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Method D: Twenty one mM acid chloride were dissolved in 10 ml tetrahydrofuran and added to a mixture of 20 mM 2-amino-5-chloropyridine, 3.5 ml (25 mM) triethylamine and 40 ml tetrahydrofuran as described in method C. The mixture was stirred for 15 min prior to filtration to remove the triethylamine hydrochloride. The solid was washed with 10 ml tetrahydrofuran and the combined filtrates evaporated under reduced pressure. In case of the oxalyl derivate, the residue was dissolved in 90 ml hot 95% ethanol and the solution filtered while still hot. The mixture was stirred and 40 mM KOH dissolved in 10 ml water were added at a rate that the temperature did not rise above 40C. The reaction was completed by stirring for a further 10 min. The product separated as white potassium salt which was collected by suction. The precipitate was dissolved in 100 ml (iodo derivative: 250 ml) hot water and filtrated. Hydrochloric acid was added to the hot filtrate until pH2. The product separated as free acid during incubation at 4C overnight. The product was further purified by recrystallisation from 95% ethanol. In case of the malonyl and adipoyl derivatives, the residue was dissolved in 200 ml MeOH and filtrated. The solution was placed in a triple-necked round bottom flask equipped with a reflux condenser, a dropping funnel and a thermometer and heated to 50C. While stirring the mixture, 40 mM KOH dissolved in 40 ml water were rapidly added through the dropping funnel and the temperature maintained at 50C. The reaction was completed by stirring at the same temperature for an additional 10 min. The surplus of KOH was neutralised by addition of 40 mM NH4Cl dissolved in 10 ml water. Most solvent was removed under reduced pressure and the residue dissolved in water (about 200 ml) and filtered. Formic acid was added to the clear filtrate until pH3. The product separated as white crystals during incubation at 4C overnight. The malonyl and adipoyl derivatives were purified by recrystallisation from 95% or 50% ethanol, respectively.
With lithium hydroxide monohydrate; In tetrahydrofuran; methanol; water; at 20℃; for 3h;
To a solution of methyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate (Int 10/3) (0.50 g, 2.30 mmol) in THF (8 mL), MeOH (5 mL) and H20 (5 mL) was added LiOH H20 (289 mg, 6.90 mmol). The mixture was stirred at rt for 3 h. It was concentrated and the residue was diluted with H2O (10 mL). It was acidified with 1 N HCI solution to pH = 6-7 and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered and concentrated to give the title compound as a yellow solid.
tert-butyl {(1R,2S,5S)-2-amino-5-[(dimethylamino)carbonyl]cyclohexyl}carbamate monooxalate[ No CAS ]
[ 552850-73-4 ]
[ 480452-36-6 ]
Yield
Reaction Conditions
Operation in experiment
91.05%
With dibutyltin(II) dilaurate; sodium hydrogencarbonate; at 50 - 70℃; for 5h;pH 7.0;Autoclave; Industrial scale;
1863.8 gTert-butyl {(1R, 2S, 5S) -2-amino-5 - [(dimethylamino) carbonyl] cyclohexyl} carbamate oxalate monohydrate (7.03 mol) was added to 50 LIn the reaction kettle,Then 20 LC2 fatty alcohol was added,Adding a saturated solution of sodium hydrogencarbonate to adjust PH = 7,After addition, 2146.7 g of 2- [(5-chloropyridin-2-yl) amino] -2-oxoacetic acid (5.86 mol)The reaction solution was then heated to 50 C, dibutyltin dilaurate was added,After the addition, the reaction solution was heated to 70 C and kept stirred for 5 h. The reaction was monitored by TLC until the starting point disappeared.The reaction solution was poured into ice water, filtered, and the filter cake was washed with water,To obtain 2496.92 g of dry white powder 91.05%.
4-[4-(3-aminooxetan-3-yl)phenyl]morpholin-3-one[ No CAS ]
N'-(5-chloropyridin-2-yl)-N-{3-[4-(3-oxomorpholin-4- yl)phenyl]oxetan-3-yl}oxalamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6%
To a solution of 2 - ((5- chloropyridin-2-yl) amino) -2-oxoacetic acid (48 mg, 0.239 mmol)In N, N-dimethylformamide (1 mL)Triethylamine (100 [mu] L, 0.72 mmol)And HBTU (114 mg, 0.3 mmol),Stir for 10 minutes,4- (4- (3-Amino-3-yl) phenyl) morpholin-3- one (160 mg, 0.644 mmol)Stir at room temperature for 4 hours.The crude product was purified by column chromatography (dichloromethane / methanol (v / v) = 10/1)A pale yellow oil (6.2 mg, 6%) was obtained.
methyl 4-(1-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetyl)piperidin-4-yl)-1-naphthoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
To a stirred solution of <strong>[552850-73-4]2-((5-chloropyridin-2-yl)amino)-2-oxoacetic acid</strong> (Int 13) (160 mg, 0.80 mmol), HOBt (108 mg, 0.80 mmol), DIPEA (620 mg, 4.80 mmol), and EDCI (305 mg, 1.60 mmol) in DMF (6 ml_) was added methyl 4-(piperidin-4-yl)-1 -naphthoate (Int 20/12) (269 mg, 0.88 mmol) at rt. The mixture was stirred at rt for 16 h, diluted with H2O (20 mL) and extracted with EtOAc (3 x 20 ml_). The combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with PE: EtOAc = 1 :1 (v/v) to give the title compound as a white solid.
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