CS241932B1 - Process for preparing substituted benzisothiazolin-3-one-1,1-dioxide - Google Patents

Abstract

A method for producing benzisothiazolin-3-one-1,1-dioxide derivatives of the general formula I by reacting the sodium or potassium salt of benzisothiazolin-3-one-1,1-dioxide with alkaline agents of the general formula III in an organic solvent environment, which consists in the reaction being carried out in the presence of 2 to 10% by mole of quaternary ammonium salts or polyethers at a temperature of 50 to 150 8c, with the molar ratio of the reactants of the formula II and the general formula III being 1.0 : 1.0 to 1.5, after which the reaction mixture is evaporated to dryness after filtration and the crude product obtained is purified by crystallization. The method is useful for the industrial production of amines, it can be applied in the production of agrochemicals and in the pharmaceutical industry in the production of intermediates of drugs based on oxicams.

Description

The invention relates to a process for the production of substituted benzisothiazolin-3-one-1,1-dioxides of the general formula I, where R represents an alkyl containing 1 to 8 carbon atoms, or a phenylalkyl containing 1 to 3 carbon atoms in the alkyl part, or a group R^COC^, where R^ is an alkyl containing 1 to 2 carbon atoms or phenyl.

The compounds of general formula I are important intermediates in the production of amines /see e.g. Methoden der organischen Chemie /Houben-Weyl/, vol. XI/1, p. 103, G. Thieme Verlag, Stuttgart 1957/, fungicides /see Arzneimit.-Forsch. 14, 1301 /1984// and are used as inhibitors of human leukocyte elastase /see J.Biol. Chem. 256, 11603 /1981//. Recently, they have found application as intermediates in the production of oxicam-based drugs, which are used in human medicine as antirheumatic drugs /see e.g. Chronicle of Drug Discovery, J.wiley, New York 1981, Clinics in Rheumatic Diseases Antirheumatic Drugs II /Ed. Huskinsson/, 6,

585 /1980//.

So far, these compounds of general formula I have been prepared by treating the sodium salt of benzisothiazolin-3-one-1,1-dioxide of formula II with an alkylating agent of general formula III

R-X (III) where R has the meaning given above and X represents halogen, preferably chlorine or bromine or an OSO 3 OR 4 group where R 4 represents methyl or ethyl.

This method /Chem. Ber. 29, 530, 1048 /1896/, 30 /1265 /1897/, 55 3535 /1922// is used with minimal changes to this day /J.Ořg.Chem. 21, 583 /1956/, J.Pharm.Soc.Japan 72, 270 /1952/, J.Chem.Soc. /1957/, 492, J.Ořg.Chem. 30, 2241 /1965/. The procedure provides relatively low yields of the product, requires long reaction times

241 932 time and high reaction temperatures; it is not economically advantageous.

Some improvement in yields is achieved by procedures (see e.g. J.Amer. Chem.Soc. 77, 5628 /1955//, J.Org.Ghem. 20, 1425 /1955//, J.Pharm. Soc.Japan 75, 153 /1955//), which use dimethylformamide as a solvent at a temperature of 100 to 150 °C. The disadvantage of this procedure is the use of relatively expensive dimethylformamide as a solvent. The products are usually isolated after diluting the reaction mixture with water, and the removal of dimethylformamide from wastewater is technologically complex and economically expensive.

These known processes are followed by the process according to the invention, which brings substantial simplification and economic advantages to the production of compounds of the general formula I. The reaction of the sodium or potassium salt of the compound of the formula II with the alkylating agent of the general formula III, where R has the above-mentioned meaning, is carried out in an organic solvent environment according to the invention in the presence of quaternary ammonium salts or polyethers. The molar ratio of the reacting components of the formula II and the general formula III is 1.0:1.0 to 1.5, and the reaction is carried out at a temperature of 50 to 150 °C, preferably at 70 to 110 °C. The presence of 2 to 10 molar % of quaternary salts, polyethers increases the reaction rate substantially and shortens the reaction time significantly. As quaternary salts, hexadecyltrimethylammonium bromide, trioctylmethylammonium chloride, benzyldodecyldimethylammonium bromide are preferably used, as polyethers, cyclic polyethers are preferably used, for example 18-crown-6, dibenzo-18-crown-6, or polyethylene glycol 350-monomethylether, polyethylene glycol 600-dimethylether. As organic solvents, readily available aromatic hydrocarbons, benzene, toluene, xylene, also acetone, halogenated hydrocarbons containing 1 to 3 carbon atoms and 2 to 6 chlorine atoms, preferably 1,2-dichloroethane, 1,1,2-trichloroethane, or ethyl acetate _or a mixture thereof are preferably used. The course of the reaction can be monitored by thin layer chromatography. After the reaction is complete, the solvents are distilled off under reduced pressure and the product is isolated from the distillation residue and purified by simple crystallization.

- 3,241,932

The advantage of the method according to the invention is its simple implementation, easy isolation of the product, which is obtained in high purity and yield. Furthermore, it uses cheap and available reagents and solvents, does not require expensive operating equipment and can be carried out without difficulty in industrial conditions. It is therefore technologically and economically advantageous.

The method according to the invention is illustrated by several examples, which are merely illustrative and do not limit the scope and subject matter of the invention in any way.

Example 1

A mixture of 3.1 g of the sodium salt of the compound of formula II, 1.9 g of dimethylsulfite of general formula III, where X is a group uSO ₂ OR ₂ ^{and CI} b>

0.55 g of cetyltrimethylammonium bromide and 15 ml of benzene were stirred for 4 h at 80 °C, filtered, the solution was evaporated to dryness and the residue after crystallization yielded 2.72 g (92%) of the product of general formula I, where R is CH3, mp 130-131 °C.

Example 2

A mixture of 2.21 g of the potassium salt of the compound of formula II, 1.79 g of n-heptyl bromide of general formula III, where R is C7H15 and X is Br, 3 g of polyethylene glycol 350-monomethyl ether and 20 ml of xylene was refluxed for 4 h, filtered and evaporated to dryness. The residue after crystallization from methanol gave 2.39 g (85%) of the product of general formula I, where

R is C ₇ H ₁₅ , mp 37-38°C.

«(

Example 3

A mixture of 2.05 g of the sodium salt of the compound of formula II, 1.27 g of benzyl chloride of general formula III, where R is CgH^CH;? and X is Cl, 1 g of 18-crown-6-ether and 50 ml of acetonitrile was stirred at rt, after cooling poured into ice water, the product was filtered off with suction and washed with methanol. 2.54 g (93%) of the product of general formula I, where R is C ₆ H ₅ CH ₂ , mp. 109-110 °C were obtained.

Example 4

A mixture of 3.1 g of the sodium salt of compound II, 1.99 g of phenacyl bromide of general formula III, where R is CgH^COCl^ and X is Br, 0.2 g of trioctyl- 4 241 932 methylammonium chloride and 15 ml of dichloroethane was heated for 6 h at 90 °C. By working up according to Example 1 Dylo, 2.76 g (91%) of the product of general formula I, where R is CgH^COCHg, m.p. 193-194 °C.

Example 5

A mixture of 4.4 g of the potassium salt of compound II, 1.85 g of oromacetone of general formula III, where R is CH5COCH2 and X is Br, 1.0 g of polyethylene glycol 600*dimethyl ether and 20 ml of xylene was stirred for 4 h at 120 °C. After working up as in Example 1, 4.26 g (89%) of the product of general formula I, where R is CH5COCH2, m.p. 142-143 °C was obtained.

Claims (3)

SUBJECT OF THE INVENTION 241 932 A process for the preparation of substituted benzisothiazolin-3-on-1,1-dioxides of the general formula I, wherein R is C 1 -C 8 alkyl or C 1 -C 3 phenylalkyl, or R 1 -COCH 3; wherein R 6 is alkyl having 1 to 2 carbon atoms or phenyl, by reacting the sodium or potassium salt of benzisothiazolin-3-one-1,1-dioxide of formula II with alkylating agents of formula III Where R is as defined above and X is halogen, preferably chloro or bromo or OSO ² OR ² , wherein R ² is methyl or ethyl, in an organic solvent environment, characterized in that the reaction is carried out with the presence of 2-10 mole% of quaternary ammonium salts or polyether at a temperature of 50-150 ° C, preferably _from 70 to 110 ° C, the ratio R molórní eakčních components of formula II and formula III is 1.0: 1.0 to 1 After filtration, the reaction mixture was evaporated to dryness and the crude product obtained was purified by crystallization. 2. The method of claim 1, wherein the quaternary ammonium salts are hexadecyltrimethylammonium bromide, trioctylmethylammonium chloride and benzyldodecyldimethylammonium bromide. 3. A process according to claim 1, wherein the polyethers are cyclic polyethers, or monomethyl ether, or dimethyl ether of polyethylene glycols.