Rebamipide

Rebamipide is an inducer of endogenous prostaglandin and a oxygen-derived free radical scavenger.Target: OthersRebamipide is the first anti-gastric ulcer and antigastritis drug that not only increases endogenous prostaglandin in gastric mucosa but also scavenges oxygen-derived free radicals and inhibits their production. The inhibitory effect of rebamipide on lipid peroxidation induced by a free radical initiator was also demonstrated by the in vitro system using rat gastric mucosal homo

2-[[(4-chlorophenyl)-oxomethyl]amino]-3-(2-oxo-1H-quinolin-4-yl)propanoic acid is a secondary carboxamide.|Rebamipide has been investigated for the treatment of Stomach Ulcer, Keratoconjunctivitis Sicca, and Gastric Adenoma and Early Gastric Cancer.

In a high pressure reactor, 220 g (1 mol) was added to 3000 mL of toluene.Further, 175 g (1 mol) of p-chlorobenzoyl chloride and 10 g of catalyst palladium calcium carbonate were added, and the gas in the reaction vessel was replaced with nitrogen three times, and ammonia gas was introduced thereto, so that the pressure in the autoclave reached 0.05 Mpa, and the reaction was carried out at 90 ° C for 2 h.TLC monitors the reaction of the raw materials completely, and the reaction solution is filtered while hot. The filtrate is stirred at 0 ° C to form a large amount of solids. After suction filtration, the filter cake is added to diethyl ether.1N diluted hydrochloric acid solution was slowly added dropwise under stirring, the solid in the reaction flask was gradually dissolved completely, and dilute hydrochloric acid was continuously added dropwise, and a white solid appeared again.Adjusting the pH of the reaction solution to 3 to 4, filtering the reaction solution, drying the filter cake to obtain 330 mg of rebamipide, and the yield is 89percent;To 10 g of 2-amino-3~ [2 (IH) -quinolon-4-yl]propionic acid monohydrochloride dihydrate (the compound of the formula (5), -purity by HPLC analysis: 98.56percent) containing 2- amino-3- [6-bromo-2 (IH) -quinolon-4-yl]propionic acid (the compound of the formula (11), percentage by HPLC analysis: 1.09percent) as an impurity, 200 mL of water and 10 mL of 25 percent aqueous sodium hydroxide were added, and the mixture was dissolved. To the solution, 2 g of 50percent water-contained Raney nickel catalyst was added and stirred under 2 atm of hydrogen for 2 hours at room temperature, and then the catalyst was filtrated off. After 2 hour-stirring, a HPLC analysis indicated that the amount of 2-amino~3~ [6-bromo- 2 (IH) -quinolon-4-yl]propionic acid (the compound of the formula (H)) was 0.01percent and the amount of 2-amino~3- [2 (IH) - quinolon-4-yl]propionic acid (the compound of the formula (5) ) was 99.73percent. After adding 10 mL of 25percent aqueous solution of sodium hydroxide to the catalyst-removed solution, a solution of 10 g of 4-chlorobenzoyl chloride in 50 mL of acetone was added thereto dropwise under ice temperature. After the addition, the reaction mixture was allowed to be acidified with hydrochloric acid and the resultant crystal was filtrated. The crystal was washed with water and acetone, and air-dried at about 8O2-amino-3-(2-oxo-1, 2-dihydroquinolin-4-yl)propanoic acid 5 (20.0 g, 86.1 mmol) was taken in H20 (250 mL) in a 500 mL round bottom flask under N2 and cooled it to OoC. To it were sequentially added NaOH (17.2 g, 430.5 mmol) in H20 (50 mL) and 4- chlorobenzoyl chloride 6 (18.1 g, 103.2 mmol). The reaction mixture was then stirred at rt and monitored by TLC analysis (MeOH-DCM, 20percent) until completion. DIVIF (30 mL) was added to the reaction mixture and the pH was adjusted to 4 using 6N HC1. A white solid was precipited out which upon filtration afforded the desired product 7. It was then triturated with Et20 (3 x 50 mL) and used in the next step without further purification.Yield: (19.0 g, 59percent). ‘HNMR(400IVIHz, DMSO-d6): ö 11.64 (s, 1H), 8.91 (d, J = 7.6 Hz, 1H), 7.95 (s, 1H), 7.82 (d, J = 8.0 Hz, 3H), 7.48-7.55 (m, 3H), 7.31 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 6.44 (s, 1H), 4.71-4.75 (m, 1H), 3.47-3.50 (m, 1H), 3.23 (m, 1H).3) the amount of sodium hydroxide dissolved in a certain amount of water, Stirring until completely dissolved sodium hydroxide 5percent sodium hydroxide solution, Then, a mixed solution of 2 volumes of sodium hydroxide solution and ethanol was added thereto, And then 10g obtained in step 2)2- (4-Chlorobenzamido) -2-ethoxycarbonyl-3- [2 (1H) -quinuclidin-4-yl]Ethyl propionateAdded to the mixture, Heated to reflux hydrolysis until the disappearance of raw materials, ethanol concentration, The concentrate was added to 1N hydrochloric acid, stirred, allowed to stand, filtered, Get crude2- (4-Chlorobenzamido) -3-[2 (1H) -quinolone-4-yl] propionic acid, Then recrystallized with a mixed solvent of dimethylformamide and water, 2- (4-chlorobenzamido) -3- [2 (1H) -quinolone-4-yl] propionic acid was obtained, That isRebamipide 7.15g (yield: 94percent).

1. Shows antiulcer activity in rats
2. Antiulcer, antioxidant
3. An inducer of endogenous prostaglandin and a oxygen-derived free radical scavenger.

Molecular Weight:370.8
XLogP3:2.4
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:5
Exact Mass:370.0720347
Monoisotopic Mass:370.0720347
Topological Polar Surface Area:95.5
Heavy Atom Count:26
Complexity:598
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes