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Stage #1: dimethyl 2-nitromalonate; 2-methyl-4-octyne In toluene at 170℃; for 1h; Microwave irradiation;
Stage #2: With lithium hydroxide monohydrate; water In methanol at 20℃;
Stage #3: (Z)-tert-butyl 1-(4-(N-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate |
18.18-B; 18.18C; 18.18-D
18-B. Methyl 5-isobutyl-4-propylisoxazole-3-carboxylate and methyl 4-isobutyl-5- propylisoxazole-3-carboxylate; [00227] A mixture of 6-methylhept-3-yne (220 mg, 2 mmol), dimethyl 2- nitromalonate (567 mg, 3.20 mmol) and l-butyl-3-methylimidazolium hexafluorophosphate (0.04 ml, 0.2 mmol) in toluene (4 mL) was heated to 170°C in the microwave for 1 hr. After cooling to rt, the reaction mixture was partitioned between EtOAc (50 ml) and water (50 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated to afford an orange oil that was chromatographed on a 12 gm Isco silica gel cartridge, eluting with a 0-5%EtO Ac/Hex gradient. The fractions which contained product were concentrated to afford 228 mg, 54. % yield of a mixture of methyl 4-ethyl-5-isobutylisoxazole-3-carboxylate and methyl 5-ethyl-4- isobutylisoxazole-3-carboxylate as light yellow oil. HPLC retention time = 1.86 minutes (YMC Combi 4.6 x 30 mm S-5 ODS column) eluting with 10-90% aqueous methanol + 0.1 TFA a 2minute gradient. MS:(M+H)= 226.22. 1H NMR indicates a ~1 : 1 mixture of regioisomers. These isomers were not readily separable by normal or reverse phase chromatography and this material was used without further purification in the next step.; 18.C 5-Isobutyl-4-propylisoxazole-3-carboxylic acid and 4-isobutyl-5- propylisoxazole-3 -carboxylic acid; [00228] To a mixture of methyl 5-isobutyl-4-propylisoxazole-3-carboxylate and methyl 4-isobutyl-5-propylisoxazole-3-carboxylate (164 mg, 0.728 mmol) in MeOH- I l l - (8 mL) and water (2 mL) was added LiOH, hydrate (15.28 mg, 0.364 mmol) and the mixture was allowed to stir overnight at rt. An additional amount of LiOH, hydrate (15.28 mg, 0.364 mmol) was added and the reaction mixture was stirred at rt for 2 hr. The MeOH was removed in vacuo and the remaining aqueous was acidified to pH ~1 with IN HCl. The mixture was extracted with EtOAc (20 mL). The organic layer was washed with brine (20 mL), dried (MgSO4) and concentrated to afford (144 mg, 0.682 mmol, 94 % yield) of product which was approximately a 1 : 1 mixture of 5- isobutyl-4-propylisoxazole-3-carboxylic acid and 4-isobutyl-5-propylisoxazole-3- carboxylic acid as a light yellow oil. HPLC retention time = 1.72 minutes (YMC Combi 4.6 x 30 mm S-5 ODS column) eluting with 10-90% aqueous methanol + 0.1 TFA a 2minute gradient. MS :(M+H)= 212.20.[00229] 1H NMR indicates a ~1 : 1 mixture of regioisomers as shown in the schematic above. These isomers were not readily separable by normal or reverse phase chromatography and this material was used without further purification in the next step.; 18-D. tert-Butyl l-(4-(5-(5-isobutyl-4-propylisoxazol-3-yl)-l,2,4-oxadiazol-3- yl)benzyl)azetidine-3-carboxylate and tert-BvXyl l-(4-(5-(4-isobutyl-5- propylisoxazol-3-yl)-l,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate; [00230] A mixture of 5-isobutyl-4-propylisoxazole-3-carboxylic acid, and 4- isobutyl-S-propylisoxazole-S-carboxylic acid (42.26 mg, 0.2 mmol), (Z)-tert-butyl 1- (4-(N'-hydroxycarbamimidoyl) benzyl)azetidine-3-carboxylate (61.1 mg, 0.200 mmol), HOBt (38.3 mg, 0.250 mmol), diisopropylethylamine (0.070 mL, 0.400 mmol) and EDC (47.9 mg, 0.250 mmol) in DMF (1 mL) was stirred at rt for 18 hr. DMF (1 mL) was added and the reaction mixture was warmed to 500C for 8 hr. The reaction mixture was partitioned between EtOAc (30 ml) and saturated sodium bicarbonate solution (30 ml). The organic layer was washed with water (2 x 30 ml) and brine (30 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to afford an oil that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-100%EtO Ac/Hex gradient. The pure fractions were concentrated to afford a mixture of tert-butyl l-(4-(5-(5-isobutyl-4-propylisoxazol-3- yl)-l,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (32 mg, 0.067 mmol, 66.6 % yield) and tert-butyl l-(4-(5-(4-isobutyl-5-propylisoxazol-3-yl)-l,2,4-oxadiazol-3- yl)benzyl)azetidine-3-carboxylate (32 mg, 0.067 mmol, 66.6 % yield) as a colorless oil. HPLC retention time = 1.89 minutes (YMC Combi 4.6 x 30 mm S-5 ODS column) eluting with 10-90% aqueous methanol + 0.1 TFA a 2minute gradient. MS:(M+H)= 481.32. [00231] The mixture was separated on a Berger Prep SFC MGIII Unit on a Chiral AD-H 30 X 3 cm ID, 5μm column, eluting with 70/30 C(V(MeOH, 0.1 % diethylamine) and a flow rate of 88 mL/min, monitored at 220 nm. The fractions from the first peak to elute were concentrated to afford tert-butyl l-(4-(5-(4-isobutyl- 5-propylisoxazol-3-yl)-l,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (21 mg; 44%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ ppm 0.93 (d, J= 7.3 Hz, 6 H) 1.00 (t, J= 7.4 Hz, 3 H) 1.44 (s, 9 H) 1.79 (m, 2 H) 1.92 (m, 1 H) 2.62 (d, J= 6.7 Hz, 2 H) 2.77 (t, J= 7.4 Hz, 2 H) 3.27 (m, 3 H) 3.53 (m, 2 H) 3.66 (s, 2 H) 7.42 (d, J= 8.1 Hz, 2 H) 8.10 (d, J= 8.1 Hz, 2 H). [00232] The fractions from the second peak to elute were concentrated to afford tert-butyl l-(4-(5-(5-isobutyl-4-propylisoxazol-3-yl)-l,2,4-oxadiazol-3- yl)benzyl)azetidine-3-carboxylate (24 mg; 50%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ ppm 0.95-1.01 (m, 9 H) 1.44 (s, 9 H) 1.57-1.65 (m, 2 H) 2.10-2.19 (m, 1 H) 2.67 (d, J=7.4 Hz, 2 H) 2.69-2.73 (m, 2 H) 3.22-3.30 (m, 3 H) 3.50-3.56 (m, 2 H) 3.67 (s, 2 H) 7.42 (d, J=8.1 Hz, 2 H) 8.10 (d, J=8.1 Hz, 2 H). |
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