L-Leucinol

clear colorless to slightly yellow

To a mixture of (L)-leucine methyl ester HCl salt (254 g, 1.4 mol), NaHCO3, (118 g, 1.4 mol, 1.0 equiv.) and water (1.8 L) in EtOH (1.8 L) at 5° C. was added NaBH4, (159 g, 4.2 mol, 3.0 equiv.) in portions at such a rate that the reaction temp. did not exceed 15° C. (approximately 70 min). After the addition of NaBH4 was complete, the ice bath was removed and the reaction was heated to the reflux temp. overnight. The resulting mixture was cooled to room temp. with the aid of an ice bath. The resulting slurry was filtered and the solids were washed with EtOH (750 mL). The combined filtrates were concentrated to approximately 950 mL under reduced pressure. The residue was diluted with EtOAc (2.5 L) and extracted with a 1N NaOH solution (2.x.1 L). The aqueous layer was back-extracted with EtOAc (2.x.750 mL). The combined organics were dried (MgSO4) and concentrated under reduced pressure to yield (1S)-1-(hydroxymethyl)-3-methylbutylamine as a pale yellow oil (112 g, 65percent): 1H NMR (CDCl3) δ0.88-0.93 (m, 6H), 1.17 (t, J=7.7 Hz, 2H), 1.68-1.80 (m, 2H), 1.82 (br s, 2H), 2.86-2.91 (m, 1H), 3.22 (dd, J=10.7, 8.1 Hz 1H), 3.56, (dd, J=10.3, 3.6 Hz, 1H)Example 3 Synthesis of Compound 3 Hydrochloride salt; a. Synthesis of intermediate B; To a solution of dry THF (250 ml) was slowly charged lithium aluminum hydride (10.84 g, 0.151 mol) at 0 C over 30 minutes. To this reaction mixture was charged, in portions, L-leucine (25.Og, 0.227 mol) over a period of 45 minutes while maintaining the reaction mixture temperature between 0-5 C to control the vigorous evolution of hydrogen. The resulting reaction mixture was then heated to reflux and maintained at reflux for 16 hours at which time it was cooled to 0-5 C, diluted with diethyl ether (300 ml) and slowly quenched with DI water (12 ml). To the quenched solution was charged 15percent w/v NaOH solution (12 ml) which resulted in the precipitation of a white solid. The slurry was stirred at room temperature for 30 minutes and the white solid was removed by filtration to give a clear organic filtrate which was dried with sodium sulfate (q.s.). The sodium sulfate was removed by filtration and the organic solution was concentrated under reduced pressure to afford intermediate B as a yellow liquid (20 g, 90percent).L-Leucinol (LeuOH). Ten grams of L-Leucine (76.2 mmol) was suspended in 100 mL of THF under the nitrogen atmosphere. The suspension was cooled in the ice bath and 4 g of lithium aluminum hydride (100 mmol) was added over a 30 min period. After the addition was complete, the ice bath was removed and the reactant was warmed to room temperature and then refluxed for 24 hours under nitrogen. The reactant was quenched with water (4 mL), then aqueous 15percent of sodium hydroxide (4 mL), and water 12 mL. The solution was stirred for 30 min and white precipitate is filtrated. The filter cake was washed with Dichloromethane and the combined organic layer was dried with sodium sulfate, and concentrated under reduced pressure (8.7 g., 97 percent). The L-leucinol was isolated by distillation. Bp 90 General procedure: The activity of catalyst for hydrogenation of R-phenylglycinemethyl ester was tested in a 0.5 L stainless steelautoclave under stirring at a speed of 500rpm. After 1g catalyst (20–40 mesh) was put in the reactor, the reactorwas swept with H2 five times to flush out air. Thenthe catalyst was reduced at 1MPa H2and 250 °C for 4h. After the autoclave was cooled in H2atmosphere to roomtemperature, 1.5g R-phenylglycine methyl esters (R-p-m)diluted in 150 mL ethanol was added (R-p-m/Cat = 1.5, wt.). The typical reaction conditions were at 5 MPa of H2 and 80 °C for 10 h. After the reaction was ended, theautoclave was cooled in H2atmosphere to room temperature.Then solid catalyst was separated by centrifugation.The product was purified by column chromatography on silica gel with ethyl acetate/methanol (3/2, v/v) as the eluent.Thus we obtained the light yellow powder product byrotary evaporation. Reactants and products were analyzedby High Performance Liquid Chromatograph (HPLC, Agilent1260 Infinity) equipped with an ultraviolet detector anda column (Eclipse XDB-C18, 150 × 4.6mm, 5mm particlesize), then the conversion of R-phenylglycine methyl ester(X), yield (Y) and chemoselectivity to R-phenylglycinol (S)were calculated [18, 19], in which the yield is the LC yield.And the ee value of products was determined by HPLCequipped with an ultraviolet detector (wavelength 258nm)and a chiral column (CHIRALPAK AY-H, 250 × 4.6mm, 5m particle size) [19].To a cooled (0 0C) solution of 1.0M LAH in THF (76.0 niL, 76.0 mmol) was added D-leucine in one portion, then the mixture was warmed slowly to 60 0C. The mixture formed a fluid gel after 2 h. The mixture was cooled to 10 0C and quenched with water (2.88 mL), 4N NaOH (4.33 mL) and water (8.65 mL). Di-t-butyl dicarbonate (15.06 g, 69.0 mmol) was added and the mixture warmed from 11 0C to ambient temperature while stirring for 17 h. The solvent was removed in vacuo and the resulting residue suspended in EtOAc. The solids were removed via filtration and washed with EtOAc. The filtrate was concentrated in vacuo to afford ((R)-I -hydroxymethyl-3-methyl-butyl)-carbamic acid tert-butyl ester (17.0 g, >99%) as a colourless oil. 1H NMR (CDCl3) delta 0.92 (d, 6H, J= 6.6 Hz), 1.27-1.33 (m, IH), 1.41-1.50 (m, 10H), 1.58-1.70 (m, 3H), 3.46-3.54 (m, IH), 3.63-3.75 (m, 2H), 4.49-4.57 (m, IH).

Used as raw material for organic synthesis

Molecular Weight:117.19
XLogP3:0.4
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:3
Exact Mass:117.115364102
Monoisotopic Mass:117.115364102
Topological Polar Surface Area:46.2
Heavy Atom Count:8
Complexity:54.5
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes