)-acetic acid methyl ester (962 mg) in DMF (2 mL) was added. The mixture was then heated in an oil bath (70-80° C.) and stirred for ca. 19 hr. After cooling to room temperature, the mixture was evaporated in vacuo. The residue was dissolved in methanol-dichloromethane (5:95) and filtered through a celite pad. The filtrate was evaporated and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to give 230 mg (13%) of {1-[6-(3-cyano-5-methyl-benzoyl)-5-isopropyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-cyclopropyl}-acetic acid methyl ester (82) as a white syrup. 1H-NMR (200 MHz, CDCl3) δ 0.36-0.65 (4H, m), 1.12 (3H, d, J=7.0 Hz), 1.23 (3H, d, J=7.0 Hz), 2.17-2.32 (2H, m), 2.44-2.52 (4H, m), 3.58 (1H, d, J=15.2 Hz), 3.69 (3H, s), 3.76 (1H, d, J=15.2 Hz), 7.79 (1H, s), 7.95 (1H, s), 8.06 (1H, s), 9.36 (1H, s); m/z (EI) 423 (M+). stirred for ca. 19 hr After cooling to room temperature the mixture was evaporated in vacuo The residue was dissolved in methanol-dichloromethane (5:95) filtered through a celite pad The filtrate was evaporated the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2))

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of (1-hydroxymethyl-cyclopropyl)-acetic acid methyl ester (600 mg, 4.16 mmol) in dichloromethane (10 mL) cooled in dry ice-acetone bath (−40° C.), was added methanesulfonyl chloride (483 μL, 6.24 mmol). The mixture was then cooled to −60° C. and triethylamine (928 μA, 6.66 mmol) was added. With stirring, the mixture was warmed up to 0° C. during 1 hr. After cooling the mixture to −15° C., cold 3 N HCl solution (0.6 mL), cold brine (2 mL), and dichloromethane (25 mL) were added in this order. The mixture was washed with cold brine (25 mL) twice, dried with MgSO4, filtered, and evaporated in vacuo to give 962 mg (quantitative) of crude (1-methanesulfonyloxymethyl-cyclopropyl)-acetic acid methyl ester as a colorless oil. This crude product was used directly in the next reaction without further purification. 1H-NMR (200 MHz, CDCl3) δ 0.62-0.72 (4H, m), 2.42 (2H, s), 3.02 (3H, s), 3.70 (3H, s), 4.17 (2H, s). the mixture was warmed up to 0° C. during 1 hr After cooling the mixture to −15° C. The mixture was washed with cold brine (25 mL) twice dried with MgSO4 filtered evaporated in vacuo

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 methyl (1-{[(methylsulfonyl)oxy]methyl}cyclopropyl)acetate (appendage 3) (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, 20% 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, 20% EtOAc in toluene)

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

Procedure: To a solution of methyl [1-(hydroxymethyl)cyclopropyl]acetate (1 eq.) from the previous step in DCM (0.1 M) at −40° C. was added triethylamine (3 eq.) and then methanesulfonyl chloride (1.5 eq.). The reaction was warmed to 0° 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 3 as an oil. 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:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 8.45 g of crude methyl 2-[1-(hydroxymethyl)cyclopropyl]acetate (compound 14a) was dissolved in 85 ml dry dichloromethane. The pale yellow solution was cooled to 0° C. Then, 7.71 g triethylamine was added and 8.05 g methanesulfonyl chloride was added dropwise over 8 minutes. The yellow suspension was stirred at 0° C. TLC showed that after 10 minutes the reaction was completed. To the reaction mixture, 35 ml water and 20 ml dichloromethane were added. The water layer was washed with 20 ml dichloromethane. The combined organic layers were washed with 30 ml water, dried (Na2SO4) and evaporated to dryness, resulting in a yellow oil. The product was immediately used in the next step (synthesis of methyl 1-(bromomethyl)-cyclopropaneacetate). after 10 minutes The water layer was washed with 20 ml dichloromethane The combined organic layers were washed with 30 ml water dried (Na2SO4) evaporated to dryness resulting in a yellow oil