These common heterocyclic compound, 5181-35-1, name is 2-(2-Bromoethoxy)isoindoline-1,3-dione, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route. category: indolines-derivatives
To a solution of 2-(2-bromoethoxy) isoindoline-l,3-dione (10 g, 37 mmol) and tert-buty 2-(lH-tetrazol-5-yl)ethylcarbamate (7.88 g, 37 mmol) in dimethyl formamide (50 ml) was added cesium carbonate ((14.48 g, 44 mmole) in portion wise at 25-30 C under stirring. The reaction mixture was stirred for further 16 hours and filtered; the filtrate was slowly poured into chilled water (400 ml) under stirring and continued stirring for 30 minutes. The formed precipitates of compound were filtered and washed with water (40 ml). The solid compound was dried at 40C for 2 hour under high vacuum, yielded 12 g. The compound was column purified using hexane and acetone as an eluent. The mixture was isolated at 10-15% concentration of acetone in hexane to yield 10 g of 2-{2-[5-(2-tertiary butoxy carbonyl aminoethyl)-2H-tetrazol-2-yl]ethoxy}-lH-isoindole-l,3(2H)-dione and 2-{2-[5-(2-tertiary butoxy carbonyl aminoethyl)-lH-tetrazol-l-yl]ethoxy}-lH-isoindole-l,3(2H)-dione in 67% yield Analysis: Mass: 403 (M+l); for Molecular weight: 402 and Molecular formula: C18H22N6O5..; Hydrazine hydrate monohydrate (1.86 ml, 037.3 mmol) was added to a solution of 2-{2-[5-(2- tertiary-butoxy-carbonyl-aminoethyl)-2H-tetrazol-2-yl]ethoxy}-lH-isoindole-l,3(2H)-dione and 2- {2-[5-(2-tertiary-butoxy-carbonyl-aminoethyl)-lH-tetrazol-l-yl]ethoxy}-lH-isoindole-l,3(2H)- dione (10 g, 24.8 mmol, obtained from step 1) in dichloromethane (10 ml) under stirring at room temperature. After completion of 2 hours of stirring at same temperature the TLC confirms the completion of reaction. The reaction mass was filtered and the solid was washed with dichloromethane (50 ml). The collected filtrate was concentrated at 40C under vacuum to yield 6.75 g of the product, which was used further without any purification. Analysis: Mass: 273 (M+l); for Molecular weight: 272 and Molecular formula: CioH2oN603; To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-l,6- diaza-bicyclo[3.2.1]octane-2-carboxylic acid (6.2 g, 22 mmol) in dimethylformamide (50 ml) was added EDC.HC1 (6.45 g, 33.6 mmol) at ambient temperature under stirring. To this was added N- methyl morpholine (7.23 ml, 67.3 mmol) followed by HOBT (3.04 g, 22 mmol) under stirring and reaction mixture was stirred for 5 minutes and cooled to 15C and a solution of mixture of tert- butyl (2-{ l-[2-(aminooxy)ethyl]-lH-tetrazol-5-yl}ethyl)carbamate and tert-buty (2-{2-[2- (aminooxy)ethyl]-2H-tetrazol-5-yl}ethyl)carbamate (6.72 g, 24.7 mmol) in dimethylformamide (12 ml) was slowly added and allowed to reach ambient temperature and stirred for 16 hours. The progress of reaction was monitored by TLC, after complete conversion of starting material the reaction mixture was slowly poured onto chilled water (500 ml) and extracted with ethyl acetate (2×150 ml). The combined organic layer was washed with brine (75 ml) and organic layer was dried over anhydrous sodium sulfate. The organic layer was concentrated on rotavapour to provide 4.2 g of crude compound. The crude compound was column purified by using hexane and acetone as an eluent. The non-polar spot isolated at 10-15% concentration of acetone in hexane yielded 1.6 g of (2S,5R)-N-{2-[5-(2-tertiary butoxy carbonyl aminoethyl)-2H-tetrazol-2-yl]ethoxy}-6- benzyloxy-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamide. The polar spot isolated at 20-25% concentration of acetone in hexane and the pure fractions were collected and concentrated on Rota evaporator to yield 1.4 g of (2S,5R)-N-{2-[5-(2-tertiary butoxy carbonylaminoethyl)-lH-tetrazol-l- yl]ethoxy}-6-benzyloxy-7-oxo-l,6-diazabicyclo[3.2.1] octane-2-carboxamide as white compound, in 25% yield. Analysis: Mass: 531 (M+l); for Molecular weight: 530 and Molecular formula: C24H34N8O6. 1H NMR (DMSO-de): delta 9.30 (s, 1H), 7.43-7.33 (m, 5H), 5.05-5.02 (m, 1H), 4.90-4.83 (m, 3H), 4.47-4.43 (m, 2H), 3.92-3.91 (d, 1H, J= 7.2 Hz), 3.59-3.57 (m, 2H), 3.30 (s, 1H), 3.11-3.08 (m, 2H), 2.99-2.97(m, 1H), 2.71-2.68 (m, 1H), 2.29-2.24 (m, 2H),m 2.04-1.89 (m, 3H), 1.49 (s, 9H).
The synthetic route of 2-(2-Bromoethoxy)isoindoline-1,3-dione has been constantly updated, and we look forward to future research findings.
Reference:
Patent; WOCKHARDT LIMITED; TADIPARTHI, Ravikumar; PATIL, Vijaykumar Jagdishwar; DEKHANE, Deepak; SHAIKH, Mohammad Usman; BIRAJDAR, Satish; DOND, Bharat; PATEL, Mahesh Vithalbhai; (100 pag.)WO2017/81615; (2017); A1;,
Indoline – Wikipedia,
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