CS276217B6 - Process for the preparation of 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide - Google Patents

Abstract

■The method consists in treating the ethyl ester of the general formula II, where R2 denotes ethyl, with 2-aminopyridine in the presence of 2-alkoxyethanol in a molar ratio of 1:1.0 to 1.2:0.2 to 0.5 in an environment of alkylaromatics at their boiling point, whereby the ethanol formed during the reaction with a part of the 2-alkoxyethanol and the solvent is continuously distilled off in an efficient distillation column, after which, after the reaction is completed and cooled, the separated product of the formula I is suctioned off, or purified by crystallization from 2-alkoxyethanol or its mixture with the above-mentioned alkylaromatic. The pure product can be used in human medicine in the production of highly effective anti-inflammatory drugs.

Description

The invention relates to a process for the preparation of 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide of formula I, which may occur in its tautomeric oxo form indicated by formula la. For simplicity, only the enol form (Formula I) is provided below. The compound of formula I with the generic name piroxicam from the group of oxicams is widely used therapeutically in human medicine in the manufacture of highly effective anti-inflammatory drugs with high tolerance and minimal side effects (see, e.g., Chronicles of Drugs Discovery, p. 173, J. Wiley, New York 1981, J. Med. Chern. 14, 1171 (1971), J. Pharm. Sci. 75, 579 (1984)).

At present, there are basically two methods used on an industrial scale. In the first, oxicam-type compounds (Formula B) are prepared by cyclisation of the corresponding benzenesulfonamides (Formula A) by the action of strong basic reagents in aprotic dipolar solvents such as dimethylformamide, dimethylsulfoxide, and the like (e.g., U.S. Pat. Nos. 3,927,002; 3,954,786). , Spanish Patent No. 497,077, Japanese Paper Jpn Kokai Tokkyo, Koho 5,936,668 (Chem. Abstr. 101, 7177 (1984), etc.) The disadvantage of these processes is the relatively low product yields which depend on the reaction conditions. high laboriousness and, last but not least, expensive reagents. '

A second process for the preparation of these substances by ammonolysis of the corresponding esters of the formula II has found wide industrial application (U.S. Pat. No. 3,591,584; 4,289,879; Czech Pat. No. 228,520; J. Med. Chem. 14, 1171 (1973). ), J. Med. Chem. 14, 44, 493 (1973), Justus Liebigs Ann. Chem. 1978, 635). The disadvantage of this process for the preparation of piroxicam when using a methyl 2 ester of formula II, where R is CH 2, is the formation of an intensely yellow undesired methoxy derivative (formula C) which is very difficult to remove from the product by crystallization (product of formula I is according to USP and BP defined as white to slightly yellowish substance) and this not only significantly reduces yields and labor productivity, but also increases the consumption of expensive and difficult to dispose of solvents. Some improvement in yields and product quality was obtained using ethyl ester of formula II, wherein R is C ₂ H 2 (according to LLS Pat. Nos. 3,501,466 and 3,816,628). A significant improvement in yield and product quality was obtained when the amidation was performed with a 2-methoxyethyl ester (Formula II, wherein R is CH ₃ OCH ₂ CH ₂ ), (see U.S. Pat. No. 4,289,879; Cs. Pat. file no. 228 520). The disadvantage of this production method is the complicated preparation of said 2-methoxyethyl ester, which requires work in an inert and anhydrous environment, expensive solvents and reagents.

These known processes are followed in a positive sense by the process according to the invention. The process according to the invention is based on the reaction of an ethyl ester of general formula II, wherein R represents a C ₂ H 1 group, by the action of 2-aminopyridine in the presence of 2-alkoxyethanol in a molar ratio of reactants of 1: 1.0 to 1.2: 0.2 to 0 , 5 in the presence of alkylaromatic solvents at their boiling point. Under these conditions, the ethyl ester is directly amidated and partially transesterified to the corresponding 2-methoxyethyl ester, which is also converted to the desired product. This procedure reduces the formation of unwanted yellow product to a minimum. The ethanol formed in the reaction is distilled off with a portion of 2-methoxyethanol and solvent on an efficient distillation column in the form of an azeotrope. After the reaction is complete, the crystalline product of the formula I is filtered off with suction from the cold reaction mixture or optionally purified by crystallization from 2-alkoxyethanol or a mixture thereof with the abovementioned aromatic solvent. The 2-alkoxyethanol used is preferably 2-methoxyethanol or 2-ethoxyethanol and the alkyl aromatics are alkylbenzenes having 1 to 3, alkyl groups having 1 to 3 carbon atoms, preferably ethylbenzene, dimethylbenzene or a mixture thereof.

The advantage of the process according to the invention is the simple implementation of the reaction using readily available intermediates and reagents which are practically harmless from the point of view of work safety.

The invention and its embodiments are illustrated in several embodiments, which in no way limit the scope of the invention.

CS 276217 06 '2

Example 1.

To a solution of 6.5 kg of ethyl ester of formula II, wherein R is a group, in 50 liters of xylene and 0.35 kg of 2-methoxyethanol at 85-100 ° C was added 2.23 kg of freshly distilled 2-aminopyridine and the mixture was slowly added. brought to a boil. An azeotropic mixture of xylene, ethanol and 2-methoxyethanol was taken from the top of the distillation column at a rate of 0.7 to 1.2 liters per hour while continuously replenishing the distilled part of the solvent. The reaction was monitored by thin layer chromatography. After 25 hours, the conversion was complete, 0.5 kg of activated carbon was added to the reaction mixture, and after stirring briefly, the activated carbon was filtered off on a pressure filter at a temperature of the mixture close to the boiling point. After spontaneously cooling the filtrate (stirring) to 15-20 ° C, the precipitated crystals were filtered off with suction and washed with a small amount of 2-methoxyethanol. Evaporation of the mother liquors and recrystallization gave an additional portion (0.52 kg) of crude product, which was added to the major portion after washing with the above cold solvent. Recrystallization from 2-methoxyethanol and xylene gave 4.7 kg of the product of formula I, mp 199-201 ° C (J. Med. Chem. 14, 1171 (1971) reports 200 ° C). For C ₁₅ H ₂₃ N ₃ O ₄ S (331.4) calculated: 54.37% C, 3.95% H, 12.68% N, 9.68% S; found: 54.32% C, 3.86% H, 12.68% N, 9.57% S. Infrared spectrum (nujol) contains bands: 3,350 cm ¹ (OH),

630 cm ^-1 (C = O), 1350 and 1180 cm ^-1 η (SO ₂ ); ^{The 3} H NMR spectrum (measured in DMSO-D 6) contains signals (ppm): 2.94 s (3H, CH 2), 7.10 m and 7.64 to 8.40 m (8H, aromatic protons), δ, 92 bs (1H, NH), 13.78 bs (1H, OH).

Example 2

To a solution of 650 g of the ethyl ester of formula II, wherein R is a C ₂ H ₃ group, in 6,000 ml of ethylbenzene and 42 g (43.5 ml) of 2-ethoxyethanol at 90-95 ° C was added 223 g of 2-aminopyridine and proceeded as in Example 1. After the conversion was complete (30 hours), 60 g of activated carbon were added to the mixture, boiled briefly and the reaction mixture was filtered hot on a pressure filter. After slowly cooling the filtrate with stirring (seeded with 1 g of pure product), the precipitated crystals were filtered off with suction and proceeded as in Example 1. Recrystallization of the combined crude products gave 515 g of product of formula I, mp 199-201 ° C.

Example 3

To a solution of 1,300 g of ethyl ester of formula II (where R is a C ₂ H ₃ group) in 11.5 liters of isopropylbenzene and 96.8 ml (90 g) of 2-methoxyethanol was added 450 g at 100-105 ° C. Of 2-aminopyridine and proceeding as in Example 1. After 18 hours of heating, the conversion was complete and after the above work-up of the reaction mixture, 985 g of product of formula I, mp 198-200 ° C, were obtained.

Claims (3)

PATENT CLAIMS A process for the preparation of 4-hydroxy-2-methyl-N-2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide of formula I from esters of 4-hydroxy-2-methyl-2H-1. 2-benzothiazine-1,1-dioxide-3-carboxylic acid of formula II, wherein R is alkyl or 2-alkoxyalkyl by treatment with 2-aminopyridine in an inert solvent at elevated temperature, characterized in that 2 is ethyl ester of of formula II, wherein R is ethyl, is treated with 2-aminopyridine in the presence of 2-alkoxyethanol in a molar ratio of 1: 1.0 to 1.2: 0.2 to 0.5 in the presence of alkyl aromatics at their boiling point. Ethanol with a portion of 2-alkoxyethanol and a solvent is continuously distilled off on an efficient distillation column, after which, after completion of the reaction after cooling, the precipitated product of the formula I is filtered off with suction or purified by crystallization from 2-alkoxyethanol or a mixture thereof with the abovementioned alkyl aromatic. CS 276217 B 6 2. The process according to item 1, characterized in that the reaction is carried out in the presence of 2-methoxy- or 2-ethoxyethanol. 3. The process according to item 1, characterized in that the reaction and crystallization are carried out in the environment of alkylbenzenes containing 1 to 3 alkyl groups having 1 to 3 carbon atoms, such as toluene, xylene, ethylbenzene. .