3-Ethyl-4-[2-hydroxy-3-(2-hydroxy-acetylamino)-propoxy]-5-methyl-benzoic acid tert. butyl ester → (S)-3-Ethyl-4-[2-hydroxy-3-(2-hydroxy-acetylamino)-propoxy]-5-methyl-benzoic acid

To a suspension of 4-benzyloxy-3-ethyl-5-methyl-benzoic acid (10.0 g, 37.0 mmol) in toluene, N,N-dimethylformamide-di-tert. butyl acetal (22.6 g, 111 mmol) is added. The mixture is refluxed for 24 h before another portion of N,N-dimethylformamide-di-tert. butyl acetal (22.6 g, 111 mmol) is added. Refluxing is continued for 3 days and a third portion of N,N-dimethylformamide-di-tert. butyl acetal (22.6 g, 111 mmol) is added. After refluxing for additional 4 days, the mixture is diluted with EA (250 mL), washed with aq. sat. Na2CO3 solution, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 4-benzyloxy-3-ethyl-5-methyl-benzoic acid tert-butyl ester (9.02 g) as a pale yellow oil, 1H NMR (D6-DMSO): δ 1.16 (t, J=7.5 Hz, 3H), 1.54 (s, 9H), 2.30 (s, 3H), 2.65 (q, J=7.5 Hz, 2H), 4.85 (s, 2H), 7.35-7.40 (m, 1H), 7.43 (t, J=6.8 Hz, 2H), 7.47-7.52 (m, 2H), 7.63 (s, 2H). b) To a solution of 4-benzyloxy-3-ethyl-5-methyl-benzoic acid tert-butyl ester (9.02 g, 27.6 mmol) in THF (50 mL) and ethanol (50 mL), Pd/C (400 mg, 10% Pd) is added. The mixture is stirred at rt under 1 atm of H2. The catalyst is removed by filtration and the filtrate is concentrated. The residue is again dissolved in THF (50 mL) and ethanol (50 m) and treated with Pd/C (400 mg, 10% Pd). The mixture is stirred at rt under 1 atm of H2 for 24 h before the catalyst is again removed by filtration. The filtrate is concentrated and dried to give 3-ethyl-4-hydroxy-5-methyl-benzoic acid tert-butyl ester (7.13 g) as a pale yellow oil; 1H NMR (CDCl3): δ 1.28 (t, J=7.8 Hz, 3H), 1.61 (s, 9H), 2.30 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 5.13 (s br, 1H), 7.67 (s, 1H), 7.69 (s, 1H). c) 3-Ethyl-4-hydroxy-5-methyl-benzoic acid tert-butyl ester is converted to 3-ethyl-4-[2-hydroxy-3-(2-hydroxy-acetylamino)-propoxy]-5-methyl-benzoic acid tert. butyl ester following the procedures given for (S)-4-(3-amino-2-hydroxypropoxy)-3-ethyl-5-methylbenzonitrile and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (step a) only); LC-MS: tR=0.87 min; [M+1]+=368.11; 1H NMR (D6-DMSO): δ 1.17 (t, J=7.5 Hz, 3H), 1.53 (s, 9H), 2.28 (s, 3H), 2.66 (q, J=7.5 Hz, 2H), 3.17-3.26 (m, 1H), 3.38-3.46 (m, 1H), 3.64-3.75 (m, 2H), 3.83 (d, J=5.5 Hz, 2H), 3.91-3.97 (m, 1H), 5.28 (d, J=5.3 Hz, 1H), 5.54 (t, J=5.5 Hz, 1H), 7.59 (s, 1H), 7.60 (s, 1H), 7.68 (t br, J=5.5 Hz, 1H). d) To a cold (0° C.) solution of 3-ethyl-4-[2-hydroxy-3-(2-hydroxy-acetylamino)-propoxy]-5-methyl-benzoic acid tert. butyl ester (5.94 g, 16.2 mmol) in DCM (100 mL), TFA (5 mL) is added and the mixture is stirred at rt for 2 h. The solvent is removed in vacuo and the residue is dissolved in acetonitrile and separated by prep. HPLC to give the title compound (2.20 g) as a white powder; LC-MS: tR=0.41 min; [M+1]+=312.18.

1. additionis added
2. customThe solvent is removed in vacuo
3. dissolutionthe residue is dissolved in acetonitrile
4. customseparated by prep

ORD record

ord-288e2718d4e74d7590ee85f31428e345

Source dataset

uspto-grants-2012_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08148410B2