1-ethynylcyclohexan-1-amine

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

Procedure: A mixture of 1-ethynylcyclohexylamine (6 g, 48.7 mmol) and 1,3-propane sultone (6.55 g, 53.6 mmol) in THF (35 mL) was heated at reflux for 2 hours (thick paste). The mixture was cooled to room temperature. The solid was collected by filtration, rinsed with THF (3×5 mL), air-dried 15 minutes (7.3 g). The solid was suspended in ethanol (30 mL) and the suspension was heated at reflux for 1 hour. The mixture was then cooled to room temperature and the solid was collected by suction filtration, rinsed with ethanol (2×5 mL), air-dried for 10 min, and further dried in a vacuum oven at 60° C. overnight (crop1, 7.10 g). The combined mother liquors were stirred overnight at room temperature. There was a lot of solid. The solid was collected by filtration, rinsed with acetone (3×5 mL), air-dried for 30 minutes, and then suspended in ethanol (12 mL). The suspension was heated at reflux for 1 hour. The mixture was then cooled to room temperature and the solid was collected by suction filtration, rinsed with ethanol (2×5 mL), air-dried for 2 minutes, and further dried in a vacuum oven at 60° C. overnight (crop 2: 1.85 g). Compound DX was obtained as a fine white solid (two crops in total 8.95 g, 75% yield). 1H NMR (500 MHz, D2O) δ 0.95-1.05 (m, 1H), 1.38-1.54 (m, 5H), 1.60-1.64 (m, 2H), 1.94 (qt, J=7.8 Hz, 2H), 2.85 (t, J=7.3 Hz, 2H), 3.01 (s, 1H), 3.22 (t, J=7.8 Hz, 2H). 13C NMR (125 MHz, D2O) δ 21.8, 22.3, 24.2, 34.4, 40.9, 48.0, 59.2, 78.6, 79.3. ES-MS 243.0 (M−1). was heated at reflux for 2 hours (thick paste) The solid was collected by filtration rinsed with THF (3×5 mL) air-dried 15 minutes (7.3 g) the suspension was heated at reflux for 1 hour The mixture was then cooled to room temperature the solid was collected by suction filtration rinsed with ethanol (2×5 mL) air-dried for 10 min further dried in a vacuum oven at 60° C. overnight (crop1, 7.10 g) The solid was collected by filtration rinsed with acetone (3×5 mL) air-dried for 30 minutes The suspension was heated at reflux for 1 hour The mixture was then cooled to room temperature the solid was collected by suction filtration rinsed with ethanol (2×5 mL) air-dried for 2 minutes further dried in a vacuum oven at 60° C. overnight (crop 2: 1.85 g) Compound DX was obtained as a fine white solid (two crops in total 8.95 g, 75% yield)

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

Procedure: To a solution of 1-ethynylcyclohexanamine (40 mg, 0.32 mmol) in CH2Cl2, was added triethylamine (68 mL, 0.48 mmol), followed by 3-chlorobenzenesulfonyl chloride (68.2 mg, 0.32 mmol). After 30 min, the mixture was partitioned between ethyl acetate and 3N aq. HCl. The organic layer was washed with sat. NaHCO3, brine, dried over Na2SO4, concentrated in vacuuo to give the title compound as a white solid (90 mg, 93% yield). the mixture was partitioned between ethyl acetate and 3N aq. HCl The organic layer was washed with sat. NaHCO3, brine dried over Na2SO4 concentrated in vacuuo

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

Procedure: To a solution of 1-ethynylcyclohexanamine (40 mg, 0.32 mmol) in CH2C2 was added triethylamine (68 mL, 0.48 mmol), followed by 3-chlorobenzenesulfonyl chloride (68.2 mg, 0.32 mmol). After 30 min, the mixture was partitioned between ethyl acetate and 3N aq. HCl. The organic layer was washed with sat. NaHCO3, brine, dried over Na2SO4, concentrated in vacuuo to give the title compound as a white solid (90 mg, 93% yield); the mixture was partitioned between ethyl acetate and 3N aq. HCl The organic layer was washed with sat. NaHCO3, brine dried over Na2SO4 concentrated in vacuuo

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

Procedure: To a solution of 1-ethynylcyclohexanamine (40 mg, 0.32 mmol) in CH2C2 was added triethylamine (68 mL, 0.48 mmol), followed by 3-chlorobenzenesulfonyl chloride (68.2 mg, 0.32 mmol). After 30 min, the mixture was partitioned between ethyl acetate and 3N aq. HCl. The organic layer was washed with sat. NaHCO3, brine, dried over Na2SO4, concentrated in vacuuo to give the title compound as a white solid (90 mg, 93% yield); the mixture was partitioned between ethyl acetate and 3N aq. HCl The organic layer was washed with sat. NaHCO3, brine dried over Na2SO4 concentrated in vacuuo

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

Procedure: A solution of 1 g (8 mmol) 1-ethynylcyclohexylamine and 2 mL (15 mmol) triethylamine in 10 mL acetonitrile is combined at ambient temperature with 0.5 g (9 mmol) methylisocyanate. The colourless suspension is stirred overnight at ambient temperature and then evaporated down. The residue is taken up in dichloromethane and washed with aqueous potassium carbonate solution. The organic phase is dried and evaporated down. Yield: 1.4 g (colourless solid) evaporated down washed with aqueous potassium carbonate solution The organic phase is dried evaporated down

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

Procedure: (S)-2-(7-((1-Aminocyclohexyl)ethynyl)-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (100) was prepared by the method of Example 67 using the reduction method of Example 51 step 3 for (S)-ethyl 2-(1-(4-chlorophenyl)-3-methyl-6-(trifluoromethylsulfonyloxy) naphthalen-2-yl)-2-hydroxyacetate instead of step 5, NaBH4 step, from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-oxoacetate. The remainder of the sequence follows the method of Example 67 using 1-ethynylcyclohexanamine in Step 7. 1H-NMR: 400 MHz, (CD3OD) δ: 7.82 (d, J=8 Hz, 1H), 7.72 (s, 1H), 7.56 (m, 3H), 7.47 (d, J=8 Hz, 1H), 7.37 (s, 1H), 7.31 (d, J=8 Hz, 1H), 5.20 (s, 1H), 2.60 (s, 3H), 2.11 (m, 2H), 1.63-1.85 (m, 8H), 0.99 (s, 9H). LCMS-ESI+ (m/z): [M—NH2]+ calcd for C31H32ClO3: 487.2; found: 487.2.