CS241932B1 - Method of substituted benzisothiazoline-3-on-1,1-dioxides production - Google Patents

Abstract

Process for the preparation of benzisothiazolin-3-one-1,1-dioxide derivatives of formula (I) by reacting the sodium or potassium salt of benzisothiazolin-3-one-1,1-dioxide with alkalgšnimi of the formula III in an environment organic solvents that rests in that the reaction is carried out in the presence 2 to 10 mol% quaternary ammonium salts or polyethers at temperature 50 to 150 8c, wherein the molar ratio is of the reactants of formula II and general of formula III is 1.0: 1.0 to 1.5; the reaction mixture is evaporated to dryness after filtration and recovering the crude product obtained crystallization. The method is usable for industrial production of amines can be applied in the manufacture of agrochemicals and in the pharmaceuticals industry in the production of intermediate products oxicam-based drugs.

Description

The present invention relates to a process for the preparation of a substituted benzisothiazolin-3-one-1,1-dioxide of the general formula I wherein R represents a C 1 -C 8 alkyl, or a C 1 -C 3 phenylalkyl, or an R 4 COC 6 alkyl group. wherein R 1 is C 1 -C 2 alkyl or phenyl.

Said compounds of 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 found to be useful as inhibitors of human leukocyte elastase (see J. Biol. Chem. 256, 11603 (1981)]. Recently, they have been used as intermediates in the manufacture of oxicam-based medicaments which are used in human medicine as anti-rheumatic drugs. Huskinsson / 6

585 (1980) //.

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

R-X (III) wherein R is as defined above and X is halogen, preferably chloro or bromo or an OSOOROR group, wherein R 1 is methyl or ethyl.

This method / Chem. Ber. 29, 530, 1048 (1896), 30/1265 (1897), 55 3535 (1922) has been used with minimal changes to date (J. Org. Chem.). 21, 583 (1956), J.Pharm.Soc.Japan 72, 270 (1952), J. Chem. Soc. (1957), 492, J. Org. 30, 2241 (1965). The process provides relatively low product yields, requiring long reaction times

241,932 times and high reaction temperatures; tea is not economically advantageous.

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

These known processes are followed by a process according to the invention which brings about a substantial simplification and economic advantage for the preparation of the compounds of the formula I. The reaction of the sodium or potassium salt of the compound of formula II with an alkylating agent of formula III, wherein R is as defined above, is carried out in an organic solvent of the invention in the presence of quaternary ammonium salts or polyethers. 1.0: 1.0 to 1.5, wherein 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 mol% of quaternary salts of polyethers substantially increases the reaction rate and significantly reduces the reaction time. The quaternary salts used are preferably hexadecyltrimethylammonium bromide, trioctylmethylammonium chloride, benzyldodecyldimethylammonium bromide, cyclic polyethers such as 18-crown-6, dibenzo-18-crown-6, or polyethylene glycol 350-polyethylene ether 600-polyethylene ether. The organic solvents used are preferably readily available aromatic hydrocarbons, benzene, toluene, xylene, further acetone xtril, halogenated hydrocarbons having 1 to 3 carbon atoms and 2 to 6 chlorine atoms, preferably 1,2-dichloroethane, 1,1,2- trichloroethane, or ethyl acetate _, optionally _{from a} mixture thereof. The progress of the reaction can be monitored by thin layer chromatography. After completion of the reaction, the solvents were distilled off under reduced pressure and the product was isolated from the distillation residue and purified by simple crystallization.

- 3 241 932

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

The process of the invention is illustrated by several examples, which are illustrative only 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 the dimethylsulfate of the formula III, wherein X is uSO ₂ OR ₂ ^{and Cl} ₂

0.55 g of cetyitrimethylammonium bromide and 15 ml of benzene were stirred for 4 h at 80 ° C, filtered, the solution was evaporated to dryness and the residue crystallized to give 2.72 g (92%) of the product of formula I wherein R is CH 3, 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 the n-heptyl bromide of formula III wherein R is C 7 H 15 and X is Br, 3 g of polyethylene glycol 350-monomethyl ether and 20 ml of xylene was refluxed for 4 h. drought. The residue from crystallization from methanol gave 2.39 g (85%) of the product of formula (I) wherein

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 the benzyl chloride of the formula III, wherein R is C8H4CH3; and X is Cl, 1 g of 18-crown-6-ether and 50 ml of acetonitrile were stirred at room temperature, poured into ice water after cooling, the product was aspirated and washed with methanol. 2.54 g (93%) of the product of formula (I) wherein R is C ₆ H ₅ CH ₂ x x t were obtained. 109-110 ° C.

Example 4

A mixture of 3.1 g of the sodium salt of compound II, 1.99 g of phenacyl bromide of formula III, wherein R is C8H4COCl4 and X is Br, 0.2 g of trioctyl-4 241 932 methylammonium chloride and 15 ml of dichloroethane was heated for 6 h to 90 ° C. Treatment according to Example 1 Dylo gave 2.76 g (91%) of the product of formula (I) wherein R is C 8 H 9 COCH 3, m.p. Mp 193-194 ° C.

Example 5

A mixture of 4.4 g of the potassium salt of compound II, 1.85 g of oromacetone of formula III wherein 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 hours at 120 ° C. After work-up as in Example 1, 4.26 g (89%) of the product of formula (I) were obtained, wherein R is CH 5 COCH 2, m.p. M.p. 142-143 ° C.

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.