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2-<i>tert</i>-butoxycarbonylamino-3-methyl-butyric acid 2-<i>tert</i>-butoxycarbonylamino-1-ethylcarbamoyl-3-(3-trifluoromethyl-phenyl)-propyl ester[ No CAS ]
(R)-N-[(S)-1-[(S)-4-Guanidino-1-(thiazole-2-carbonyl)-butylcarbamoyl]-2-(3-trifluoromethyl-phenyl)-ethyl]-3-phenyl-2-phenylmethanesulfonylamino-propionamide[ No CAS ]
N-(trans-4-aminomethylcyclohexylcarbonyl)-3-trifluoromethyl-DL-phenylalanine morpholinoamide hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In tetrahydrofuran;
EXAMPLE 15 Synthesis of N-(trans-4-aminomethylcyclohexylcarbonyl)-3-trifluoromethyl-DL-phenylalanine morpholinoamide hydrochloride (Compound No. 29) <strong>[142995-31-1]N-(t-butoxycarbonyl)-3-trifluoromethyl-DL-phenylalanine</strong> (0.30 g) was dissolved in dry tetrahydrofuran (10 ml) and, under ice-cooling, triethylamine (0.13 ml) was further added. After stirring for 10 minutes, a solution of ethyl chlorocarbonate (0.10 g) in dry tetrahydrofuran (0.5 ml), followed by stirring for 30 minutes. Thereafter, morpholine (0.10 g) was added at once and the mixture was stirred at room temperature for 2 hours. After filtering off the solid substances, the resultant reaction mixture was concentrated in vacuo. The residue was extracted with ethyl acetate and the organic layer was washed with water, a 10% aqueous citric acid, water, a 5% aqueous sodium bicarbonate, and a saturated aqueous sodium chloride, followed by drying over anhydrous sodium sulfate. After concentrating in vacuo, <strong>[142995-31-1]N-(t-butoxycarbonyl)-3-trifluoromethyl-DL-phenylalanine</strong> morpholinoamide (I) (0.28 g), which was confirmed by an NMR analysis, was obtained in the form of a colorless oil. Following the procedure of Examples 4, 5, and 7, the final compound N-(trans-4-aminomethylcyclohexylcarbonyl)-3-trifluoromethyl-DL-phenylalanine morpholinoamide hydrochloride (II) (0.17 g) was obtained in the form of hygroscopic white powder from the compound (I).
N-(trans-4-aminomethylcyclohexylcarbonyl)-3-phenoxy-DL-phenylalanine 2-nicotinylamide dihydrobromide[ No CAS ]
[ 142995-31-1 ]
N-(trans-4-aminomethylcyclohexylcarbonyl)-3-trifluoromethyl-DL-phenylalanine morpholinoamide hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In tetrahydrofuran;
Example l5 Synthesis of N-(trans-4-aminomethylcyclohexylcarbonyl)-3-trifluoromethyl-DL-phenylalanine morpholinoamide hydrochloride (Compound No. 29) <strong>[142995-31-1]N-(t-butoxycarbonyl)-3-trifluoromethyl-DL-phenylalanine</strong> (0.30 g) was dissolved in dry tetrahydrofuran (l0 ml) and, under ice-cooling, triethylamine (0.l3 ml) was further added. After stirring for l0 minutes, a solution of ethyl chlorocarbonate (0.l0 g) in dry tetrahydrofuran (0.5 ml), followed by stirring for 30 minutes. Thereafter, morpholine (0.l0 g) was added at once and the mixture was stirred at room temperature for 2 hours. After filtering off the solid substances, the resultant reaction mixture was concentrated in vacuo. The residue was extracted with ethyl acetate and the organic layer was washed with water, a l0% aqueous citric acid, water, a 5% aqueous sodium bicarbonate, and a saturated aqueous sodium chloride, followed by drying over anhydrous sodium sulfate. After concentrating in vacuo, <strong>[142995-31-1]N-(t-butoxycarbonyl)-3-trifluoromethyl-DL-phenylalanine</strong> morpholinoamide (I) (0.28 g), which was confirmed by an NMR analysis, was obtained in the form of a colorless oil. Following the procedure of Examples 4, 5, and 7, the final compound N-(trans-4-aminomethylcyclohexylcarbonyl)-3-trifluoromethyl-DL-phenylalanine morpholinoamide hydrochloride (II) (0.l7 g) was obtained in the form of hygroscopic white powder from the compound (I).
tert-Butyl (S)-I -(5-(4-chlorothieno[2,3-c]pyridin-2-yl)-l, 3,4-thiadiazol-2- ylamino)-1-oxo-3-(3-(trifluoromethyl)phenyl)propan-2-ylcarbamate. (S)-2-((tert- Butoxycarbonyl)amino)-3-(3-(trifluoromethyl)phenyl)propanoic acid (1 g, 3 mmol) purchased from Peptech was mixed with EDC (0.766 g, 4 mmol) and HOBt (0.810 g, 6 mmol) in 5 mL DMF in a round bottom flask. The mixture was stirred at room temperature for 30 minutes. 5-(4-Chlorothieno[2,3-c]pyridin-2-yl)-1,3,4-thiadiazol-2- amine (0.268 g, 1 mmol) was added to the flask followed by addition of DEEA (1.4 mL, 8 mmol). The mixture was heated at 50C for one hour. After the DMF was removed under reduced pressure, the remaining residue was mixed with 200 mL EtOAc. The EtOAc solution was washed three times with saturated ammonium chloride aqueous solution, three times with saturated aqueous NaHCO3, and then dried over Na2SO4. After removing the solvent, the product was obtained and used directly in the next step.
lambda/-[(1 ,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.2 g, 12.6 mmol) was dissolved in THF (200 ml.) and stirred at 0 0C for 20 min. A solution of Borane-THF complex (1.0M in THF, 50 ml_, 50 mmol) was added via an addition funnel over 1 h, and the contents were stirred for an additional 3 h at 0 0C. The reaction mixture was then stored in a freezer (ca. -15C), overnight. The reaction mixture was returned to ice bath and with stirring slowly quenched with methanol (50 ml_). The mixture was concentrated in vacuum. The residue was treated with methanol and concentrated, in duplicate. The residue was purified by flash chromatography (eluant: 10% to 100% (1 % NH4OH, 9% methanol 90% chloroform) gradient in chloroform) to afford the title compound as a solid. (3.4 g, 85%) MS(ES)+ m/e 320 [M+H]+. This material was used as-is without further purification
63%
(S)-tert-Butyl 1 -hydroxy-3-(3-(trifluoromethyl)phenyl)propan-2- ylcarbamate. In a 500 mL round bottom flask, LiBH4 (1.0 g, 45 mmol, Fluka) was dissolved in THF (100 mL) at 0 0C, and Me3SiCl (12 mL, 90 mmol, Aldrich) was added dropwise. The reaction mixture was stirred for 20 minutes at 23 C. The mixture was then cooled to 0 0C and (S)-2-(tert-butoxycarbonylamino)-3-(3- (trifluoromethyl)phenyl)propanoic acid (5.0 g, 15 mmol, Chem-Impex catalog number 07390) was added. The reaction mixture was stirred for 2 hours at 23 0C and then cooled to 0 0C and 20 mL of MeOH was added dropwise via an addition funnel., Next, 60 mL of IO N NaOH was added. The reaction mixture was extracted twice with 70 mL of EtOAc. The organic layers were combined, washed with brine and concentrated. The residue was then purified by silica gel chromatography eluting with 0 - 40 % EtOAc/hexane to give the title compound (3.0 g, 63 %). MS m/z: 320 (M+ 1).
With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 6.25h;
(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propan-1-ol To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-(trifluoromethyl)phenyl]-propanoic acid (Aldrich) (10.00 g, 30.00 mmol) in tetrahydrofuran (25 mL) with stirring, 1.0 M borane-THF complex in THF (100.0 mL, 100.0 mmol) (newly opened) was added dropwise to keep the internal temperature at 0 C. (release gas, about 15 min). After addition the reaction was stirred at room temperature (rt) for 6 hrs, cooled down with ice-bath, quenched with AcOH:MeOH (1:5, 50 mL), and partitioned between saturated aqueous NaHCO3 and DCM, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give an oil residue, which was purified by combi-flash chromatography to give the desired intermediate. LC-MS found: 320.1 (M+H)+.
General procedure: (S)-2-((tert-Butoxycarbonyl)amino)-3-phenylpropanoic acid (compound 5a, 203.6 mg, 0.768 mmol) in DMF (5 mL) was added HOBt (283.2 mg, 2.10 mmol) and EDCI (257.8 mg, 1.396 mmol). After stirring for 30 min compound 4 (187.2 mg, 0.698 mmol) and additional TEA (0.30 mL, 2.10 mmol) were added. This solution was allowed to stir at room temperature for 20 h and then the saturated NaHCO3 was added. The mixture was extracted with EtOAc and washed with saturated NaCl, dried over Na2SO4 and concentrated. The residue was purified with flash chromatography on silica gel, eluted with a mixture of PE/EA (4/1, v/v) to afford 6a (130 mg, 54%) as a white solid.
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