3-aMino-oxetane-3-carboxylic acid Methyl ester

Thionyl chloride (336 mg) was added to a mixture of IIA (513 m g) in acetonitrile, and the mixture was stirred at 80C for 5 h to precipitate a solid. The acetonitrile was distilled off under reduced pressure, and the solid was added to toluene and spin-dried. The solid was then dissolved in dichloromethane and a mixed solution of IIIA (337 mg) and dichloromethane was added dropwise at -30C. After dripping, continue stirring for 5 minutes and add triethylamine dropwise to pH 6~7.Afterwards, continue to react for 1 hour. The temperature was raised to -5C, washed with sodium dihydrogen phosphate dihydrate solution, sodium hydrogencarbonate solution and saturated saline in that order, and dried over anhydrous sodium sulfate. The residue was spin-dried and purified by column chromatography to give 482 mg of a pale yellow oil. Yield 71.5% .To a suspension of benzyl (2, 5-dioxopyrrolidin-1-yl) carbonate (2.34 g) in tetrahydrofuran (2.4 ml) was added at 0C a suspension of 10105] 2, 6-Difluoro-4-phenylethynyl-phenylamine (Example 1, step 1) (180 mg, 0.79 mmol) was dissolved in toluene (3.0 ml) and bis(trichloromethyl) carbonate (93 mg, 0.31 mmol, 0.4 equiv.) was added at room temperature. The mixture was stirred for 1 hour at 110 C. To the mixture Et3N (397 mg, 0.55 ml, 3.93 mmol, 5 equiv.) and ethyl 2-(isopropylamino)acetate hydrochloride (171 mg, 0.94 mmol, 1.2 equiv.) were added and stirred for 16 hours at 110 C. The reaction mixture was cooled and loaded directly onto a silica gel colunm. The crude product was purified by flash chromatography eluting with an ethyl acetate:heptane gradient 0:100 to 60:40. The desired 3-[2, 6-difluoro-4-(2-phenylethynyl)phenyl] -1- isopropyl-imidazolidine-2, 4-dione (164 mg, 59% yield) was obtained as a white solid, MS: mle=355.2 (M+H). The title compound was obtained as a light yellow solid, MS: mle=353.2 (M+H), using chemistry similar to that described in Example 1, step 2 from 2, 6-difluoro-4- phenylethynyl-phenylamine (Example 1, step 1) and methyl 3-aminooxetane-3 -carboxylate.Intermediate A9-1 (1.55 g, 4.978 mmol) in 75 mL methanol is hydrogenated (H2 atmosphere, 50 psi) with Pd/C (10%) at room temperature for 9 h. The reaction mixture is filtered and concentrated in vacuo to give the product without further purification. MS (ESI+): m/z=132 [M+H]+ HPLC (Method A): Rt=0.13 min.Intermediate A9-1 (1 .55 g, 4.978 mmol) in 75 mL methanol is hydrogenated (H2 atmosphere, 50 psi) with Pd/C (10 %) at room temperature for 9 h. The reaction mixture is filtered and concentrated in vacuo to give the product without further purification. MS (ESI+): m/z = 132 [M+H]+ HPLC (Method A): Rt = 0.13 min.To a mixture of Compound 306C (20 g, 64.3 mmol) in methanol (100 mL) and ethyl acetate (100 mL) was added Pd/C (10%, 2 g), stirred under hydrogen (1 atm.) at room temperature overnight, and filtered.The filtrate was concentrated to give a crude product Compound 306D. LC-MS (ESI) m/z: 132 [M+H]+;1H-NMR (CDCl3, 400 MHz): delta (ppm) 2.08 (s, 2H), 3.88 (s, 3H), 4.53 (d, J = 6.4 Hz, 2H), 5.00 (d, J = 7.6 Hz, 2H).

Molecular Weight:131.13
XLogP3:-1.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:131.058243149
Monoisotopic Mass:131.058243149
Topological Polar Surface Area:61.6
Heavy Atom Count:9
Complexity:130
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes