Zepastine

Originator

Zepastine,ZYF Pharm Chemical

Manufacturing Process

5,11-Dihydro-11-methyl-5,10,10-trioxodibenzo[c,f][1,2]thiazepine 16 g is suspended at 300 ml of methanol and treated with of 3 g of sodium borohydride. The reaction mixture is kept at room temperature overnight, heated to dissolve precipitated material, acidified with 10% acetic acid and allowed to cool. The crystalline product is collected on a filter, washed with water and recrystallized from isopropanol, MP: 138°C.
5-Chloro-5,11-dihydro-10,10-dioxo-11-methyldibenzo[c,f][1,2]thiazepine:
A portion of the above product, 5 g, is dissolved in 50 ml of benzene and the solution is saturated with hydrogen chloride. External cooling is supplied in order to maintain the temperature near room temperature. The product crystallizes from the solution during this process. The mixture is kept at room temperature for one hour and the product is collected on a filter, yield 5 g; MP: 224-225°C. This material is purified by recrystallization from toluene, MP: 230°C.
3-(5,11-Dihydro-10,10-dioxo-11-methyldibenzo[c,f][1,2]thiazepin-5- yloxy)tropane and the hydrogen maleate salt thereof. (This name was given by the authors of U. S. Patent No 3 700 633. It corresponds to endo-6,11- dihydro-6-methyl-11-[(8-methyl-6-azabicyclo[3.2.1]oct-3-yl)oxy]dibenzo[c,f] [1,2]thiazepine 5,5-dioxide and 6,11-dihydro-6-methyl-11-(8-methyl-8- azabicyclo[3.2.1]octan-3α-yloxy)dibenzo[cf][1,2]thiazepin-5,5-dioxide).
The above chloro intermediate product, 3 g and 3.5 g of tropine with 25 ml of toluene as reaction medium are refluxed for 3 hrs. The reaction mixture is then concentrated in a vacuum until the solvent and other volatile materials are removed. The residue is treated with dilute aqueous hydrochloric acid, and ether. The aqueous layer is separated and neutralized with aqueous sodium hydroxide. Insoluble material, which thereupon separates is dissolved in ether, and the ether solution separated. It is washed several times with water, dried and evaporated, leaving the free base form of the desired product (zepastine) which crystallizes on standing, MP: 157°C. It is recrystallized from ethyl acetate, MP: 162°C.
The base is converted to the hydrogen maleate salt by treatment in ethyl acetate solution with one molecular proportion of maleic acid. This material is recrystallized from ethanol, MP: 215°C.

Therapeutic Function

Antihistaminicá Anticholinergic