CS248909B1 - Method of n-(omega-carboxyalkyl) benzinethiazoline-3-on-1,1-dioxides' esters production - Google Patents

Abstract

The invention relates to a process for the preparation of esters N- / cu • carboxyalkyl / benzisothiazolin-3-one -1,1-oxides of formula I so, N- (CH 2) n COOR / 1 / by reacting the sodium or potassium salt of benzisothiazoline-3-oh-1,1-dioxide of formula II esters ca; -haloalkyl of the formula III X- (CH 2) n COO R (111). The reaction is carried out in an organic medium % of solvents in the presence of 2 to 10 mol%. quaternary salts or polyethers or superficially ethylene oxide-based active substances alkylphenols at 30 to 150 ° C, whereupon the reaction mixture, optionally after distilling off the organic solvent, diluted with water and the precipitated solid of formula (I) is filtered off with suction and purified by crystallization.

Description

The invention relates to a process for the preparation of N- (N-carboxyalkyl) -benzisothiazolin-3-one-1,1-dloxides esters of the general formula I,

WHAT

- (CH ₂ ) _n COOR ^ΙτΙ ' ^SO 2 where R denotes alkyl having 1 to 6 carbon atoms, phenylalkyls containing 1 to 3 carbon atoms in the alkyl moiety, or the same alkyl or phenylalkyl interrupted by 1 or 2 oxygen atoms or 1 sulfur atom and denotes 0 to 6.

Said compounds of formula (I) are important intermediates in the production of amino acids (see, for example, Methoden der Organischen Chemie (Houben-Wey1), Vol. XI / 2, p. 269).

G. Thieme Verlag, Stuttgart, 1958; Synthetic Production and Utilization of Amino Acids, Eds. T. Kaneka, Y. Izumi (J. Wlley, New York 1974).

In recent years, they have found application in the manufacture of oxicam-based drugs which are used in human medicine as anti-rheumatic drugs with significant anti-inflammatory effects / Chronicle of Drug Discovery, J. Wiley, New York, 1981; Clinics in Rheumatic Diseases Anti. Rheumatic Drugs II / Ed. Huskinsson, 66, 585 (1980).

To date, these compounds of formula I (wherein n - 0 and 1) are prepared essentially by the formation of the sodium salt of benzisothiazolin-3-on-1,1-dioxide of formula II

(11) is treated with a formic or acetic acid ester at elevated temperature. This method (see Chem. Ber. 30, 1265 (1,897) has been used to date with practically minimal changes (J). Copper. Chem. 14, 1171 (1971); J. Med. Chem. 16, 4 (3) (1973); US Pat. No. 3,591,584]. The process provides relatively low product yields and requires long cracking times and is therefore of low economic benefit.

Another improved method described in US Pat. No. 4,289,879 performs the reaction in dimethylformamide at 120 ° C and isolates the product after diluting the reaction mixture with sufficient water. A disadvantage of this process is the use of relatively expensive dimethylformamide as a solvent whose removal from wastewater is technologically complex and economically expensive.

A process for the preparation of higher esters of formula I wherein R is C 2 -C 12 alkyl (see US par. 3,591,584 (starting from methyl ester I (R - CH3)) with a sequence of reactions: hydrolysis of the methyl ester to an acid which is converted to the acid halide followed by treatment with a higher alcohol to give the desired ester of formula I wherein R is alkyl to C This embodiment has virtually no technological significance for complexity.

These known processes are followed by the process according to the invention, which brings a considerable simplification and economic advantage to the synthesis of the compounds of the formula I.

The process according to the invention is characterized in that the sodium or potassium salt of the compound II is reacted with

X- (CH ₂ ) _n ° ^{C (} R) 111 where X is chlorine or bromine and R is as defined above.

It is carried out in an organic solvent in the presence of quaternary salts or polyethers or surfactants based on ethylene oxidized alkylphenols. In this reaction, it is preferable to use the reactants II and III in a molar ratio of 1.0: 1.0 to 1.5. wherein the reaction is carried out at a temperature of 30 to 150 ° C, preferably at 70 to 110 ° C.

• The presence of 2 to 10 mol%. % of quaternary salts, polyethers or surfactants substantially increases the reaction rate and thus substantially reduces the reaction time. As quaternary salts, preferably hexadecyltrimethylammonium bromide, hexadecyltributylphosphonium bromide, trioctylmethylammonium chloride, benzyldodecyldimethylammonium bromide, such as polyethers, preferably 18-crown-6, dibenzene-18-crown-6, polyethylene glycol ether / polyethylene glycol ether 600 are used. . in Phase Transfer Catalysis, Verlag Chemie, Weinheim, 1980, Can. J. Chem. 60, 2456 (1982), DOS 2 914 <06; J, Org. Chem.

43, 1532 (1978), Brit. U.S. Pat. 2,021,562 /.

The organic solvents used are readily available aromatic hydrocarbons benzene, toluene and xylenes, furthermore acetonitrile, 1,2-dichloroethane, ethyl acetate or mixtures thereof. An advantage of embodiments of the invention is that the progress of the reaction is easily monitored by thin layer chromatography. Upon completion of the reaction, after any evaporation of the solvent, the reaction mixture is diluted with water and the precipitated product of formula 1 is purified by crystallization.

The process of the invention is simple and the product is readily isolated in high yield and purity. Furthermore, it does not require expensive operating equipment and can be carried out easily under industrial conditions. 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.

He did

A mixture of 3.1 g of the sodium salt of the compound of formula II, 1.73 g of methyl chloracerate, 0.55 g of cetyltrimethylammonium bromide and 15 ml of toluene was stirred for 4 hours at 100-105 ° C, after cooling the crystals were sucked off, washed with water and ethanol. 3.47 g of product of formula (I) where R ⁼ CH3, n => 1, m.p. 117 DEG-119 DEG C., in 90% yield, were obtained.

Example 2

A mixture of 22.1 g of the potassium salt of the compound of formula II, 15.3 g of methoxyethyl chloroacetate / formula III, R ^CHjCHjOCHj, X-Cl, n = 1), 5 g of polyethylene glycol-350 monomethyl ether and 150 ml of xylene was refluxed for 6 hours. After cooling, the inorganic salts were aspirated, the solution evaporated to dryness and the residue crystallized from methanol. Yield 27.8 g / 93% / of the product of formula I where R = CH ₂ CH ₂ O-CH _3, n = 1, mp 91-93 ° C.

Example 3

A mixture of 31.0 g of the sodium salt of the compound of formula II, 16.4 g of ethyl chloroformate of the formula III, wherein R RCH CHCHj, η = 0, X = Cl, and 2 g of 18-crown-6 ether were in 150 ml of acetonitrile After stirring for 4 hours at boiling point, poured into ice water after cooling and the precipitated product was filtered off with suction and washed with ethanol. 32.9 g (86%) of the product of formula I were obtained, wherein R = CH ₃ CH ₂ , n = 0, mp 134-136 ° C.

OF

Example 4

A mixture of 3.1 g of the sodium salt of compound II, 2.67 g of ethyl bromoacetate of the formula III, wherein R 6 CH ₃ CH ₂ , X = ⁵ Br, n = 1, and 0.3 trioctylmethylammonium chloride and 15 ml of toluene was heated for 6 hours at 90 to 95 ° C and work-up as in Example 1 afforded 3.55 g / 88 4 / product I, R 'CH ₃ CH _2, n' 1, mp 104-105 ° C.

Example 5

A mixture of 3.1 g of the sodium salt of the compound of formula II, 2.62 g of ethoxyethyl chloroacetate of the formula III, wherein R = CjHj-OCHjCHj, X ·Cl, n = 1, and 1.0 g of polyethylene glycol 600 dimethyl ether and 20 ml of dichloroethane 4 hours at boiling of solvent. Working up was carried out as in Example 1 and 4.3 g (91%) of product I were obtained, R = C ₂ H, OCH ₂ CH ₂ n => 1, mp 58-59 ° C.

Claims (8)

A process for the preparation of N- (C 1 -C 3 -carboxyalkyl) benzlsothiazolin-3-one-1,1-dioxide oxides of the general formula (I). CO 1 - (CH ₂ ) _n COOR SO ^7/1 / R being alkyl having 1 to 6 carbon atoms or fenylaiky1 the alkyl portion contains 1-3 carbon atoms, respectively. interrupted by 1 or 2 oxygen or sulfur atoms and n is 0 to 6, by reaction of the sodium or potassium salt of the benzisothiazolin-3-one-2,1-dioxide of formula XI SO3 (11) with esters of <uI> -halogenic acids of the general formula III X- (CH ₂ ) _n COR (111), wherein X is chlorine or bromine and R is as defined above, characterized in that the reaction is carried out in an organic solvent environment in the presence of 2 to 10 mol%. the quaternary salts or polyethers or surfactants based on ethylene oxidized alkylphenols at a temperature of 30 to 150 [deg.] C., after which the reaction mixture, if necessary after distilling off the organic solvent, is diluted with water and the precipitated solid product of formula I is suctioned off and purified by crystallization. 2. The process of claim 1 wherein the organic solvent is an aromatic hydrocarbon such as benzene, toluene and xylene. 3. The process of claim 1, wherein the organic solvent is acetonitrile, 1,2-dichloroethane and ethyl acetate. 4. The process of claim 1 wherein the quaternary salts are hexadecyltrimethylammonium bromide, hexadecyltributylphosphonium bromide, trioctylmethylammonium chloride, and benzyldodecyldimethylammonium bromide. 5. The process of claim 1 wherein the polyether is 18-crown-6, dibenzo-18-crown-6, polyethylene glycol-350 monomethyl ether and polyethylene glycol-600 dimethyl ether. 6. The process of claim 1, wherein the surfactant is ethylenoxidized p-nonyl or p-dodecylphenol. 7. The process of claims 1 to 6, wherein the reaction is carried out at a temperature of 70 to 110 ° C. 8. A process according to claims 1 to 7, wherein the molar ratio of the reactants