2-BroMo-4-(1,3-dioxoisoindolin-2-yl)butanoic acid

Comparative 2-bromo-4- (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) butanoic acid; 4-(1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) butanoic acid (3.00 g, 12.9 mmol) and SOCl2 (20 ml) were heated to reflux for 2h. Br2 (2.06 g, 12.9 mmol) was added slowly during 4 h while heating was continued. The reaction was heated to reflux until all starting material was consumed, approximately 48h (followed with LC-MS). Excess SOC12 was removed in vacuum. Crushed ice was added to the residue and it was left over night. The white solid that had formed was filtered and dried in a vacuum oven to give 4.01 g of the crude product. This material was used in the next step without further purification. 'H NMR (270 MHz, METHANOL-D4) 6 ppm 2.19-2. 38 (m, 1 H) 2.39-2. 58 (m, 1 H) 3.83 (t, J=6. 68 Hz, 2 H) 4. 37 (t, J=7. 18 Hz, 1 H) 7.73-7. 91 (m, 4 H). HPLC 71percent, Rr 1.12 min (System A, 30-80percent MeCN over 3 min). MS (ESI+) for C12H, oBrNO4 mlz 312 (M+H) +; Comparative Example 5 (BVT063226); 2-bromo-4- (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) butanoic acid; 4-(1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) butanoic acid (11.0g, 47. 2mmol) was dissolved in thionyl chloride (50 mL) and the reaction mixture was heated to reflux for 2h. Bromine (2.7 mL 51.9mmol) was added over 6h using a syring pump under reflux. The reaction mixture was refluxed overnight. The reaction mixture was then cooled to rt and the solvent was removed under reduced pressure. The crude product was used without further purifications. 'H NMR (270 MHz, METHANOL-D4) 8 ppm 2.22-2. 33 (m, 1 H) 2.41-2. 56 (m, 1 H) 3.84 (t, J=6. 68 Hz, 1 H) 4.37 (t, J=7. 05 Hz, 1 H) 7.75-7. 91 (m, 4 H). HPLC 95percent RT=1.80 (System A. 10-97percent MeCN over 3 min), 96percent RT=1.69 (System B. 10-97percent MeCN over 3 min). MS (ESI+) for C12H10BrN04 nzlz 314 (M+H) +.General procedure: In this work, previously reported N-benzyl-2-bromo-4-(1, 3-dioxoisoindolin-2-yl)butanamide derivatives (25a-e) [44] were obtained by activating the carboxylic acid group of 24 (1 eqv) by using n-propanephosphonic acid anhydride (T3P, 50% in EtOAc, 1 eqv). The reaction was carried out under argon atmosphere for 2hat 0C in dry methylene chloride. Then, distilled triethylamine (1.2 eqv) and the appropriate N-benzylamine (1.1 eqv) were added to the reaction mixture [57]. The reaction was continued at room temperature for 12h. The products were purified by column chromatography over silica gel (DCM/acetone=9:1) to yield 25a-e as a white solid.General procedure: In this work, previously reported N-benzyl-2-bromo-4-(1, 3-dioxoisoindolin-2-yl)butanamide derivatives (25a-e) [44] were obtained by activating the carboxylic acid group of 24 (1 eqv) by using n-propanephosphonic acid anhydride (T3P, 50% in EtOAc, 1 eqv). The reaction was carried out under argon atmosphere for 2hat 0C in dry methylene chloride. Then, distilled triethylamine (1.2 eqv) and the appropriate N-benzylamine (1.1 eqv) were added to the reaction mixture [57]. The reaction was continued at room temperature for 12h. The products were purified by column chromatography over silica gel (DCM/acetone=9:1) to yield 25a-e as a white solid.General procedure: In this work, previously reported N-benzyl-2-bromo-4-(1, 3-dioxoisoindolin-2-yl)butanamide derivatives (25a-e) [44] were obtained by activating the carboxylic acid group of 24 (1 eqv) by using n-propanephosphonic acid anhydride (T3P, 50% in EtOAc, 1 eqv). The reaction was carried out under argon atmosphere for 2hat 0C in dry methylene chloride. Then, distilled triethylamine (1.2 eqv) and the appropriate N-benzylamine (1.1 eqv) were added to the reaction mixture [57]. The reaction was continued at room temperature for 12h. The products were purified by column chromatography over silica gel (DCM/acetone=9:1) to yield 25a-e as a white solid.General procedure: In this work, previously reported N-benzyl-2-bromo-4-(1, 3-dioxoisoindolin-2-yl)butanamide derivatives (25a-e) [44] were obtained by activating the carboxylic acid group of 24 (1 eqv) by using n-propanephosphonic acid anhydride (T3P, 50% in EtOAc, 1 eqv). The reaction was carried out under argon atmosphere for 2hat 0C in dry methylene chloride. Then, distilled triethylamine (1.2 eqv) and the appropriate N-benzylamine (1.1 eqv) were added to the reaction mixture [57]. The reaction was continued at room temperature for 12h. The products were purified by column chromatography over silica gel (DCM/acetone=9:1) to yield 25a-e as a white solid.General procedure: In this work, previously reported N-benzyl-2-bromo-4-(1, 3-dioxoisoindolin-2-yl)butanamide derivatives (25a-e) [44] were obtained by activating the carboxylic acid group of 24 (1 eqv) by using n-propanephosphonic acid anhydride (T3P, 50% in EtOAc, 1 eqv). The reaction was carried out under argon atmosphere for 2hat 0C in dry methylene chloride. Then, distilled triethylamine (1.2 eqv) and the appropriate N-benzylamine (1.1 eqv) were added to the reaction mixture [57]. The reaction was continued at room temperature for 12h. The products were purified by column chromatography over silica gel (DCM/acetone=9:1) to yield 25a-e as a white solid.

Molecular Weight:312.12
XLogP3:2.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:310.97932
Monoisotopic Mass:310.97932
Topological Polar Surface Area:74.7
Heavy Atom Count:18
Complexity:360
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes