tert-Butyl 1-benzyl-2-oxo-2-[(3-Pyridinylsulfonyl)amino]ethylcarbamate

 tert-Butyl 1-benzyl-2-oxo-2-[(3-Pyridinylsulfonyl)amino]ethylcarbamate

 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (939 mg, 4.9 mmol), 1-hydroxybenzotriazole hydrate (562 mg, 4.15 mmol), and N-methylmorpholine (952 mg, 9.42 mmol) were added to an ice-cold solution of N-tert-butoxycarbonyl-L-phenylalanine (1.0 g, 3.77 mmol) in dichloromethane (20 ml), and the mixture stirred for 15 minutes. 3-Pyridinesulphonamide (Mon. für Chemie; 72; 77; 1938) (596 mg, 3.77 mmol) was added, and the reaction stirred at room temperature for 24 hours. The mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate (50 ml) and water (50 ml), and the layers separated. The aqueous layer was extracted with ethyl acetate, then dichloromethane, the combined organic extracts dried (MgSO₄) and evaporated under reduced pressure. The crude product was purified twice by column chromatography on silica gel, using an elution gradient of ethyl acetate:ethanol (100:0 to 90:10) to give the desired product as a white foam, 1.01 g, 66; 

¹H NMR (DMSOd₆, 300 MHz) δ: 1.30 (s, 9H), 2.77 (m, 1H), 2.97 (m, 1H), 3.84 (m, 1H), 5.95 (bs, 1H), 6.96 (m, 2H), 7.08 (m, 3H), 7.42 (m, 1H), 8.05 (d, 1H), 8.60 (d, 1H), 8.84 (m, 1H); [α]_D=−10° (0.1% solution in methanol).

(5-Bromo-3-pyridinyl)(phenyl)methanol

(5-Bromo-3-pyridinyl)(phenyl)methanol

n-Butyl lithium (17 ml, 2.5M in hexanes, 42.5 mmol) was added dropwise to cooled (−78° C.) solution of 3,5-dibromopyridine (10 g, 42.2 mmol) in ether (200 ml), so as to maintain an internal temperature <−70° C. The mixture was then stirred for 15 minutes and a solution of benzaldehyde (4.5 g, 42.5 mmol) in ether (20 ml) was added dropwise, again maintaining the temperature <−70° C. The mixture was stirred for 15 minutes, then allowed to warm to room temperature over an hour. The reaction was quenched by the addition of 0.9M ammonium chloride solution (200 ml), the layers separated, and the aqueous phase extracted with ether. The combined organic extracts were dried (MgSO₄) and evaporated under reduced pressure. The residual yellow oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane:ether (95:5 to 80:20) to give the title compound as a yellow oil, 7.6 g, 68%; 

¹H NMR (D₂O, 300 MHz) δ: 5.80 (s, 1H), 7.37 (m, 5H), 7.90 (s, 1H), 8.40 (s, 1H), 8.44 (s, 1H).

(1S,3R)-3-Aminocyclopentanecarboxamide hydrochloride

(1S,3R)-3-Aminocyclopentanecarboxamide hydrochloride

Hydrogen chloride gas was bubbled through an ice-cooled solution of the amide from preparation 10 (438 mg, 1.92 mmol) in dichloromethane (50 ml) for 10 minutes, and the resulting suspension stirred at room temperature for 2 hours. The mixture was purged with nitrogen, then evaporated under reduced pressure. The residue was triturated with ether, to afford the title compound as a solid; 

¹H NMR (D₂O, 400 MHz) δ: 1.63-1.82 (m, 3H), 1.92-2.07 (m, 2H), 2.19 (m, 1H), 2.82 (m, 1H), 3.62 (m, 1H).

(5-Methyl-1,3,4-thiadiazol-2-yl)methylamine hydrochloride

(5-Methyl-1,3,4-thiadiazol-2-yl)methylamine hydrochloride

 Hydrogen chloride gas was bubbled through an ice-cooled solution of the thiadiazole from preparation 14 (425 mg, 1.85 mmol) in dichloromethane (50 ml) for 15 minutes, and the reaction stirred at room temperature for 1 hour. The mixture was purged with nitrogen, then evaporated under reduced pressure to afford the title compound as a white solid; 

¹H NMR (DMSOd₆, 400 MHz) δ: 2.75 (s, 3H), 4.48 (m, 2H), 8.80 (bs, 3H).

2-Amino-4-butylpyridine

2-Amino-4-butylpyridine

A mixture of 4-butylpyridine (5.0 g, 37.0 mmol) and 95% sodium amide (1.7 g, 40.7 mmol) in xylene (10 ml) was heated at 150° C. for 18 hours. The cooled mixture was diluted with ether (100 ml) and extracted with 2N hydrochloric acid (twice). The aqueous extracts were basified using sodium hydroxide solution, and re-extracted with ether. These combined organic extracts were dried (MgSO₄) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (97:3:0.15) as eluant, to afford the title compound as a crystalline solid, 2.1 g, 38%; 

¹H NMR (CDCl₃, 300 MHz) δ: 0.96 (t, 3H), 1.38 (m, 2H), 1.60 (m, 2H), 2.52 (t, 2H), 4.38 (bs, 2H), 6.38 (s, 1H), 6.55 (d, 1H), 7.98 (d, 1H);

 Anal. Found: C, 72.01; H, 9.47; N, 18.53. C₉H₁₄N₂requires C, 71.96; H, 9.39; N, 18.65%.

5-(Cyclopropylmethyl)-1,3,4-thiadiazol-2-amine

5-(Cyclopropylmethyl)-1,3,4-thiadiazol-2-amine

Oxalyl chloride (3.13 ml, 35.9 mmol) and N,N-dimethylformamide (1 drop) were added to a solution of cyclopropylacetic acid (3 g, 29.9 mmol) in dichloromethane (30 ml), and the reaction stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and azeotroped with dichloromethane to give a brown oil. A mixture of this intermediate acid chloride (887 mg, 7.48 mmol) and thiosemicarbazide (455 mg, 4.99 mmol) were heated at 70° C. for 18 hours, then cooled. Water was added, the mixture basified to pH 9 using 50% aqueous sodium hydroxide solution, and the resulting precipitate filtered and dried, to give the title product, 410 mg, 53%; 

¹H NMR (CD₃OD, 400 MHz) δ: 0.28 (m, 2H), 0.60 (m, 2H), 1.02 (m, 1H), 2.77 (d, 2H); 

LRMS: m/z 155.2 (MH⁺).

2-Amino-4-butylpyridine

2-Amino-4-butylpyridine

A mixture of 4-butylpyridine (5.0 g, 37.0 mmol) and 95% sodium amide (1.7 g, 40.7 mmol) in xylene (10 ml) was heated at 150° C. for 18 hours. The cooled mixture was diluted with ether (100 ml) and extracted with 2N hydrochloric acid (twice). The aqueous extracts were basified using sodium hydroxide solution, and re-extracted with ether. These combined organic extracts were dried (MgSO₄) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (97:3:0.15) as eluant, to afford the title compound as a crystalline solid, 2.1 g, 38%;

 ¹H NMR (CDCl₃, 300 MHz) δ: 0.96 (t, 3H), 1.38 (m, 2H), 1.60 (m, 2H), 2.52 (t, 2H), 4.38 (bs, 2H), 6.38 (s, 1H), 6.55 (d, 1H), 7.98 (d, 1H);

Anal. Found: C, 72.01; H, 9.47; N, 18.53. C₉H₁₄N₂requires C, 71.96; H, 9.39; N, 18.65%.