CHEMBRDG-BB 7959525

1, 1 -Carbonyldiimidazole (CDT) (127.3 g) was added to a mixture of 2, 5- dichlorobenzoic acid (100 g) in acetonitrile (500 mL) under nitrogen atmosphereat ambient temperature. The reaction mixture was stirred for 1 hour at the same temperature to obtain compound of formula TTa’. After stirring, the reaction mass was added to a mixture of water (1500 mL), sodium hydroxide (NaOH; 31.4 g)and glycine (58.9 g) at 0-10°C. The obtained reaction mass was stirred for 1 hour at 0-10°C. After completion of the reaction, the reaction mixture was maintained at pH 2-3 with hydrochloric acid solution to obtain a solid residue. The solid residue was filtered to obtain N-(2, 5-dichlorobenzoyl)glycine. (Yield: 97.7 percent)Synthesis of 4-(/?, S)-(carboxymethyl)-2-( (R)-I -(2-(2, 5- dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-l, 3, 2-dioxaborinane-4- carboxylic acid (1-1) Step l: 2, 5-r(dichlorobenzoyI)aminolacetic acid[0310] To a mixture of NaOH (12 g, 300 mmol) and glycine (18 g, 239 mmol) in water (120 mL) was added dropwise over 45 min a solution of 2, 5-dichlorobenzoyl chloride (10 g, 48 mmol) in THF (15 mL) keeping the internal temperature below about 25 Water (900 ml) was added to glycine (43 gms) at 25-30°C and cooled the reaction mixture temperature to 0-5°C. Aqueous sodium hydroxide solution (24.8 gms dissolved in 300 ml of water) was added to the above reaction mixture at 0-5°C. 2, 5-Dichlorobenzoyl chloride (100 gms) in tetrahydrofuran (150 ml) was added to the above reaction mixture at 0- 5°C and stirred for 3 hours at same temperature. Acidified the reaction mixture with 2M HC1 at 0-5°C and stirred for 2 hours at same temperature. Filtered the precipitated solid, washed with water. 20percent of Ethyl acetate in cyclohexane solvent mixture was added to the above obtained compound and stirred for 2 hours at 25-30°C. Filtered the precipitated solid, washed with cyclohexane and then dried to afford the title compound. (Yield: 86.0 gms, M.R: 170- 175°C).The compound 13 (100 mg, 0.402 mmol) and the compound 25 (152.4 mg, 0.402 mmol) were added to a reaction flask, TBTU (142 mg, 0.44 mmol) was added under nitrogen protection, and dissolved by adding 2 mL of anhydrous DMF. DIPEA (156 mg, 1.21 mmol) was added dropwise under an ice bath. After the addition, the reaction was warmed to room temperature and stirred for 1 hour. After TLC detected the reaction was completed, the mixture was diluted with a small amount of water and extracted 3-4 times with EtOAc. The organic phases were combined, washed with brine, concentrated and then purified by silica gel column chromatography to give a product (183 mg, yield: 91.9%). LC-MS (APCI): m/z = 497.4(M+1)+.The compound 16 (100 mg, 0.405 mmol) and the compound 13 (154 mg, 0.405 mmol) were added to a reaction flask, TBTU (143 mg, 0.46 mmol) was added under nitrogen protection, and dissolved by adding 2 mL of anhydrous DMF. DIPEA (157 mg, 1.21 mmol) was added dropwise in an ice bath. After the addition, the reaction was warmed to room temperature and stirred for 1 hour. After TLC detected the reaction was completed, the mixture was diluted with a small amount of water and extracted 3-4 times with EtOAc. The organic phases were combined, washed with brine, concentrated, and then purified by silica gel column chromatography to give a product (148 mg, yield: 73.8%). LC-MS (APCI): m/z = 496.5(M+1)+.The compound 13 (56 mg, 0.226 mmol) and the compound 30 (86.4 mg, 0.226 mmol) were added to a reaction flask, TBTU (80 mg, 0.25 mmol) was added under nitrogen protection, and dissolved by adding 2 mL of anhydrous DMF. DIPEA (87.6 mg, 0.34 mmol) was added dropwise in an ice bath. After the addition, the reaction was warmed to room temperature and stirred for 1 hour. After TLC detected the reaction was completed, the mixture was diluted with a small amount of water and extracted 3-4 times with EtOAc. The organic phases were combined, washed with brine, concentrated and then purified by silica gel column chromatography to give a product (88 mg, yield: 78.6%). LC-MS (APCI): m/z = 498.4(M+1)+.

Molecular Weight:248.06
XLogP3:2.2
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:246.9802985
Monoisotopic Mass:246.9802985
Topological Polar Surface Area:66.4
Heavy Atom Count:15
Complexity:260
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes