CS236209B1 - Method of 2-chlor-5-(1-hydroxy-3-oxo-1-isoindolinyl)benzenesulphonamide's cleaning - Google Patents

Abstract

Purification Method 2-Chloro-5- (1-hydroxy-3-oxo-1-isoindolinyl) benzenesulfonamide formula I, known under the generic name chlortalidone, allows reaction to be obtained from the crude product 3-chloro-3- (4-chloro-3-chlorosulfonylphenyl) -phthalide with ammonia practically a chromatographically uniform substance, wherein solvents can be easily regenerated used for crystallization. For crystallization using an anhydrous mixture of methanol and toluene, composition azeotropic distillate (methanol ratio) -toluene 69 wt. : 31 wt.%, Temperature boiling at normal pressure of 63.6 ° C). This mixture can be regenerated, associated with own crystallization technology, use it for another crystallization batch.

Description

The invention relates to a process for the purification of 2-chloro-5- (1-hydroxy-3-oxo-lisoindolinyl) benzenesulfonamide of formula I,

known under the generic name chlalidalidone, which is used in human medicine as a diuretic 8 by a hypertensive effect.

The hitherto known processes for the preparation of the orthortalidone of formula I are based on the action of ammonia on 3-chloro-3- (4-chloro-3-chlorosulfonylphenyl) phthalide of formula II,

both in the aquatic environment (W. Graf et al., Helv. Chim. Acta 42, 1085, 1959, U.S. Pat. Nos. 95774, 107580 and 107581) and in the anhydrous environment (U.S. Pat. 190699 and MS and No. 220694). The crude product is then purified by crystallization from aqueous ethanol, optionally with the addition of sodium bicarbonate (W. Graf et al. Helv. Chim. Acta 42, 1085, 1959 and U.S. Pat. Nos. 95774, 107580 and 107581), and ~ various anhydrous solvents and mixtures thereof, in particular aliphatic alcohols having 1 to 3 carbon atoms;

236,209 mixtures thereof with 6 to 8 aromatic hydrocarbons having an aromatic hydrocarbon content

or 8 chlorinated hydrocarbons of 1 to 2 carbon atoms 9 * 4 ·

No. 190699), wherein a mixture of 1: 1 to 1: 1.5 methanolithium and tallow is preferred, or in a mixture of two polar solvents, one of which is an aliphatic alcohol of 1 to 3 carbon atoms and the other is an ester acetic acids and aliphatic alcohols having 1 to 4 carbon atoms (cf. PV 7059-82), preferably in a mixture of methanol and ethyl acetate ·

A disadvantage of crystallization from an aqueous medium is that, in the presence of water, the impurities contained in the crude product precipitate in almost unchanged amounts. Crystallization from an anhydrous medium then yields a much higher particle size, practically chromatographically uniform. However, the industrial implementation of these relatively advantageous cleaning methods on a larger scale is hampered by the difficult and expensive energy and investment recovery of the solvents used.

Surprisingly, it has now been found that these drawbacks in the possibilities of easy solvent recovery in the previously known crystallization processes can be largely eliminated by using an anhydrous mixture of methanol and toluene corresponding to the composition of the azeotropic distillate according to the invention. toluene used in an anhydrous mixture of 65 to 70% by weight of methanol and 30 to 35% by weight of toluene. This mixture boils under normal pressure at 63.8 ° C.

Compared with the prior art, the novel and superior effect of the invention is that, using the said ratio of solvents, the mixture easily and regenerates the loss base and its preferred boiling point ensures gentle crystallization conditions. Advantageously, solvent recovery can be combined with the crystallization technology itself, resulting in a virtually waste-free technology. The method according to the invention saves about 30% of the energy and investment costs despite the favorable environmental impact. Combination of inadequate solvent recovery and proprietary technology creates a closed production cycle with minimal use of flammable substances.

The following example illustrates the process according to the invention but is not limited thereto.

Example:

In 500 liters of a mixture of 69% by weight of methanol and 31% by weight of toluene and at a temperature of 50 ° C, 34 kg of crude chlortalidone was added with the addition of 4 kg of activated carbon. At this temperature and filtration, the activated carbon is separated and washed with 30 L of azeotropic methanol-toluene mixture.

236 · 209

The filtrate is concentrated to a volume of about 100 liters, whereby the product is precipitated while regenerating azeotropic venison. Toluene (100 L) was added and distillation continued until methanol was present in the vapor, i.e. up to a vapor temperature of about 70 ° C. After cooling slightly, 40 l of azeotropic distillate are added to the crystallized product to redissolve the undesirable impurities which are soluble in the polar solvent. After cooling, the product was filtered and washed with an azeotropic mixture of methanol and toluene. After drying, 29 kg of chromatographically practically uniform chlorothalidone, which is 85.3% th, is obtained. An additional 2 to 3 percent of the product can be recovered from the mother liquor recovery, yielding additional azeotropic methanol-toluene distillate and toluene alone. The solvents thus obtained can be used for further processing without further treatment.

Claims (1)

SUBJECT OF THE INVENTION 236 209 A process for purifying 2-chloro-5- (1-hydroxy-3-oxo-1-isoindolinyl) benzenesulfonamide of formula I by crystallization, characterized in that the crystallization is carried out in an anhydrous mixture of 65 to 70% by weight of methanol and 30 to 70%. 35 wt.% Toluene.