| 94.87% |
With sulfuric acid for 18h; Reflux; |
|
| 93.17% |
With sulfuric acid at 80℃; |
Esterification of 2-(4-Isobutyl-phenyl)-propionic acid (Ibuprophen)gives rise ibuprofen ethyl ester by following the generalprocedure, after minor modification. Ibuprofen (20 g)was dissolvedin excess amount of ethanol followed by addition of some drops ofsulfuric acid. The reaction mixture was refluxed over night at 80 Cand was kept for overnight. Excess amount of solvent was removedunder rotary evaporator and residue neutralized with 10% sodiumhydrogen carbonate. The light orange color ester was extractedtwice with chloroform and kept in vacuum desiccator over anhydrouscalcium chloride (yield 21.15 g, 93.17%). 1H NMR in CDCl3 (d):7.23 (d, J 8.2 Hz, 2H), 7.11 (d, J 8.2 Hz, 2H), 4.25-3.98 (m, 2H),3.70 (d, J 6.9 Hz, 1H), 2.47 (d, J 6.9 Hz, 2H),1.87 (t, J 6.6 Hz, 1H),1.50 (dd, J 7.3,1.4 Hz, 3H),1.22 (td, J 7.1,1.4 Hz, 3H),1.00-0.81 (m,7H). 13C NMR (CDCl3) d 174.75, 140.46, 138.05, 129.52, 127.24, 77.29,60.65, 45.21, 30.71-29.24, 22.65, 18.71, 14.20, 1.15. |
| 87% |
With sulfuric acid for 22h; Heating; |
|
| 80% |
With boron trifluoride diethyl ether complex Reflux; |
|
| 80% |
With sulfuric acid for 6h; Reflux; |
3.2.1. Procedure for the Synthesis of Compound 2 and 7
General procedure: Ibuprofen (1) and flurbiprofen (6) (2 mmol), in two separatereactions, were dissolved in ethanol (50 mL) followedby addition of sulphuric acid (1 mL) and refluxed for 6 h.The reaction progress was monitored by using pre-coatedsilica gel TLC plates under UV light using chloroform:methanol (9:1) as an eluent. The obtained esters (2, 7) werecollected from ethanol by rotary evaporation and recrystallized.A mixture of compound (2, 7) (0.011 mol) and hydrazinehydrate (0.02 mol) in ethanol (50 mL) was heated for 8h under reflux to get corresponding hydrazides (3, 8)(Scheme 1). This time, ethyl acetate and petroleum ether(1:1) was used as an eluent. The reaction progress was monitoredusing TLC plates. The solid compounds were obtainedby recrystallization from methanol. |
| 80% |
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 3h; |
|
|
With thionyl chloride for 2h; Heating; |
|
|
With sulfuric acid Reflux; |
|
|
Acidic conditions; |
|
|
With sulfuric acid |
|
|
With sulfuric acid at 0℃; for 7.08333h; Reflux; Inert atmosphere; |
|
|
With sulfuric acid |
|
|
With sulfuric acid In water monomer; toluene Reflux; |
2 General method for the chemical synthesis of ibuprofen esters (1-5)
General procedure: To a solution of 0.1mol of the racemic acid in 100ml toluene, 0.5mol of corresponding alcohol (methanol, ethanol, propanol, n-butanol and iso-butanol) was added followed by few drops of sulphuric acid (98%) [41]. The mixture was stirred under reflux over night and the solvent was evaporated under vacuum and the residue was neutralized with 10% sodium hydrogen carbonate. The ester was extracted twice with 50ml chloroform and then dried over anhydrous sodium sulphate. After filtration, the solvent was evaporated under vacuum to afford the racemic ibuprofen esters. |
|
at 80℃; Acidic conditions; |
|
|
With sulfuric acid for 6h; Reflux; |
Ethyl 2-[4-(2-methylpropyl)phenyl]propanoate (2)
A solution of Ibuprofen 1 (2 g, 9.6 mmol) and 0.5 mL concentrated sulfuric acid in ethanol (20 mL) was refluxed for 6 h. The solvent was removed under reduced pressure and the residue was taken up in CHCl3 (30 mL). The solution was extracted with saturated aqueous NaHCO3 solution (2615 mL)and water. The organic layer was dried over anhydrous Na2SO4, filtered and solvent was evaporated under reduced pressure, affording 2 (2.1 g, 95%) as a clear oil. |
|
With sulfuric acid |
|
|
With sulfuric acid Heating; |
|
|
With sulfuric acid at 65℃; |
4.3. Synthesis of ibuprofen, naproxen and ketoprofen ethyl ester
General procedure: The reactant (2.5 g of racemic ibuprofen, naproxen or ketoprofen)was mixed with EtOH (100 mL) ethanol and sulfuric acid(1 mL). The mixture was stirred at 65 C overnight. Then calcium carbonate (2.5 g) was then added and the mixture was stirred again for 30 min. The precipitate was removed by filtration and the filtrate was dried under reduced pressure. The reaction was followedby Thin Layer Chromatography analysis (TLC) using hexane/isopropanol (99/1 v/v) as the eluent. 1H NMR spectra were recorded on a Bruker AC-200.1 (200.1 MHz) spectrometer and confirmedthe purity of both esters. |
|
Heating; Acidic conditions; |
1
Ibuprofen (carboxylic acid) was esterified using alcohol (ethanol). Ibuprofen ethanoate (insoluble) was reacted with purified chitosan oligosaccharide with weight average molecular weight <3000 in an aqueous solution to form a homogenous solution containing ibuprofen-chitosan conjugate, Fig 1. Slight acidic medium of hydrochloric acid may enhance the conjugation process and increase solubility of ibuprofen chitosan conjugate in aqueous solution, Fig 2. |
|
Acidic conditions; Heating; |
1
Chitosan, a natural product obtained mainly from cramps and fish, has a high adsorption affinity towards fatty substances that may attach to its structure during the process of preparation. Thus, purification of chitosan needs the use of organic solvents such as n-hexane and ethanol to get rid of fatty materials or other impurities. These impurities may deactivate the primary amine groups (active sites) present in chitosan. Purification from these impurities may increase the ability for binding to drug molecules. Ibuprofen (carboxylic acid) was esterified using alcohol (ethanol). Ibuprofen ethanoate (insoluble) was reacted with purified chitosan in an aqueous solution, Fig 1. Slight acidic medium of hydrochloric acid was added to enhance the conjugation process and to solubilize chitosan polymer in aqueous solution. Ibuprofen ethanaote was then reacted with chitosan and a homogenous mixture of ibuprofen-chitosan conjugate was formed. |
|
Acidic conditions; Heating; |
1
Chitosan, a natural product obtained mainly from cramps and fish, has a high adsorption affinity towards fatty substances that may attach to its structure during the process of preparation. Thus, purification of chitosan needs the use of organic solvents such as n-hexane and ethanol to get rid of fatty materials or other impurities. These impurities may deactivate the primary amine groups (active sites) present in chitosan. Purification from these impurities may increase the ability for binding to drug molecules. Ibuprofen (carboxylic acid) was esterified using alcohol (ethanol). Ibuprofen ethanoate (insoluble) was reacted with purified chitosan in an aqueous solution, Fig 1. Slight acidic medium of hydrochloric acid was added to enhance the conjugation process and to solubilize chitosan polymer in aqueous solution. Ibuprofen ethanaote was then reacted with chitosan and a homogenous mixture of ibuprofen-chitosan conjugate was formed. |
|
With thionyl chloride for 3h; Reflux; |
|
|
Stage #1: ibuprofen With dicyclohexyl-carbodiimide In dichloromethane at 0℃;
Stage #2: ethanol Reflux; |
3.1.1. General Synthesis of Compounds b, d, f, h, j and l
General procedure: To a cooled (0 C) solution of 1 mmol of a, c, e, g, i, or k in dry dichloromethane,1.1 mmol N,N-dicyclohexylcarbodiimide was added and the reaction mixture was stirredat 0 C for 20-90 min. The mixture was then brought to room temperature and 10 mmolabsolute ethanol was added dropwise. After the addition, the reaction mixture washeated at reflux for 4-24 h, after which it was diluted with dichloromethane, washed withwater, NaHCO3 5% solution and brine. The organic phase was dried over anhydroussodium sulfate and evaporated to dryness. The crude product was purified by flashchromatography to give an ethyl ester of a, c, e, g, i, and k, respectively. Subsequently,1 mmol of the respective ethyl ester was dissolved in dry diethylether and was addeddropwise to a suspension of 1.2 mmol lithium aluminum hydride in dry diethylether, underArgon. The reaction mixture was stirred at room temperature for 1-2 h and then dilutedwith ethyl acetate and ltered. The precipitate was thoroughly washed with diethylether.The filtrate was diluted with diethylether and washed with H2SO4 15% solution, water,NaHCO3 5% solution and water, dried over anhydrous sodium sulfate and evaporated todryness. The crude product was purified by flash chromatography to give pure b, d, f, h, j,and l.2-(4-Isobutylphenyl)propanoic acid (b) Total yield: 62%, colorless oil. 1H-NMR (CDCl3,200 MHz), (ppm): 0.90 (d, J = 6.8 Hz, 6Hz, -CH(CH3)2), 1.26 (d, J = 7.2 Hz, 3H, -CH(CH3)),1.36 (brs, 1H, -OH), 1.85 (sep, J = 6.4 Hz, 1H, -CH(CH3)2), 2.45 (d, J = 7.2 Hz, 2H, -CH-CH2-),2.93 (sex, J = 6.8 Hz, 1H, -CH(CH3)), 3.68 (d, J = 4.4 Hz, 2H, -CH2OH), 7.11-7.15 (4H,aromatic). |
|
With sulfuric acid for 18h; Reflux; |
4.1. Synthesis of ethyl 2-(4-isobutylphenyl) propanoate[2] and 2-(4-isobutyl phenyl) prapano-hydrazide [3]
A few drops of sulphuric acid were added into 10 ml ofethanolic ibuprofen solution (0.02 mol) (1), and refluxed fora period of 18 hrs. The mixture (2) was allowed to cool atroom temperature and then an excess of 0.06 mol hydrazinehydrate was added to it. The mixture was further refluxed for a period of 5 hrs. The product was concentrated under reducedpressure and cooled. The solid compound (3) waswashed with cold water and recrystallized from hot water. |
|
With sulfuric acid at 60℃; for 5h; |
|
|
With sulfuric acid at 100℃; for 4h; |
4.1.1 Synthesis of Ibuprofen-, quinoxalinyl- and pyridinyl-based azomenthine derivatives 4, 9, 13
General procedure: To a solution of respective acids 1, 6 and 10 (1mmol) in absolute ethanol (15mL) was added catalytic amount of concentrated sulphuric acid (4-6 drops) at 100°C for 6-12h. After completion, as monitored by TLC (10% Petroleum ether), excess of ethanol was removed by evaporation, the resulting mixture was dissolved in water (10mL) and it was extracted using diethyl ether (3X 20mL). The ether layer was dried over Na2SO4 and evaporated under reduced pressure to give the crude esters. The ester derivatives 2, 7, 11 were then subjected to reaction with hydrazine-hydrate (99%) in ethanol (10mL) and were refluxed for 3-8h. The completion of reaction was monitored by TLC (25% Petroleum ether). The excess ethanol was removed by evaporation and to the resulting residue crushed ice was added to precipitate out the crude hydrazide 3, 8 and 12. The hydrazides were filtered dried over vacuum and were used further for the preparation of azomethine derivatives (Schiff bases) 4a-k, 9a-f and 13a-h. The preparation of hydrazide derivatives was carried out by reacting 1:1 equivalent of hydrazides (1mmol) and substituted aromatic aldehydes (1mmol) in ethanol (10mL) at 25°C for 2-6h. the product was precipitated out by pouring in ice. The solid obtained was filtered, dried, and recrystallised from ethanol. |
|
With sulfuric acid In water monomer for 15h; Reflux; |
|
|
With sulfuric acid at 100℃; for 4h; |
4.1.1 Synthesis of Ibuprofen-, quinoxalinyl- and pyridinyl-based azomenthine derivatives 4, 9, 13
General procedure: To a solution of respective acids 1, 6 and 10 (1mmol) in absolute ethanol (15mL) was added catalytic amount of concentrated sulphuric acid (4-6 drops) at 100°C for 6-12h. After completion, as monitored by TLC (10% Petroleum ether), excess of ethanol was removed by evaporation, the resulting mixture was dissolved in water (10mL) and it was extracted using diethyl ether (3X 20mL). The ether layer was dried over Na2SO4 and evaporated under reduced pressure to give the crude esters. The ester derivatives 2, 7, 11 were then subjected to reaction with hydrazine-hydrate (99%) in ethanol (10mL) and were refluxed for 3-8h. The completion of reaction was monitored by TLC (25% Petroleum ether). The excess ethanol was removed by evaporation and to the resulting residue crushed ice was added to precipitate out the crude hydrazide 3, 8 and 12. The hydrazides were filtered dried over vacuum and were used further for the preparation of azomethine derivatives (Schiff bases) 4a-k, 9a-f and 13a-h. The preparation of hydrazide derivatives was carried out by reacting 1:1 equivalent of hydrazides (1mmol) and substituted aromatic aldehydes (1mmol) in ethanol (10mL) at 25°C for 2-6h. the product was precipitated out by pouring in ice. The solid obtained was filtered, dried, and recrystallised from ethanol. |
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