2-氨基-2-甲基丙酸乙酯盐酸盐

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A stirred suspension of 2-amino-2-methylpropanoic acid (165 g) in ethanol at 0° C. was saturated with hydrogen chloride gas. The mixture was heated at reflux for 4 hours and the solvent was evaporated under reduced pressure to give ethyl 2-amino-2-methylpropanoate hydrochloride as a white solid. Sodium carbonate (100 g) was slowly added to a suspension of the solid in water followed by 40% aqueous formaldehyde solution (150 g) and the suspension was stirred for 3 hours. The mixture was extracted with ether, the organic solution was washed with water, dried (magnesium sulphate) and solvent evaporated under reduced pressure to give ethyl 2-(N-methyleneamino)-2-methylpropanoate (137.8 g) in equilibrium with its trimer 1,3,5-tri(1-ethoxycarbonyl-1-methylethyl)hexahydrotriazine as a colourless oil, IR (liquid film) 2980(s), 1725(vs), 1250(s), 1140(vs). The mixture was heated at reflux for 4 hours the solvent was evaporated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Triethylamine (3 g) was added to a suspension of ethyl 2-aminoisobutyrate hydrochloride (5 g) in toluene (60 mL) at room temperature. 2-Mercaptophenylacetic acid (6.44 g) was added to the mixture, which was then stirred at room temperature. After 10 minutes, a 35% formaldehyde aqueous solution (2.61 g) was added dropwise to the mixture. After the addition was completed, a catalytic amount of p-toluenesulfonic acid was added, and the mixture was allowed to react under heating at reflux for 4 hours, while water generated was excluded by azeotropic distillation from the reaction system. The reaction mixture was cooled to room temperature, to which ethyl acetate was added, and was then washed with a saturated sodium hydrogencarbonate aqueous solution and a saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled under reduced pressure to give 5.49 g of the title compound as viscous oil. After the addition to react under heating generated was excluded by azeotropic distillation from the reaction system The reaction mixture was cooled to room temperature, to which ethyl acetate was added was then washed with a saturated sodium hydrogencarbonate aqueous solution a saturated aqueous sodium chloride and dried over anhydrous sodium sulfate The solvent was distilled under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of ethyl aminoisobutyrate hydrochloride (10 g) in DMF (50 mL) was cooled to 0° C. To the solution were added potassium carbonate (18 g) and 1-chloro-3-iodopropane (12 g), and the mixture was stirred overnight at 0° C. to room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 12.5 g of crude ethyl 2-(3-chloropropylamino)isobutyrate. the mixture was extracted with ethyl acetate The organic layer was washed with water dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 500 mg of the compound obtained in Example 13, 300 mg of 1-ethoxycarbonyl-1-methylethylamine hydrochloride and 550 mg of BOP were mixed with 2 ml of DIPEA and 50 ml of DCM and the reaction medium was stirred for 30 minutes at room temperature. It was then concentrated under vacuum and the residue was taken up with water and then extracted with AcOEt, washed successively with 1N HCl , with 1N NaOH and then with water, dried over sodium sulfate and concentrated under vacuum. The residue was purified by chromatography on a silica column using a DCM/AcOEt mixture (97/3; v/v) as the eluent. 170 mg of the expected product were obtained in the form of a white solid by crystallization from an AcOEt/iso ether mixture (10/90; v/v). M.p.=202° C. It was then concentrated under vacuum extracted with AcOEt washed successively with 1N HCl , with 1N NaOH with water, dried over sodium sulfate concentrated under vacuum The residue was purified by chromatography on a silica column

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1.52 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carboxylic acid and 1.45 ml of N-ethyldiisopropylamine were suspended in 15 ml of N,N-dimethylformamide; 1.37 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 3 hours. To the reaction mixture, 1.41 g of 2-aminoisobutyric acid ethyl ester hydrochloride was added, followed by stirring at room temperature for 4 hour. Water was added, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the crystal precipitated was washed with ethyl ether, collected by filtration and dried to yield 1.48 g of the title compound. The filtrate was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and concentrated under reduced pressure to yield 450 mg of the title compound. by stirring at room temperature for 4 hour followed by extraction with ethyl acetate-tetrahydrofuran (1:1) the extract was washed with saturated saline dried with magnesium sulfate The dry product was concentrated under reduced pressure the crystal precipitated was washed with ethyl ether collected by filtration dried

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1.52 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carboxylic acid and 1.45 ml of N-ethyldiisopropylamine were suspended in 15 ml of N,N-dimethylformamide; 1.37 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 3 hours. To the reaction mixture, 1.41 g of 2-aminoisobutyric acid ethyl ester hydrochloride was added, followed by stirring at room temperature for 4 hour. Water was added, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the crystal precipitated was washed with ethyl ether, collected by filtration and dried to yield 1.48 g of the title compound. The filtrate was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and concentrated under reduced pressure to yield 450 mg of the title compound. by stirring at room temperature for 4 hour followed by extraction with ethyl acetate-tetrahydrofuran (1:1) the extract was washed with saturated saline dried with magnesium sulfate The dry product was concentrated under reduced pressure the crystal precipitated was washed with ethyl ether collected by filtration dried

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1.28 g of 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid was suspended in 12 ml of N,N-dimethylformamide; 1.16 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 30 minutes. To the reaction mixture, 1.20 g of 2-aminoisobutyric acid ethyl ester hydrochloride and 1.00 ml of triethylamine were added, followed by stirring at room temperature for 16 hours. Water was added, the crystal precipitated was collected by filtration; the filtrate was extracted with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was combined with the above crystal collected by filtration and subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (2:1). The desired fraction was collected and concentrated under reduced pressure to yield 1.20 g of the title compound. by stirring at room temperature for 16 hours the crystal precipitated was collected by filtration the filtrate was extracted with ethyl acetate the extract was washed with saturated saline dried with magnesium sulfate The dry product was concentrated under reduced pressure collected by filtration eluted with hexane:ethyl acetate (2:1) The desired fraction was collected concentrated under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 430 g (2.56 mol) of ethyl 2-aminoisobutyrate hydrochloride was dissolved in 2 l of DMAc, and 652 g (6.46 mol) of triethylamine and 373 g (4.03 mol) of chloroacetone were added thereto. The mixture was stirred and reacted under nitrogen stream at 80° C. for 3 hours. After completion of the reaction, the reaction solution was poured into 20 l of ice water and extracted twice with 2 l of ethyl acetate. The extracted solution was treated by a conventional method to obtain 402 g (yield: 84%) of the desired product. reacted under nitrogen stream at 80° C. for 3 hours After completion of the reaction extracted twice with 2 l of ethyl acetate The extracted solution was treated by a conventional method

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 430 g (2.56 mol) of ethyl 2-aminoisobutyrate hydrochloride was dissolved in 2 l of DMAc, and 652 g (6.46 mol) of triethylamine and 373 g (4.03 mol) of chloroacetone were added thereto. The mixture was stirred and reacted under nitrogen stream at 80° C. for 3 hours. After completion of the reaction, the reaction solution was poured into 20 l of ice water and extracted twice with 2 l of ethyl acetate. The extracted solution was treated by a conventional method to obtain 402 g (yield: 84%) of the desired product. reacted under nitrogen stream at 80° C. for 3 hours After completion of the reaction extracted twice with 2 l of ethyl acetate The extracted solution was treated by a conventional method

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-((3,5-dimethylisoxazol-4-yl) methyl)-1H-pyrazole-4-carbonyl azide (Example 10-1a) (10 g, 41.0 mmol) is stirred under nitrogen in dry toluene (150 mL) along with molecular sieves at reflux until no emission of nitrogen was observed, which indicates complete conversion of 1-((3,5-dimethylisoxazol-4-yl) methyl)-1H-pyrazole-4-carbonyl azide into 4-((4-isocyanato-1H-pyrazol-1-yl)methyl)-3,5-dimethylisoxazole. The solution was cooled down to 50° C. and ethyl 2-amino-2-methylpropanoate hydrochloride (5.30 g, 41.0 mmol) was added in one portion. Stirring continued for 3 hours at 50° C. followed by reflux for 12 hours. The mixture was filtered over a pad of celite. The filtrate was concentrated on the rotovap and the residue was purified over silica gel using 25% ethyl acetate in hexanes. Yield 65% (8.00 g), white solid. 1H NMR (DMSO-d6, 400 MHz): □s, 6H), 2.15 (s, 3H), 2.41 (s, 3H), 5.18 (s, 2H), 7.78 (d, J=0.4 Hz, 1H), 8.16 (d, J=0.4 Hz, 1H), 8.59 (br s, 1H). MS 304 (MH+). This compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 2.27 μM. at reflux until no emission of nitrogen by reflux for 12 hours The mixture was filtered over a pad of celite The filtrate was concentrated on the rotovap the residue was purified over silica gel using 25% ethyl acetate in hexanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Prepared as in Example 12-1b from 3,5-bis(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-3c) and ethyl 2-amino-2-methylpropanoate hydrochloride. Yield 88%, colorless liquid. MS 482 (MH+).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Prepared as in Example 12-1b from 3,5-bis(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-3c) and ethyl 2-amino-2-methylpropanoate hydrochloride. Yield 88%, colorless liquid. MS 482 (MH+).