| 89.45% |
Stage #1: 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran With sodium hydroxide In water for 0.25h;
Stage #2: dibutyl-(3-chloro-propyl)-amine In water at 80℃; for 5.25h; |
1.1
Example 1.1:In a 250 ml round bottom flask was charged 2-n-butyl-3-(4-hydroxybenzoyl)- 5-nitrobenzofuran (10.0 g) (29.46 mmols), water (50.0 ml) and NaOH (1.18 g) (29.50 mmols) and stirred for 15 minutes. Heated the reaction mass to 80.0°C and charged N,N- dibutyl-3-chloro-l-propanamine (9.09 g) (44.40 mmols) dropwise within 15 minutes. Reaction mass was maintained at 80.0°C for 5 hours. At the end of this time the reaction mass was cooled at 30.0°C and extracted in toluene (150.0 ml). The toluene layer was washed with 10.0% NaOH solution (50.0 mlx2) followed by water wash (50.0 mlx2). Finally the toluene layer was dried over sodium sulphate and concentrated to get reddish yellow oil (13.5 g). Molar yield: 89.45%HPLC purity: 93.22% |
| 89.08% |
Stage #1: 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran With sodium hydroxide In water for 0.25h;
Stage #2: dibutyl-(3-chloro-propyl)-amine In water at 90℃; for 5.25h; |
1.1.2
In a 2.0 liter round bottom flask was charged 2-n-butyl 3-(4- hydroxy benzoyl) 5-nitrobenzofuran (200.0 g) (589.00 mmols), water (600.0 ml) and NaOH (35.39 g) (884.75 mmols) and stirred for 15 minutes. Heated the reaction mass to 90.0°C and charged N,N- dibutyl-3-chloro-1-propanamine (120.45 g) (589.00 mmols) dropwise within 15 minutes. Reaction mass was maintained at 90.0°C for 5 hours. At the end of this time the reaction mass was cooled at 30.0°C and extracted in toluene (1500.0 ml). The toluene layer was washed with water (1000.0 mlx2). Finally the toluene layer was dried over sodium sulphate and concentrated to get reddish yellow oil (258.0 g). Molar yield: 86.08% HPLC purity: 97.92% |
| 85% |
With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 4h; |
(2-butyl-5-nitrobenzofuran-3-yl)(4-(3-(dibutylamino)propoxy)phenyl)methanone (49):
Compounds 47 (0.730 mmol, 0.248 g), 48 (0.803 mmol, 0.165 g) and K2CO3 (0.730 mmol, 0.101 g)were dissolved in DMF (4.5 mL) and the reaction mixture was stirred at 85 C for 4 hrs. Aftercompletion of the reaction, the reaction mixture was diluted with water and DCM. The aqueous layerwas extracted with DCM three times and the combined organic layers were dried over anhydrous MgSO4 and filtered. The solvents were removed in vacuo and the residue was then purified by flash column chromatography (CHCl3:MeOH, 30:1) to yield 49 as a yellow oil (0.316 g, 85%).1H NMR (400 MHz, CDCl3) δ 8.36 (d, 1H), 8.23 (dd, J = 9.0, 2.3 Hz, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.57(d, J = 9.0 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 4.14 (t, J = 6.3 Hz, 2H), 2.93 (t, J = 7.6 Hz, 2H), 2.64 (t, J= 6.9 Hz, 2H), 2.51 - 2.38 (m, 4H), 2.03 - 1.91 (m, 2H), 1.83 - 1.72 (m, 2H), 1.48 - 1.40 (m, 4H), 1.38- 1.29 (m, 6H), 0.91 (t, 9H).13C NMR (101 MHz, CDCl3) δ 189.02, 167.01, 163.64, 156.30, 144.64, 131.69, 130.75, 127.94,120.16, 117.69, 117.34, 114.48, 111.33, 66.62, 53.95, 50.33, 29.90, 29.47, 29.06, 27.93, 27.00,22.31, 20.68, 14.05, 13.62.HRMS (ESI+): m/z [M+H+] calcd for C30H41N2O5: 509.3015 , found: 509.3008. |
| 72.4% |
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 65℃; for 5h; Inert atmosphere; |
(2-butyl-5-nitrobenzofuran-3-yl)(4-(3-(dibutylamino)propoxy)phenyl)methanone5
To a solution of compound 4 (2.0 g, 5.90 mmol) in DMF (12 mL) was addedN-butyl-N-(3-chloropropyl)butan-1-amine (1.35 mL, 5.90 mmol), potassium iodide(98 mg, 0.59 mmol) and K2CO3 (0.82 g, 5.90 mmol).The mixture was stirred at 65°C for 5 hours. The reaction mixture was added into water (10 mL) and then extracted with EA (320 mL). The organic phase was washed with brine (50 ml), then dried over Na2SO4,filtered and concentrated to give the crude product, which was purified byflash chromatography [PE/EA=1:1] to give 5 (2.17g, 72.4%) as a yellowoil. 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 2.2 Hz,1H), 8.21 - 8.18 (m, 1H), 7.83 - 7.78 (m, 2H), 7.54 (d, J = 9.0 Hz, 1H), 6.96(d, J = 8.9 Hz, 2H), 4.11 (t, J = 6.2 Hz, 2H), 2.90 (t, J = 7.6 Hz, 2H), 2.61(t, J = 7.0 Hz, 2H), 2.45 - 2.40 (m, 4H), 1.98 - 1.90 (m, 2H), 1.78 - 1.70 (m,2H), 1.43 - 1.38 (m, 4H), 1.32 - 1.22 (m, 6H), 0.91 - 0.84 (m, 9H). |
| 72% |
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 65℃; for 5h; |
1 Synthesis of compound 5:
In the DMF (12mL) solution of compound 4 (2.0g, 5.90mmol) was added n-butyl-N-(3-chloropropyl)butan-1-amine (1.35mL, 5.90mmol), potassium iodide (98mg, 0.59mmol) ) And K2CO3 (0.82g, 5.90mmol). The mixture was stirred at 65°C for 5 hours. The reaction mixture was extracted with ethyl acetate. The organic phase was washed with water (50ml), dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography [petroleum ether/ethyl acetate=1:1] to obtain compound 5 (2.17g, 72.0%) , It is a yellow oil. |
|
Stage #1: 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran With potassium carbonate In butanone at 20℃; for 0.5h;
Stage #2: dibutyl-(3-chloro-propyl)-amine In butanone at 78 - 82℃; for 12h; |
1
EXAMPLE 1[0099] Preparation of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5- nitrobenzofuran, compound of formula IIITo a solution of lOOg of 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran in l OOOmL of methyl ethyl ketone was added 48.8g of potassium carbonate at about room temperature. The reaction mass was stirred for about 30min and 69.7g of l -chloro-3-di-n- butylaminopropane was added to it. The reaction mass was heated to reflux (about 78°C to about 82°C) and stirred at about the same temperature for about 12h. The reaction mass was then cooled to about room temperature and the insoluble solid was filtered and washed with lOOmL of methyl ethyl ketone. The filtrate and washings were collected together and concentrated under vacuum at about temperature below 50°C to obtain pale brown thick oil which was degassed under vacuum at about temperature below 50°C for about 30min. The oil was then dissolved in 700mL of ethyl acetate at about room temperature and 200mL of water was added to it under stirring. The two layers were separated and the organic layer was washed twice, each with 200mL of water. The organic layer was dried over sodium sulphate and concentrated under vacuum at about temperature below 50°C to give pale brown thick oil which was degassed under vacuum at about temperature below 50°C for about 30min. Yield: 160gPurity (HPLC): 98.71% |
|
With sodium hydroxide In dichloromethane; water at 20℃; for 48h; |
1
To a suspension of 10 g (0.03 mole) of 2-n-butyl-3-(4-hydroxybenzoyl)-5- nitrobenzofuran in 50 ml dichloromethane was added 60 ml of 15% aqueous sodium hydroxide solution, 7.2 g (0.04 mole) of l-chloro-3-(di-«-butylamino)propane and 0.2 g (2.0% w/w) of Adogen 464. The mixture was stirred at r.t. for 24 hours, an additional 0.1 g (1% w/w) of Adogen 464 was added and the stirring continued for further 24 hours. The mixture was settled and the product enriched organic layer was separated. The aqueous layer was extracted once with methylene chloride, the combined organic layers were washed with DM water and concentrated under vacuum to obtain residue of 2-«-butyl-3-[4-[3-di-«-butylamino)propoxy]benzoyl]-5- nitrobenzofuran (6) as a gummy mass. |
|
With potassium carbonate In butanone at 20 - 81℃; Reflux; |
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. |
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