tert-Butyl 2-(2-acetylhydrazino)-2-oxoethylcarbamate

 tert-Butyl 2-(2-acetylhydrazino)-2-oxoethylcarbamate

2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (7.06 g, 28.5 mmol) was added to a solution of N-tert-butoxycarbonylglycine (5.0 g, 28.6 mmol) in dichloromethane (75 ml), and the solution stirred for 15 minutes. Acetic hydrazide (2.6 g, 35.1 mmol) was added, and the reaction stirred at room temperature for 18 hours. The resulting precipitate was filtered, and dried in vacuo, to afford a white crystalline solid, 2.42 g. The filtrate was concentrated under reduced pressure, diluted with ether, and the resulting precipitate filtered and dried in vacuo, to afford additional product as a white solid, 4.4 g, 67% in total; 

¹H NMR (CDCl₃, 400 MHz) δ: 1.41 (s, 9H), 2.02 (s, 3H), 3.87 (d, 2H), 5.22 (bs, 1H), 8.27 (bs, 1H), 8.84 (bs, 1H); LRMS: m/z 249.2 (MNH₄ ⁺);

2-[2-(2-Oxo-1-piperidinyl)ethyl]-1H-isoindole-1,3(2H)-dione

2-[2-(2-Oxo-1-piperidinyl)ethyl]-1H-isoindole-1,3(2H)-dione

Pthalimide (952 mg, 6.47 mmol) was added to a solution of the product from preparation 5 (842 mg, 5.88 mmol) in tetrahydrofuran (30 ml), and the mixture sonicated until a solution was obtained. Polymer supported triphenyl phosphine (2.5 g, 7.5 mmol) and diethyl azodicarboxylate (1.15 ml, 7.31 mmol) were added, and the reaction stirred at room temperature for 18 hours. The mixture was filtered through Arbocel®, the filtrate concentrated under reduced pressure and the residue azeotroped with dichloromethane. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (70:30 to 100:0), to give the title compound as a white foam, 1.6 g (containing some impurities); 

¹H NMR (CDCl₃, 400 MHz) δ: 1.60-1.80 (m, 4H), 2.17 (m, 2H), 3.30 (m, 2H), 3.60 (m, 2H), 3.83 (m, 2H), 7.62 (m, 2H), 7.79 (m, 2H); LRMS: m/z 273.2 (MH⁺).

tert-Butyl-3-bromopropionate

tert-Butyl-3-bromopropionate

To a solution of 3-bromopropionic acid (6.0 kg, 39.2 mol) in dichloromethane (60 L) at 0° C. was added tert-butanol (0.6 L) and conc. sulfuric acid (0.33 L). The resultant solution was cooled to −15° C. and isobutylene was bubbled through (11 kg, 196 mol). The reaction was then stirred for 3 hours at −5° C. before warming to 20° C. over 4 hours and was then stirred at this temperature for 15 hours. The reaction was quenched by cautious addition into saturated aqueous sodium bicarbonate solution (0.6 M, 72 L, 43.2 mol). The layers were then separated and the organic layer was washed with saturated aqueous sodium bicarbonate solution (2×48 L) followed by deionised water (48 L). This washing cycle was repeated and the pH of the aqueous layer was measured and was shown to be above pH 7. Potassium carbonate (90 g, 1.5% w/w) was added to the organic layer before concentrating the solution to a volume of 9 L by distillation at atmospheric pressure. Tetrahydrofuran (40 L) was added and the remainder of the dichloromethane was removed by distillation at atmospheric pressure to give a solution (12 L) of the title compound (5.27 kg, 25.2 mol, 64% yield) in tetrahydrofuran that was used directly in the next step;

¹H-NMR (CDCl₃, 300 MHz,) δ: 1.45 (s, 9H), 2.80 (t, 2H), 3.53 (t, 2H); LRMS (El): m/z [MH⁺] 209 (⁷⁹Br).

EASY NMR

 Benzyl 2-{[1-(chlorocarbonyl)cyclopentyl]methyl}entanoate

Oxalyl chloride (1.15 ml, 13.2 mmol) was added to an ice-cooled solution of 1-{2-[(benzyloxy)carbonyl]pentyl}cyclopentanecarboxylic acid (EP 274234, Example 16) (2.0 g, 6.3 mmol) in dry dichloromethane (20 ml), and the solution stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue azeotroped with dichloromethane (3×), to give the title compound as a golden oil, 2.1 g; 

¹H NMR (CDCl₃, 300 MHz) δ: 0.88 (t, 3H), 1.28 (m, 2H), 1.43 (m, 2H), 1.63 (m, 6H), 2.00 (m, 1H), 2.08-2.35 (m, 3H), 2.44 (m, 1H), 5.15 (s, 2H), 7.28 (m, 5H).

N-Methoxy-N-methyl-2-(2-oxo-1-pyrrolidinyl)acetamide

N-Methoxy-N-methyl-2-(2-oxo-1-pyrrolidinyl)acetamide

2-Chloro-N-methoxy-N-methylacetamide (ex Aldrich Chemical Co.) (3.2 g, 23.3 mmol) was added to a suspension of 2-pyrrolidinone (2.0 g, 23.5 mmol) and sodium hydride (940 mg, 60% dispersion in mineral oil, 23.5 mmol) in tetrahydrofuran (60 ml), and the reaction stirred at room temperature for 48 hours. The mixture was quenched with water (150 ml), and extracted with ethyl acetate (200 ml) and dichloromethane (200 ml). The combined organic extracts were dried (MgSO₄) and evaporated under reduced pressure. The residue was triturated with hexane, then ether to afford the title compound as white crystals, 1.8 g, 41%; 

¹H NMR (CDCl₃, 400 MHz) δ: 2.02 (m, 2H), 2.40 (t, 2H), 3.17 (s, 3H), 3.48 (t, 2H), 3.72 (s, 3H), 4.19 (s, 2H); LRMS: m/z 186.9 (MH⁺).

1-(2-Oxopropyl)-2-pyrrolidinone

1-(2-Oxopropyl)-2-pyrrolidinone

[0487] Methylmagnesium chloride (2.7 ml, 3M in tetrahydrofuran, 8.1 mmol) was added to a cooled (−20° C.) solution of the amide from preparation 15 (1.5 g, 8.1 mmol) in tetrahydrofuran (50 ml), and the reaction allowed to warm to room temperature, then stirred for an hour. The mixture was quenched by the addition of aqueous ammonium chloride solution, then extracted with ethyl acetate (3×50 ml). The combined organic solutions were dried (MgSO₄), and evaporated under reduced pressure to give the title compound as an oil, 645 mg, 56%; 

¹H NMR (CDCl₃, 400 MHz) δ: 2.07 (m, 2H), 2.17 (s, 3H), 2.42 (t, 2H), 3.42 (t, 2H), 4.10 (s, 2H).

Dad can teach you NMR...........1-[2-(Hydroxyimino)propyl]-2-pyrrolidinone

1-[2-(Hydroxyimino)propyl]-2-pyrrolidinone

Hydroxylamine hydrochloride (316 mg, 4.55 mmol) and then pyridine (37011, 4.58 mmol) were added to a solution of the amide from preparation 16 (643 mg, 4.55 mmol) in ethanol (30 ml), and the reaction stirred at room temperature for 18 hours. The mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (97:3 to 90:10). The product was triturated with ether to give the title compound as a white solid, 375 mg, 53%; 

¹H NMR (DMSOd₆, 400 MHz) δ: 1.60 (s, 3H), 1.87 (m, 2H), 2.20 (t, 2H), 3.19 (t, 2H), 3.78 (s, 2H), 10.77 (s, 1H); LRMS: m/z 157.4 (MH⁺).