CS272942B1 - Method of oxicame's intermediate-alkyl-n-(alcoxycarbonyl-methyl)-n-methyl-2-sulphamoylbenzoate production - Google Patents

Abstract

A method of production of alkyl-N-(alkoxycarbonyl-methyl)-N-methyl-2-sulphamoylbenzoates of general formula I, where R represents alkyl containing 1 to 4 carbon atoms, possibly interrupted by 1 atom of oxygen, from saccharin acetates of general formula II, where R has the abovementioned meaning, from which, by the action of strong bases in an environment of a polar solvent, diester of general formula III, where R has the abovementioned meaning, and from which, by the action alkyl halogenide or dialkylsulphate, substituted 2-sulphamoylbenzoate of general formula I is prepared. The method is based on the fact that saccharin-2-acetate of general formula II is subjected to the action of a reagent selected from a group including anhydrous alkaline carbonate or acetate in a molar ratio of 1:1.2 and transformed into diester III in an environment of alcohol ROH, where R has the abovementioned meaning in all general formulas, whereupon, without isolation of diester of general formula III, a 1 to 1.2 molar quantity of an alkylation reagent from a group including dimethyl sulphate, p-toluene sulphonate or benzene methylic sulphate is added directly to the reaction mixture to the used alkaline carbonate or acetate and, after complete reaction of the reaction components the reaction mixture is diluted with water and the derived product of general formula 2 is sucked off and possibly purified by crystallisation. The substituted 2-sulphamoylbenzoates are intermediate products of oxicames, which are among progressive medicaments with anti-inflammatory properties.<IMAGE>

Description

The present invention relates to a process for the preparation of alkyl N- (alkoxycarbonylmethyl-N-methyl-2-sulfamoyl benzoates), oxicam intermediates of formula (I) wherein R is C1-C4 alkyl optionally interrupted by 1 to 2 oxygen atoms.

Said compounds of formula (I) are an important intermediate in the production of 4-housroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (oxicams), which currently represent a class of progressive drugs with anti-inflammatory effects, particularly in the treatment of rheumatic diseases. disease (J. Med. Chem. 14, 1171 (1971); J. Med. Chem. 16, 44 (1973)}

J. Heterocycl. Chem. 17, 1281 (1980), J. Heterocycl. Chem. 20, 155 (1983). US Pat. Nos. 3,957,792, 3,978,073, 4,022,796} Chronicle of Drug Discovery, J.Filey New York 1981; Clinics in Rheumatic Diseases, Antirheumatio Drugs II (Ed. Huskinsson), 6,585 (1980).

To date, compounds of formula (I) may be prepared from 2-carboxymethyl-benzisothiazolin-3-one-1,1-dioxide esters (saccharin-2-acetate esters) of formula (II) wherein R is as defined above by strong bases (alkaline). of alkoxides prepared in situ from the corresponding alcohol and an alkali metal or alkali hydroxide) are most conveniently converted to the 2 - [(N-alkoxycarbonylmethyl) -8-sulfamoyl] -benzoic acid ester of formula III wherein R is as defined above in an anhydrous alcohol or dipolar aprotic solvent environment; from which, in the next step, treatment with an alkylating agent in the presence of an alkali alkoxide yields a compound of formula IJ Pharm, Soc. Jap., 53, 1318 (1953); (J. Org. Chem. 39, 1554 (1974-)} J. Heterocycl. Chem. 17, 1281 (1980),

In all cases, starting from a compound of formula (II) wherein R is C 1 -C 4 alkyl such as methyl, ethyl, isopropyl, or tertiary butyl. Compound III is formed in variable yields, highly dependent on the reaction conditions. For this reason, this method is disadvantageous for technological production. A substantial simplification of the process for the preparation of the compounds of the formula I (for R = C ^-C)) is protected in DD 247 672. In this process, the two-step reaction (i.e. opening of the benzoisothiazoline ring and subsequent alkylation at the nitrogen atom) isolating the compound of formula III by treatment with alkali metal alkoxides. or alkali earth metals or alkali metal hydroxides at temperatures of 0 to 40 ° C in an alcohol medium, followed by methylation with methyl halides or dimethyl sulphate, only a good yield of the compound of formula I for methyl esters is obtained. The disadvantage of this process is the use of aggressive and hazardous chemicals, the preparation of alkali alkoxides and, last but not least, the use of relatively large dilutions.

The disadvantage of the present invention is to provide a compound of formula (II) wherein R is as defined above in an environment of the corresponding alcohol with an anhydrous alkali metal carbonate or acetate acetate reagent, preferably potassium carbonate. or sodium acetate in a molar ratio of reactants of 1: 1.2, preferably 1: 1.05, at a temperature of 20 ° C to 5 ° 0, the progress of the reaction being monitored by silica gel thin-layer chromatography (toluene-ethanol-acetic acid eluent). ratio 80: 3 with 5). After the disappearance of saccharin-2-acetate of formula (II), wherein R is as defined above, from the reaction mixture after about 10 to 30 minutes, the alkylating agent is added in an amount corresponding to the molar amount of the base used at the above temperature. Dimethyl sulfate or methyl p-toluenesulfonate is preferably used as the alkylating agent. After the alkylation reaction - about 30 to 150 minutes, the reaction mixture is diluted with water in an amount of 2-4 times the alcohol used and crystallization is initiated after complete mixing. I, wherein R is as defined above. Finally, the precipitated crystalline product is filtered off with suction, washed with water, with alcohol and recrystallized if necessary. Under the reaction conditions, a product is obtained which, after drying without further purification, can be used in the next step.

CS 272942 Bl

The advantage of the process according to the invention is that it makes use of readily available and inexpensive reagents, the process proceeds with minimal energy requirements and the product can be easily isolated in very good purity. The solvents used need not be dehydrated.

The process of the invention is illustrated by several examples, which are illustrative only and do not limit the scope of the invention in any way.

Example 1

To a suspension of 59 g (0.43 mol) of KgCO3 in 800 ml of methanol was added 100 g (0.39 mol) of methyl saccharin-2-acetate of formula II, where R = CH3, and the mixture was stirred at room temperature for 15 minutes . Then, 54 g (0.43 mol) of dimethyl sulfate was added over 5 minutes and the suspension was further stirred for 1 hour. Isolation was performed by pouring 2.5 liters of ice water. Stirring and seeding resulted in a suspension of the desired product after 5 minutes, which was filtered after 20 minutes of stirring, washed with water and cold 2-propanol. After drying (60 ° C, 30 minutes), 89 g (76%) of white crystalline solid was obtained. Compounds of formula (I) wherein RaCHy Its purity was verified by TLC (toluene-ethanol-acetic acid 80: 5: 3 eluent). Example 2

To a mixture of 100 mL of 2-methoxyethanol and 6.4 g (46 mmol) of potassium carbonate was added with stirring 11.7 g (39 mmol) of the ester of formula II wherein R is 2-methoxyethyl and the mixture was stirred for 30 min. Methyl p-toluenesulfonate (8.7 g, 46 mmol) was added dropwise over 15 minutes, and the mixture was stirred at 20 ° C for 3 hours, diluted with 300 mL of ice water. After analogous work-up as in Example 1, 9.7 g (64%) of the ether of formula I where R is 2-methoxyetbyl, m.p. 63-65 ° C, were obtained.

Claims (3)

SUBJECT OF THE INVENTION 1, A process for the preparation of alkyl N- (alkoxycarbonylmethyl) -N-methyl-2-sulfamoylbenzoates, oxicam intermediates of formula I wherein R is C1 -C4 alkyl, optionally interrupted by 1 oxygen atom, from saccharinacetates of formula II wherein R is as defined above, treatment with strong bases in a polar solvent environment affords a diester of formula III wherein R is as defined above, from which a compound of formula I wherein R is prepared by treatment with an alkyl halide or C 1 -C 3 dialkyl sulfate as defined above, characterized in that the saccharin-2-azetate of formula (II) is converted to the diester III in an ROH alcohol medium by treatment with an agent selected from anhydrous alkali carbonate or acetate at a molar ratio of 1: 1.2. R is as defined above, then added directly to the reaction mixture an alkylating agent selected from methylsulfate, p-toluenesulfonate or benzenesulfonate in an amount of 1 to 1.2 molar amounts, in the amount of alkali carbonate or acetate used, and after the reaction components are fully reacted, the reaction mixture is diluted with water and the precipitated product of formula I sucked off, eventually purified by crystallization, 2. 2. The process of claim 1, wherein the alkali carbonate is potassium carbonate. 3. 5. The process of claim 1 wherein the alkali acetate is sodium acetate.