CS239134B1 - Process for the preparation of benzothiazine-1,1-dioxide derivatives - Google Patents

Abstract

These substances are produced by alkylation. compounds of general formula II where R has the above-mentioned meaning. The essence of the invention lies in the fact that as an alkylating agent, dialkyl sulfate or alkyl-p-toluenesulfonate is used, where alkyl represents R1 and has the above-mentioned meaning, in a two-phase environment organic - aqueous phase in the presence of alkali and a phase transfer catalyst at a temperature of 15 to 100 , whereby 1 to 5 moles of alkali, 0.5 to 2 moles of alkylating agent and 0.01 to 0.2 moles of phase transfer catalyst are used per 1 mole of compound of general formula II, after which the product of general formula 1 is isolated from the organic phase after the reaction is completed. The compounds mentioned are intermediates in the synthesis of drugs with significant antirheumatic effects.

Description

The present invention relates to a process for the preparation of benzothiazine-1,1-dioxide derivatives of the general formula I (or a tautomeric oxo form thereof) wherein R represents an alkyl of 1 to 4 carbon atoms, optionally interrupted by 1 oxygen atom or phenylalkyl containing in the alkyl chain of 1 to 4. 5 carbon atoms, optionally interrupted by 1 oxygen atom; denotes methyl or ethyl. These compounds are intermediates in the synthesis of drugs with significant anti-rheumatic effects and the generic name oxicams / Chronicles of Drug Discovery, p. 173,

J. Wiley, New York 1981].

To date, compounds of formula I have been prepared by alkylation on nitrogen of non-alkylated compounds of formula II, unless R is as defined above.

Most often, alkyl iodides in aqueous ethanol were used to alkylate the compounds of Formula II (see, e.g., Org. Prep. Why. Int. 12, 2.69 (1980)] or lower ketones such as acetone, or aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide (see, e.g., U.S. Pat. No. 4,289,879). Procedures are described wherein dimethylsulfate in dimethylsulfoxide or aqueous suspension is used as the alkylating agent (see, e.g., U.S. Pat. No. 3,960,856]. These processes have a number of disadvantages. Alkylations carried out with an alkyl iodide in an aqueous alcohol medium provide low product yields, the alkyl iodides being relatively expensive reagents. Another disadvantage of these processes is the difficult recovery of iodine from wastewater. Processes using aprotic polar solvents, while providing good yields of the desired N-alkylated product, however, the recovery of expensive solvents or wastewater contamination, make them economically and environmentally disadvantageous.

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These known processes are followed in a positive way by the process according to the invention, which removes the above-mentioned drawbacks.

The process according to the invention is characterized in that the starting compound of the formula II is prepared according to known methods. Heterocyclic, Chem. 17, 1281 (1980)) alkylates under phase catalysis conditions. An aqueous alkali solution is added to the mixture of a compound of formula II, an alkylating agent and a catalytic amount of a phase transfer catalyst in an organic solvent medium with vigorous stirring of the reaction mixture at a temperature of 15 to 100 ° C. The alkylating agent to the alkali catalyst is 1: 0.5 to 2: 0.01 to 0.2: 1 to 5. The organic solvents used are halogenated alkanes containing 1 to 5 carbon atoms and 2 to 6 chlorine atoms. dichloromethane or l, 2-dichloroethane _R or aromatic hydrocarbons e.g. benzene, toluene and chlorobenzene. As the alkali, alkali metal hydroxides and carbonates, preferably sodium or potassium hydroxide or carbonate, are used. In this alkylation, quaternary ammonium or phosphonium salts, preferably benzyltriethylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, hexadecyltrimethylammonium bromide or hexadecyltriethylphosphonium bromide or hexadecyltributylphosphide are used as phase transfer catalysts. The progress of the alkylation is easily monitored by thin layer chromatography on silica gel. After completion of the alkylation, about 0.5 to 4 hours, the organic layer is separated, the aqueous is extracted with the same solvent, the combined extracts are washed with dilute brine, dried, and the solvents obtained after distillation.

The process of the invention has a number of advantages: a) using readily available and inexpensive reagents and solvents; b) the product is easily isolated and purified; c) simple method of waste water treatment; d) the reaction is carried out in a standard technological equipment. From the above, it is clear both the technological and economic advantages of the process according to the invention.

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The invention and its effects are illustrated in the following examples which are merely illustrative and in no way limit the scope of the invention.

Example 1

Methyl-4-H, Hydroxy-2-ethyl-2H-l, 2-benzothiazine-3-carboxylate-l, 1-dioxide / 1, wherein R = CH3, R ¹ = CH ₂ CH ₅ /

To a vigorously stirred mixture of 2.9 g of ester II (f = GH ^), 2.5 ml of diethyl sulfate, 0.2 g of triethylbenzylammonium chloride and 50 ml of dichloromethane was added dropwise over 15 minutes 15 ml of 1 N NaOH. The mixture was stirred for 1 h at 40 ° C, the organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. After evaporation was recrystallized from ethanol afforded 3.0 g / 93% / of the product I where fi ^ = CH, R ¹ = CH ₂ CH _5, mp 94-95 ° C.

Example 2

2-Methoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide (1, where R = OII ₂ CH ₂ OCH ₅ , R ¹ = GH 2)

To a mixture of 30 g of ester II (where R - CH ₂ GH ₂ OCH 4), 14 g of dimethyl sulfate, 0.5 g of tetrabutylammonium hydrogen sulfate and 100 ml of toluene was added with stirring over 1 h 14 g of potassium carbonate in 50 ml of water. The mixture was stirred for 3 h. After work-up as in Example 1, 28.9 g (92%) of ester I was obtained, where R - CH ₂ GH ₂ OCH 1, R 1 = OH-1, mp 107-9, Low: 14 ° C.

Example 3

3-Ethoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate -1,1-dioxide (1, where R = CH ₂ CH ₂ OCH ₂ CH ₅ , R ¹ = GH 2)

A mixture of 3.1 g of ester II (where R - CH ₂ GH ₂ OCH ₂ Cl ₂ 15), 3.7 g of methyl 4-toluenesulfonate, 50 ml of dichloroethane, 0.2 g of hexadecyltriethylphosphonium bromide and 20 ml of 1N NaOH was stirred vigorously for 3 h at 60 ° C. The organic layer was worked up as in Example 1. 3.0 g (92%) of ester I were obtained, where R = CH ₂ CH ₂ OCH ₂ CH ₅ , R ¹ = CH ₅ , mp 108-111 ° C.

Example 4

2-Phenoxyethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate -1,1-dioxide (1, where R = CH ₂ Cl ₂ OC ₆ H ₅ , R ¹ = CH ₅ )

A mixture of 3.61 g of ester II wherein R = CHgCHgOCgH3, sulfate, 0.2 g of trioctylmethylammonium chloride, 20 ethylene and 20 mL of 1N NaOH was stirred vigorously.

3.5 g / 88% / of ester I, wherein R = CHgGHgO-Cg ^, R ¹

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2.5 ml of dimethylml 1,1,2-trichloro at 40 ° C for 2 h.

1, It was obtained ^: CH2, m.p. 125

Claims (5)

SUBJECT OF THE INVENTION 239 134 A process for the preparation of the benzothiazine-1,1-dioxide derivatives of the general formula I, also existing as tautomeric oxoform, in which R denotes alkyl having 1 to 4 carbon atoms, optionally interrupted by 1 to 10 oxygen atoms or phenylalkyl having 1 to 3 carbon atoms optionally interrupted in the alkyl moiety by an oxygen atom, R @ ¹ denotes methyl or ethylyalkylation of a compound of formula II or its tautomeric oxoform, wherein R is as defined above, wherein the alkylating agent is dialkyl sulfate or alkyl p-toluenesulfonate, In the two-phase environment, the alkyl radical R @ 1 is an organic phase in the presence of alkali and a phase transfer catalyst at a temperature of 13 to 100 DEG C., with 1 to 5 moles of alkali being used per mole of the compound of formula II; 0.5 to 2 moles of alkylating agent and 0.01 to 0.2 moles of phase transfer catalyst, followed by 0.5 to 2 mol from the organic phase, the product of formula (I) is isolated. The process according to claim 1, wherein the alkali is an alkali metal hydroxide or carbonate, for example sodium hydroxide or potassium carbonate. 3. A process according to claim 1, wherein the phase transfer catalyst is quaternary ammonium or phosphonium salts such as benzyltriethylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, hexadecyltrimethylammonium bromide or hexadecyltriethylphosphonium bromide or hexadecyltriethylphosphonium bromide. 4. The process of claim 1 wherein the reaction is carried out at a temperature of 20 to 60 ° C. 5. A process according to claim 1, wherein the organic phase is halogenated aliphatic hydrocarbons having 1 to 3 benzene or carbon atoms.