Itopride hydrochloride

Crystalline SolidItopride, a gastroprokinetic benzamide derivative was launched in Japan for the relief of gastrointestinal symptoms in patients with chronic gastritis. ltopride is a dopamine D2-receptor antagonist that stimulates acetylcholine (Ach) release on the postganglionic cholinergic neurons to cause Ach accumulation at muscarinic receptors and, therefore, enhances Ach-induced gastric contractions.

The equivalent wet product corresponding to 16 kg of dry itopride coming from Example 4 and 56 kg of sec-butanol are charged into a reactor and heated to 50- 55 °C until solution. 4.8 kg of 37percent hydrochloric acid are added dropwise, the pH is checked to ensure it is <2.0, and the mixture is stirred at 50-55 °C for at least 30 minutes; it is cooled to 15-25 °C and it is then centrifuged, the precipitate is washed with 16.0 kg of sec-butanol. The product is then dried at 70-80°C. 16.5 kg of itopride hydrochloride with HPLC purity higher than 99.8percent are obtained. Reaction yield compared to itopride: 93.7percent.50 g of etorilide was added to 150 ml of ethanol, cooled to 0 ° under ice bath, Into the dry hydrogen chloride gas, a white crystal precipitation, filtration, washing, Dried to give 51.8 g of white crystals in 93percent yield.Add 80g Itopride 300ml ethanol was heated to dissolve, then add 35percent HCl / ethanol solution 40g, white crystals precipitated, cooled to -5 deg.] C, filtered, washed, and dried to give a white itopride hydrochloride crystals 80.0g, yield 90percent, HPLC purity was 99.9percent.IPA(240 ml) is charged into 500 ml 3neck RBF equipped with mechanical stirring , water condenser, calcium chloride guard tube and thermowel mounted on an oil bath. Itopride (40 gms) is charged. The reaction mass is heated to dissolve the material. Activated charcoal (4 gms) is added and the reaction mass is refluxed for 30 minutes. The hot solution (~ 40 to 50Example-8 448 g of the resulting amide product and 2-chloro-N, N-dimethylethylamine 260 g were placed in a dry reaction flask containing 1300 ml of DMF.Then add 2.6g of potassium iodide, stir and heat to 130-135°C, reaction for 8-10h, the reaction is over, and the solvent is evaporated under reduced pressure.Rear, 1200 ml of anhydrous ethanol was added to the bottle, stirred and dissolved, 8 ml of 30percent hydrochloric acid was added, and a small amount of activated carbon was used for decolorization.filter. The mother liquor was frozen, crystallized, filtered and dried to obtain 538 g of itopride hydrochloride hydrochloride with a purity of 99.5percent. Yield 87percent.Step third, 16.3g 3, 4-dimethoxybenzonitrile and 19.5g 4-(2-Dimethylaminoethoxy) benzyl alcohol dissolved in 50 ml of toluene, added the 15 g of trifluoromethanesulfonic acid and reaction is carried out at 80 ° C for 8 hours, after completion of the reaction, the reaction solution cooled at 0 ° C under ice bath, and then adjust the reaction solution to get neutral with sodium bicarbonate solution, and then added 20ml of toluene, for liquid separation, the organic layer is dried over anhydrous sodium sulfate, filter and add pressure for recovering toluene, when crude dichloromethane is re-crystallized then obtained the 32.9g of Itopride, yield is 92percent.Step forth, 50g Itopride added into the 150 ml of ethanol, under the ice bath cooling at 0 ° C, pass through the dry hydrogen chloride gas, then there is white crystal precipitation happing, filter, washed and dried then obtained 51.8g white crystals, yield is 93percent.2 - (dimethylamino) ethanol 9.20 ml (0.09 mol)and NaOH 7.26 g (0.18 mol) were dissolved at the toluene 300ml and it mixedreflux for 30 minutes. 4- ((3, 4-dimethoxybenzamido) methyl)phenylmethanesulfonate 30.51 g (0.08 mol) was injected in this mixture and it mixedreflux for 30 1 hour the minute. This mixture was cooled at the roomtemperature (20~25) and it was concentrated under reduced pressure afterthe filtering. The dichloromethane 600ml and purified water 300ml were injectedin this mixture and it separated layer. The dichloromethanelayer was separated and 1N HCl aqueous solution 450ml was injected and itseparated layer. The dichloromethane 600ml and 3N NaOH aqueous solution 225mlwere injected and 1N HCl aqueous solution liquid was layer separated. It wasthe organic layer concentrated under reduced pressure and it crystallized usingthe acetic ether and hexane and 23.94 g (80.0percent) the intended compound wasobtained.

Anti-Spasmodics

Molecular Weight:394.9
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:9
Exact Mass:394.1659350
Monoisotopic Mass:394.1659350
Topological Polar Surface Area:60
Heavy Atom Count:27
Complexity:411
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes