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5-amino-2-n-butyl-3-[4-(3-di-n-butylamino propoxy)benzoyl]benzofuran bisoxalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69.49%
Stage #1: (2-butyl-5-nitrobenzofuran-3-yl)(4-(3-(dibutylamino)propoxy)phenyl)methanone With hydrogen In methanol at 30℃; for 6h; Autoclave;
Stage #2: oxalic acid In methanol at 0℃; for 2h; Reflux;
3
In 1.0 L autoclave charged 2-n-butyl 3-[4 (3-di-n-butylamino-propoxy) benzoyl] 5- nitrobenzofuran (20.0 g) (39.37 mmols), methanol (140.0 ml) and 5% Pd/C (2.0g) (50 % moisture). Hydrogen pressure was applied up to 5.0 Kg/cm2 at 30.0°C and stirred the reaction mass for 6 hours. At the end of this time the reaction mass was filtered through hyflo bed. Filtrate was collected and transferred in 250.0 ml round bottom flask (Small sample was isolated and analyzed HPLC purity 92.36%). To this solution of 5-amino-3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butylbenzofuran in methanol was added oxalic acid (7.78 g) (86.44 mmols) in one lot and heated the reaction mass to reflux for 1 hour. The reaction mass was cooled to 0°C and stirred for 1 hour. The precipitated solid was filtered and dried at 50.0°C under vacuum for 2 hours. (Dry weight: 18.0 g) Molar yield: 69.49% HPLC purity: 98.64%
Stage #1: (2-butyl-5-nitrobenzofuran-3-yl)(4-(3-(dibutylamino)propoxy)phenyl)methanone With hydrogen In methanol at 55℃; for 8h;
Stage #2: oxalic acid In methanol at 25 - 65℃; for 0.5h;
4.1.A
Example-4: -Preparation of 5-amino 3-f4-(3-di-n-butylamino-propoxy)benzoyll-2-n-butyl benzofuranMethod-l:(A) 5-amino 3-f4-(3-di-n-butylamino-propoxy)benzoyll-2-n-butyl benzofuran dioxalate salt100 g 2-n-butyl-3-[4-(3-di-n-butylamino-propoxy)benzoyl]-5-nitro benzofuran, 700 mL methanol and 15 g of Raney Nickel were taken under nitrogen atmosphere at 25°C in 2.0 L autoclave. Hydrogen pressure of 0.5-1.0 Kg was flushed two times and released at 25°C. The hydrogen pressure upto 3.0 Kg/cm2 was applied and the reaction mixture was heated to 55°C. Further the pressure was increased to 5.0 Kg/cm2 and maintained for 8 hours at 55°C. After the completion of the reaction as monitored by TLC, the reaction mixture was cooled to 25°C. The reaction mixture was flushed with nitrogen pressure two times and filtered under nitrogen atmosphere at 25°C followed by washing with 50 mL methanol. The filtrate was distilled under vacuum at 65°C to obtain residue. The residue was dissolved in methanol at 25°C and 52.20 g oxalic acid solution in methanol was added. The reaction mixture was heated to 65°C and stirred for 30 min at 50°C followed by cooling to 25°C. The product was filtered and washed with methanol and dried to obtain 5-amino 3-[4-(3-di-n-butylamino-propoxy)benzoyl]- 2-n-butyl benzofuran dioxalate salt. Purity > 98% (HPLC)The dioxalate salt is characterized by XRD substantially as depicted in FIG.17 and DSC substantially as depicted in FIG.18
Stage #1: (2-butyl-5-nitrobenzofuran-3-yl)(4-(3-(dibutylamino)propoxy)phenyl)methanone With hydrogen; acetic acid In ethyl acetate at 15 - 21℃; Inert atmosphere; Autoclave;
Stage #2: With ammonia In water; ethyl acetate at 25 - 35℃;
Stage #3: oxalic acid In methanol at 45 - 55℃;
1
Preparation of 2-n-butyl-3-(4-(3-dibutylaminopropoxy) benzoyl)-5- aminobenzofuran dioxalateIn to a 5.0 lit RBF, 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran (100 g), Methyl ethyl ketone (600 ml), potassium carbonate (44.69 g) & l-Chloro-3-dibutylaminopropane (66.54 g) was charged at R.T. Heat the reaction mixture to 78+/-3°C (Reflux temperature). Stirred the reaction mixture for 8-10 hr at 78+/-3°C. Cool the reaction mixture to 30+/-5°C. Filter it & distilled out organic layer under vacuum completely up to 50°C. Ethyl acetate and water was added to reaction mixture. The organic layer was separated and aqueous layer was discarded. Charge organic layer & add activated charcoal (2.5 g) at 30+/-5°C. Stir the reaction mass for 30-40 min at 30+/-5°C. Distil out ethyl acetate completely u/v up to 45 °C to obtain 2-n-butyl-3-(4-(3-dibutylaminopropoxy)benzoyl)-5- nitrobenzofuran (oil). Charge Ethyl acetate (750 ml), Acetic acid (-90 ml) up to pH 4.5 -4.8 & Pd/C (15 g) into above obtained oil at R.T. Cool the reaction mixture up to 18+/-3°C. Apply pressure (1+/-2 kg) to the autoclave by Nitrogen gas. Stir the reaction mixture for 10 minutes at 18+/-3°C & release nitrogen gas from autoclave. Apply pressure (4+/-1 kg) to the autoclave by Hydrogen gas and stir for 10 minutes at 18+/-3°C. Release Hydrogen gas from autoclave & maintain pressure (4+/-1 kg) to the autoclave for 3-7 hours at 18+/-3°C. After the completion of the reaction, filter the reaction mass through hyflo bed. Wash the bed with ethyl acetate & charge the filtrate. Charge aq. Ammonia solution in to reaction mass (Aq.ammonia (-25%)) in to water. Stir the reaction mass for 20-30 minutes at 30+/-5°C. Settle the reaction mass followed by separating organic layer & discarding aqueous layer. Distil out the ethyl acetate completely under vacuum at 25- 45°C to obtain oil. Charge Methanol & Oxalic acid dehydrate in the obtained oil. Stir the reaction mixture for 1.5- 2.0 hr at 50+/-5°C. Cool the reaction mass up to 30+/-5°C. Stir the reaction mass at 30+/-5°C for 2.0 -2.5 hours & filter the solid. Wash the solid with methanol & dry the solid at 50+/-5°C to obtain the desired product.
With palladium on activated charcoal; ammonium formate at 55℃;
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