HCID 87606470, compound → HCID 87607721, compound

A solution of (3R,5R)-5-Methyl-3-((4S,5R)4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoic acid tert-butyl ester(3.9 g, 9.34 mmol) in dichloromethane (150 mL) was treated with trifluoroacetic acid (7.21 mL, 93.4 mL) and stirred 18 hours at ambient temperature. After the solvents and reagent were removed in vacuo, the resulting residue was tritrurated in 100 mL hexanes to provide 3.38 g of the title compound (100%) mp 142-143° C. MS M+1=362.1. 1H NMR (400 MHz; CDCl3) δ 0.85(2t, 6H, J=7.1 Hz), 0.93(d, 3H, J=6.1 Hz), 1.14(m, 1H), 1.2-1.49(m, 6H), 2.56(dd, 1H, J=4.15 and 17.57 Hz), 2.81(dd, 1H, J=17.33 and 10.74 Hz), 4.28(m, 1H), 4.74(quint, 1H, J=6.84 Hz), 5.64(d, 1H, J=7.32 Hz), 7.29-7.43(m, 5H). [4R-Methyl-2R-(4S-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl)heptyl]carbamic acid benzyl ester. A solution of 5R-methyl-3R-(4S-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl)octanoic acid (1.98 g, 5.48 mmol) and triethylamine (0.92 mL, 6.57 mmol) was treated with diphenylphosphorylazide (1.2 mL, 5.48 mmol), stirred 30 min at ambient temperature and then heated at reflux for 3 hours. After cooling briefly, the reaction mixture was treated with benzyl alcohol (2.8 mL, 27.4 mmol) and heated for an additional 3 h at reflux. The reaction mixture was cooled, diluted with ethyl ether (150 mL), washed successively with sat'd NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to an oil. Chromatography (MPLC, elution with 4:1 hexanes:ethyl acetate) provided the title compound (2.0 g, 78.3%) as an oil. MS M+1=467.1. 1H NMR (400 MHz; CDCl3) δ 0.86(2t, 6H, J=7.1 Hz), 0.93(d, 3H, J=5.9 Hz), 1.14(m, 1H), 1.09-1.36(m, 6H), 1.50(d, 1H, J=5.2 Hz), 3.49(t, 1H, J=6.1 Hz), 4.10(m, 1H), 4.71 (quint, 1H, J=6.61 Hz), 5.06(d, 2H, J=3.42 Hz), 5.20(t, 1H, J=5.61 Hz), 5.64(d, 1H, J=7.08 Hz), 7.29-7.43(m, 10H). 2R-(Benzyloxycarbonylaminomethyl)-4R-methylheptanoic acid. A solution of 4R-methyl-2R-(4S-methyl-2-oxo-5R-phenyloxazolidine-3-carbonyl)heptyl]carbamic acid benzyl ester (4.12 g, 8.83 mmol) in 3:1 THF:water (100 mL) was cooled to 0° C. and treated with a mixture of 0.8 N LiOH (17.5 mL, 14 mmol) and 30% H2O2 (4.94 mL, 44 mmol). After the reaction mixture was stirred in the cold 3 hours, it was quenched with a slurry of NaHSO3 (2.37 g) and Na2SO3 (4.53 g) in water (30 mL) and stirred 1 hour. The reaction mixture was diluted with ethyl ether (200 mL), partitioned, and the organic layer washed with brine and dried (MgSO4). The concentrated organic extract was chromatographed (MPLC) eluting with ethyl acetate to give 1.25 g of 2R-(benzyloxycarbonylaminomethyl)-4R-methylheptanoic acid (46%). MS M+1=308.1. 1H NMR (400 MHz; CDCl3) δ 0.83(t, 3H, J=6.84 Hz), 0.87(t, 3H, J=6.35 Hz), 1.14(m, 1H), 1.06-1.54(m, 7H), 2.7(br s, 1H), 3.30(m, 2H), 5.05(q, 2H, J=12.2 Hz), 5.14(t, 1H, J=5.61 Hz), 7.30(br s, 5H). (2R,4R)-2-Amino-4-methyl-heptanoic acid hydrochloride. A mixture of 2R-(benzyloxycarbonylaminomethyl)-4R-methyl-heptanoic acid (1.25 g, 4.07 mmol) and Pd/C (20%, 0.11 g) in methanol (50 mL) was hydrogenated at 50 psi for 18 hours. After the catalyst was removed by filtration, the solvent was removed in vacuo and the resulting solid triturated in ether to provide (2S,4R)-2-amino-4-methyl-heptanoic acid hydrochloride (0.28 g, 40%) mp 226.3-228.0° C. MS M+1=174.0. 1H NMR (400 MHz; CD3OD) δ 0.89(t+d, 6H, J=6.35 Hz), 1.11(m, 1H), 1.25-1.40(m, 4H), 1.47-1.62(m, 2H), 2.48(br s, 1H), 2.93(m, 2H). Anal. Calc'd for C9H19NO20.1H2° C.: 61.75H, 11.06 N, 8.00. Found C, 61.85; H: 10.83 N, 8.01.

1. customAfter the catalyst was removed by filtration
2. customthe solvent was removed in vacuo
3. customthe resulting solid triturated in ether

ORD record

ord-0e471cdf10b648a292cb6d3376c9cef1

Source dataset

uspto-grants-2009_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07517909B2