1-aminocyclopentane-1-carboxamide

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

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

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ammonia solution (20%; 20 g, 0.30 mol.) is added to a solution of 126 g of 1-aminocyclopentanecarboxamide (>98%, 0.98 mol.) in 150 g of water. 86 g of valeraldehyde (0.99 mol.) are then added at 15° C., during which the temperature rises to 32° C. The reaction mixture is heated to 70° C. and stirred for 7 hours at that temperature. 350 ml of MIBK are added to the emulsion, and the mixture is cooled, with stirring, and the organic phase is separated off. The extract is extensively concentrated by evaporation (200 g), and 200 g of n-hexane are added, and the crystals are filtered off. After drying there remain 125 g of 2-butyl-1,3-diaza-spiro [4.4]nonan4-one (HPLC: 98.6%). rises to 32° C the mixture is cooled with stirring the organic phase is separated off The extract is extensively concentrated by evaporation (200 g), and 200 g of n-hexane are added the crystals are filtered off After drying there remain 125 g of 2-butyl-1,3-diaza-spiro [4.4]nonan4-one (HPLC: 98.6%)

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

Procedure: The same procedure was employed as for amine 50, using 1-aminocyclopentanecarboxamide, to provide the product 52. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.11-7.21 (m, 3 H), 7.06 (d, J=8.3 Hz, 2 H), 6.85 (m, J=8.6 Hz, 2 H), 4.39 (d, J=9.6 Hz, 1H), 4.12 (d, J=9.3 Hz, 1 H), 4.06 (t, J=4.9 Hz, 2 H), 3.94 (s, 2 H), 3.34-3.54 (m, 3 H), 2.92 (t, J=4.8 Hz, 2 H), 2.20 (s, 3 H), 2.14 (s, 3 H), 2.06-2.13 (m, 2 H), 1.75-1.83 (m, 6 H); MS (ES+) [M+H]+=531.

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

Procedure: 4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)butanoic acid (39, 46 mg, 0.10 mmol), 1-aminocyclopentanecarboxamide (26 mg, 0.20 mmol), HATU (57 mg, 0.15 mmol), and DIPEA (52 μL, 0.30 mmol) were combined in DMF (0.5 mL) and stirred overnight at room temperature. The reaction was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine (with back extraction), dried over MgSO4, filtered, and concentrated under vacuum. The material was purified by prep HPLC (C18 30×100 mm column, 20-60% CH3CN/10 mM aqueous ammonium formate, 45 mL/min) and lyophilized to give 35 mg (61% yield) of amide 41 as a white solid. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.10-7.19 (m, 3 H), 7.04 (d, J=8.6 Hz, 2 H), 6.81 (m, J=8.6 Hz, 2 H), 4.39 (d, J=9.3 Hz, 1 H), 4.12 (d, J=9.1 Hz, 1 H), 3.96 (t, J=6.2 Hz, 2 H), 3.92 (s, 2 H), 3.34-3.50 (m, 3 H), 2.41 (t, J=7.5 Hz, 2 H), 2.12-2.22 (m, 8 H), 2.04 (quin, J=6.9 Hz, 2 H), 1.93 (dt, J=12.8, 5.1 Hz, 2 H), 1.64-1.75 (m, 4H); MS (ES+) [M+H]+=573. washed with saturated aqueous NaHCO3 and brine (with back extraction) dried over MgSO4 filtered concentrated under vacuum The material was purified by prep HPLC (C18 30×100 mm column, 20-60% CH3CN/10 mM aqueous ammonium formate, 45 mL/min)

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

Procedure: The same procedure was employed as for amine 24, using 1-aminocyclopentanecarboxamide, to provide the product 26 with 0.5 equivalents of formic acid. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.52 (s, 0.5 H, formate), 6.98-7.22 (m, 7 H), 4.39 (d, J=9.6 Hz, 1 H), 4.13 (d, J=9.3 Hz, 1 H), 3.91-4.01 (m, 2 H), 3.34-3.51 (m, 3 H), 2.50-2.68 (m, 4 H), 2.21 (s, 3 H), 2.14 (s, 3 H), 2.10 (d, J=7.3 Hz, 2 H), 1.73-1.87 (m, 6 H), 1.63-1.72 (m, 2 H), 1.58 (d, J=7.1 Hz, 2 H). MS (ES+) [M+H]+=543.

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

Procedure: 20 g (0.156 mol) of 1-aminocyclopentane-1-carboxamide and 28 g (0.19 mol) of trimethyl orthoformate are refluxed for 1 hour. The condenser is then changed to a "No hold up" condenser, and the temperature is elevated to 140° C. inner temperature. The residue is dissolved in 150 ml of acetone the pH is adjusted to 1-2 with concentrated hydrochloric acid and after cooling the resulting suspension the product is filtered of. 25 g of the title compound is obtained, yield 92.2%. is elevated to 140° C. after cooling the resulting suspension the product is filtered of

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