FI63231B - PROCEDURE FOR FRAMSTATION OF N- (2-PYRIDYL) -2-METHYL-4-HYDROXY-2H-1,2-BENZOTIAZINE-3-CARBOXAMIDE-1,1-DIOXIDE - Google Patents

Description

I. rBl ANNOUNCEMENT

WV lBJ (11) UTLÄGÖNIN0SSKR1FT 00Ζ0Ί * 3? § (45) (51) Kv.ik.Va3 C 07 D 417/12 // C 07 Ώ 279/12 FINLAND — FINLAND pi) νμ (Μ ^ -μμμιιιμι · ι 763680 (22) HikniltpSivt - AnaOMogmi * / 22.12.76 ^ (23) AlkapUvt — GlMglMttdag 22.12.76 (41) Talkie laUdMkd — ilhrtt offantIlf 13.07.77 PBtantti-) * Registry Board (44) NlhtMtalpeia · | * kuiil | altotan | -

Petut · och register styrel ten Aiwefcan utbfd och utUkrtft · * publtc * r »d 31.01.63 (32) (33) (31) Pyrdvey« uolk — t prtorlM * 12.01.76 USA 61 US 8507 (71) Pfizer Inc., 235 East l * 2nd Street, New York, NY, USA (US) (72) Joseph George Lombardino, Niantic, Connecticut, USA (US) (7 * 0 Oy Roister Ab (5¾) Method N- (2- pyridyl) -2-methyl-1 * -hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide - Preparation of N- (2-pyridyl) -2-methyl-1 * -hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

The present invention relates to a process for the preparation of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide of the formula ΟόΓ "^ 02 <* 3 and its time metal and earth for the preparation of alkali metal salts.

3,4-Dihydro-2-alkyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxides have previously been prepared synthetically by amination of the corresponding 3-carboxylic acid ester or by treatment of the starting 3,4-dihydro- 2-alkyl-4-oxo-2H-1,2-benzothiazine-1,1-dioxide with the appropriate isocyanate. (Lombard-2,63231 no. Et al., J. Med. Ohem., 14, 1171 (1971) and Zlnnes, et al., Ibid. 16, 43 (1973) and U.S. Patent No. 3 591 584). In addition, there are Zinnes and partner. described in the above-mentioned publication the preparation of 3-carboxamides by treating 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-1,1-dioxide-pyrrolidine-enamine with phosgene, followed by the formation of 3- the carbonyl chloride is treated with the appropriate amine.

U.S. Patent 3,853,862 discloses a process for preparing N-aryl-2-alkyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxides at 50-150 ° C: N-aryl-N'-alkyl-N- (2'-alkoxycarbonylbenzenesulfonyl) -glycinamides are treated with an alkali or alkaline earth metal hydride using a solvent inert to the reaction.

U.S. Patent 3,714,155 describes 4-hydroxy-2-N-dimethyl-2H-1,2-benzothiazine-3-carboxanilide-1,1-dioxides as anti-inflammatory drugs which can be prepared by methylation of the corresponding N-phenyl carboxamide with dimethyl sulfate in the presence of sodium hydride.

It has now been found that an anti-inflammatory compound of formula I can be prepared by reacting a compound of formula II

OH

An alkali or alkaline earth metal salt to react at 0-100 ° C with at least one mole of methylating agent in a solvent inert to the reaction and, if desired, preparing a pharmaceutically acceptable salt of the resulting compound.

In the preferred process of the invention, ethanol is used as the inert solvent, sodium salt as the alkali metal salt and methyl iodide as the methylating agent, and the reaction temperature is about 25 ° C.

Although the alkali metal or alkaline earth metal salt of 4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide of formula II can be prepared separately and then added to an inert solvent, this salt is suitably prepared "in situ". in said solvent. This is conveniently done by treating a solution of N- (2-pyridyl) -4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide with an equivalent amount of alkali metal or alkaline earth metal hydride, hydroxide or alkoxide. . All hydrides, hydroxides and alkoxides of early metals and alkaline earth metals can be used in the process according to the invention.

The preparation is conveniently carried out in a solvent inert to the reaction, as already mentioned above. By such a solvent or mixture of solvents is meant those which, under the conditions of the process of the invention, do not substantially react with the starting reagents or products, and in which the reaction components are suitably soluble. Relatively polar solvents are suitably used. Suitable solvents or mixtures thereof in this group include di- (lower) alkyl sulfoxide, aqueous solutions of lower alkanols, di- (lower) alkyl- (lower) alkali amides and hexa- (lower) alkylphosphoramide. Water can also be used with all of these solvents or mixtures thereof. Preferred solvents for the process of the invention are dimethylformamide, ethanol and dimethyl sulfoxide. Ethanol is particularly recommended as the solvent. The solvent should also preferably be miscible with water, although this is not necessary.

The reaction temperature range is 0 to 100 ° C, and a suitable temperature is about 25 ° C.

The length of the reaction is not critical, but typically depends on the concentration, reaction temperature, and reactivity of the starting materials. When temperatures of about 25 ° C are used, the reaction time will vary in the range of 12-18 hours.

The order of addition of the reaction components is not critical, but for practical reasons, the benzothiazine-1,1-dioxide salt is first added to the reaction solvent, followed by the addition of the methylating agent. In the case where the salt is developed "in situ" in a reaction solvent, benzothiazine-1,1-dioxide is suitably added to the solvent, followed by the addition of a hydride, alkoxide or hydroxide of the desired alkali metal or alkaline earth metal, followed by a methylating agent.

As for the molar ratio of the reaction components, at least one mole of methylating agent per mole of salt is suitably used to ensure that the reaction is complete. Larger amounts of 4,63231 can be used without particularly affecting the course of the reaction, and this procedure is suitably carried out. For practical reasons, this excess may be as high as 100-200% of said substance, but larger amounts may be used.

The methylating agents used in the process of the invention are already known to those skilled in the art and include methyl halides, dimethyl sulphate, methyl alkyl or aryl sulphonate esters or diazomethane. Preferably methyl bromide, methyl iodine, dimethyl sulfate, methyl methyl sulfonate and methyl p-tosylate are used, and quite preferably methyl iodide.

As already mentioned above, the compounds prepared by the process of the invention are suitable for use as anti-inflammatory drugs, and U.S. Patent 3,592,584 describes how these compounds are used for this purpose.

The intermediates used in the process of the invention are prepared from compounds well known to those skilled in the art and described below.

The following examples illustrate the invention.

Example 1 N- (2-pyridyl) -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide A. 2-benzyl-4-hydroxy-2H-1 , 2-Benzothiazine-3-carboxylic acid methyl ester 1,1-dioxide A solution of 5.1 g of 4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid methyl ester-1,1-dioxide (J. Med. Chem., 14, 1171 (1971)), 6.8 g of p-bromotoluene and 20 ml of a 1N aqueous solution of sodium hydroxide in 20 ml of water and 60 ml of ethanol are stirred overnight at room temperature. The product is dried under reduced pressure to give 5.5 g of crude product, m.p. 143-153 ° C. Recrystallization from ethanol gives 4.4 g of purified product, m.p. 157-159 ° C.

Analysis calculated for C 17 H 15 O 5 NS: C 15 H 2> 4.4 N, 4.7 Found: C, 59.3? H, 4.4 N, 4.1 B. N- (2-pyridyl) -4-hydroxy-2-benzyl-2H-1,2-benzothiazil-3-carboxamide-1,1-dioxide Heat a suspension of 10.0 g of 2-benzyl-4-63231 5-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid methyl ester 1,1-dioxide and 3.3 g of 2-aminopyridine in 1000 ml of dry xylene, and the xylene is allowed to slowly distill off. After a total distillation of 7 hours, the solvent is replaced with fresh xylene every other hour and the reaction mixture is refluxed overnight. The solution is then evaporated to 350 ml, cooled in an ice bath and the precipitated product is filtered off and dried under reduced pressure. The crude material thus obtained is used in the next reaction without further purification.

C. N- (2-pyridyl) -4-hydroxy-2H-1,2-benzothiazine-3-carbosamide-1,1-dioxide 1.5 g of palladium on carbon (10%) are added to a solution in which 1.2 g of N- (2-pyridyl) -4-hydroxy-2-benzyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide in 175 ml of a solution of chloroform and methanol (2: 1 by volume) and the resulting suspension is shaken in hydrogen gas for 4 hours at an initial hydrogen pressure of 302 kPa. The spent catalyst is filtered off and the filtrate is evaporated to dryness. The residue is recrystallized from ethanol.

D. N- (2-pyridyl) -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

To a solution of 8.0 g of N- (2-pyridyl) -4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, 22 ml of water, 80 ml of ethanol and 24 ml of 1N sodium hydroxide solution are added 3.6 ml of methyl iodide. The resulting mixture is stirred overnight at room temperature. The suspension is cooled in an ice bath for 30 minutes, after which the solid precipitate is filtered off, dried under reduced pressure and recrystallized from a mixture of methanol and dimethylacetamide.

Example 2 N- (2-pyridyl) -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

A solution of 3.34 g of N- (2-pyridyl) -4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide in 30 ml of dimethylformamide is treated with 240 mg sodium hydride, and the resulting reaction mixture is stirred at room temperature for 10 minutes. 1.5 g of methyl iodide are added dropwise with stirring and the reaction mixture is slowly heated to 60 ° C, after which the reaction temperature is maintained at 60 ° C for 4 hours. The mixture is cooled to room temperature and diluted with about 40 g of ice and water. The precipitate formed is filtered off and dried. The pure product is obtained by crystallization from a mixture of methanol and dimethylacetamide.

Example 3

The procedure of Example 2 is repeated but the sodium hydride is replaced by the bases listed in the following table, the dimethylformamide with the following solvents, the methylating agent with methyl iodide, and the following reaction temperatures are used instead of 30 ° C:. Base__Solvent__Temperature ° C Methylating agent_ KH (CH3) 2NCHO 40 (CH30) 2SO2

LiH (CH3) 2SO 10 CH-jBr

RfcH (CH3) 2SO 25 CH3SO3CH3

NaOC2H5 C2H5OH 60 CH3I

CaH2 ^ 7cH3) 2N_73PO 80 P "CH3C6H4SO3CH3

MgH Z1CH3) 2N_73PO 100 p-CH3C6H4SO3CH3

BaH2 ^ 7CH3) 2N_73PO35 CH2N2

KOH C2H50H-H2O 25 CH3I

Ca (OH) 2 (CH3) 2NCHO 35 CH3I

LiOH C 2 H 50 H-H 2 O 35 (CH 3 O) 2 SO 2 A. N- (2-pyridyl) -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide a suspension in a 1 liter round-bottomed flask equipped with an extractor (containing 100 g of molecular sieve) containing 7.1 g of 4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid methyl ester and 2.9 g of 2-aminopyridine in 522 ml of m xylene, heated to reflux. After heating for 17 hours, the condenser is removed and 250 ml of solvent are evaporated off under normal pressure. The reaction solution is cooled to 23 ° C within one hour, and the precipitate formed is filtered off and dried to give 3.4 g of product, m.p. 193-200 ° C. Recrystallization from tetrahydrofuran-water gives 2.4 g of pure product, m.p. 199-201 ° C.

B. N- (2-pyridyl) -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

Claims (2)

7,63231 A solution of 41 mg of methyl iodide, 79 mg of N- (2-pyridyl) -4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide and 12 mg of sodium hydroxide 2 , In 4 ml of acetone and 2.2 ml of water, is stirred at room temperature for 6 hours. An additional 5 drops of methyl iodide are added and the solution is stirred overnight at 28-30 ° C. To the reaction mixture is added 5 ml of water, the solids are filtered and dried to give 20 mg of product, m.p. 190-197 ° C. This compound is identical to N- (2-pyridyl) -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide prepared in U.S. Patent 3,591,584. A process for the preparation of N- (2-pyridyl) -2-methyl-4-hydroxy-1,2-benzothiazine-3-carboxamide-1,1-dioxide, O 2 '3 and its alkali metal and alkaline earth metal salts , characterized in that the alkali metal or alkaline earth metal salt of the compound of formula II is reacted with at least one mole of methylating agent in an inert solvent and at 0-100 ° C, and the resulting compound is prepared, if necessary, into a pharmaceutically acceptable solvent. salt. Process according to Claim 1, characterized in that the inert solvent is ethanol, the alkali metal salt is a sodium salt, the methylating agent is methyl iodide and the reaction temperature is about 25 ° C.