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Preparation IV Synthesis of trans-1-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3-amino-5-methylhexane. [Q--(CH2)2 CH(NH2)-CH2 CH(CH3)2 ]. To a solution of 43.06 gm (500 mMol) isovaleraldehyde in ethanol (150 ml) were added 52 gm (500 mMol) malonic acid followed by 57.75 gm (750 mMol) ammonium acetate. The suspension was stirred at reflux for 5 hours and the resulting solution was then cooled to 0 C. The resulting solid was filtered, washed with 1:1 ethyl acetate:ethanol (200 ml) and dried under vacuum for 18 hours to give 40 gm of crude 3-amino-5-methylhexanoic acid.
10
[ 3653-34-7 ]
[ 24424-99-5 ]
[ 138165-75-0 ]
Yield
Reaction Conditions
Operation in experiment
63%
To a solution of DL-beta-homo leucine (45 g, 0.31 mol) in 1N NaOH (1 L) at 0 C., a solution of (Boc)2O (87.8 g, 0.403 mol) in 1,4-dioxane (500 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight, cooled to 0 C. and neutralized with 1 N HCl (ca. 1000 mL). The solid was filtered off and dried under vacuum to yield 3-(tert-butoxycarbonylamino)-5-methylhexanoic acid (48.0 g, 63%) as a solid.
With sodium methylate; In methanol; at 130℃; for 4.5h;Microwave irradiation; Sealed tube;
l-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (75 mg, 0.234 mmol) and 3-Amino-5-methyl-hexanoic acid (175 mg, 1.2 mmol) were placed in a CEM 10 mL Microwave vessel and sodium methoxide-methanol solution (0.5M; 2.4 mL, 1.2 mmol) was added via syringe. The vessel was sealed and heated to 130 C in a CEM microwave apparatus for 4.5 hours. The reaction mixture was diluted with water and treated with IN hydrochloric acid and extracted three times with ethyl acetate then dried over sodium sulfate. The crude product was purified by MPLC (methylene chloride-methanol) to provide the title compound as an off-white solid in 41% yield. MS ESI(-) m/e: 432.1062 (M-l).
General procedure: Phenylacetyl chloride (0.044 mol) was added dropwise to 100 mL of NaOH solution (10%, w/v) of racemic mixture of an amino acid (0.04 mol) kept on ice bath. The reaction mixture was acidified to pH 2 with 6 M HCl, and N-phenylacetyl amino acid (N-PhAc amino acid) was extracted three times with ethyl acetate and recrystallized from the ethyl acetate solution. Purity of the product was determined by HPLC using C-8 reverse phase column. Eluent consisted of H2O (containing 0.1% TFA): acetonitrile in ratio 7:3. For more details on products yields, chemical shifts in the 1H NMR and 13C NMR spectra and data from MS analyses see Supplementary data (Figs. S1-S7).